Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study.
Neuropsychobiology
INTRODUCTION:Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. METHODS:Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. RESULTS:LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230-0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. CONCLUSION:This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.
10.1159/000528316
Casual effects of gut microbiota on risk of infections: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:The correlation between gut microbiota and infections has garnered significant attention in previous studies; nevertheless, our understanding of the causal relationships and mechanisms between specific microbial species and infections remains limited. Methods:This study aimed to employ Mendelian randomization (MR) using single-nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) data of European ancestry to explore the genetic-level relationships between distinct types of gut microbiota and susceptibility to infections. Our analysis encompassed three prevalent infections: intestinal infections, pneumonia, and urinary tract infections, while concurrently examining various types of gut microbiota. Results:We identified 18 protective gut microbiotas alongside 13 associated with increased infection risk. Particularly noteworthy are certain microbial communities capable of producing butyrate, such as the and families, which exhibited both favorable and unfavorable effects. Additionally, we observed a few certain communities linked to infection susceptibility, including (OR = 0.13, 95% CI: 0.054-0.33, = 1.24E-05), (OR = 3.25, 95% CI: 2.00-5.27, = 1.87E-06), and (OR = 1.24, 95% CI: 1.09-1.40, = 1.12E-03). Conclusion:This study reveals complex relationships between gut microbiota and various infections. Our findings could potentially offer new avenues for exploring prevention and treatment strategies for infectious diseases.
10.3389/fmicb.2023.1284723
A causal effects of gut microbiota in the development of migraine.
The journal of headache and pain
BACKGROUND:The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear. METHODS:The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS:In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results. CONCLUSION:Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them.
10.1186/s10194-023-01609-x
Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases.
Nature genetics
Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
10.1038/s41588-019-0350-x
Causal effect of gut microbiota on pancreatic cancer: A Mendelian randomization and colocalization study.
Journal of cellular and molecular medicine
The causal relationship between gut microbiota (GM) and pancreatic cancer (PC) remains unclear. This study aimed to investigate the potential genes underlying this mechanism. GM Genome-wide association study (GWAS) summary data were from the MiBioGen consortium. PC GWAS data were from the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalogue. To detect the causal relationship between GM and PC, we implemented three complementary Mendelian randomization (MR) methods: Inverse Variance Weighting (IVW), MR-Egger and Weighted Median, followed by sensitivity analyses. Furthermore, we integrated GM GWAS data with blood cis-expression quantitative trait loci (eQTLs) and blood cis-DNA methylation QTL (mQTLs) using Summary data-based Mendelian Randomization (SMR) methods. This integration aimed to prioritize potential GM-affecting genes through SMR analysis of two molecular traits. PC cis-eQTLs and cis-mQTLs were summarized from The Cancer Genome Atlas (TCGA) data. Through colocalization analysis of GM cis-QTLs and PC cis-QTLs data, we identified common genes that influence both GM and PC. Our study found a causal association between GM and PC, including four protective and five risk-associated GM [Inverse Variance Weighted (IVW), p < 0.05]. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found. The gene SVBP was identified as a GM-affecting gene using SMR analysis of two molecular traits (FDR<0.05, P_HEIDI>0.05). Additionally, two genes, MCM6 and RPS26, were implicated in the interaction between GM and PC based on colocalization analysis (PPH4>0.5). In summary, this study provides evidence for future research aimed at developing suitable therapeutic interventions and disease prevention.
10.1111/jcmm.18255
Causal relationship between gut microbiota and diabetic nephropathy: a two-sample Mendelian randomization study.
Frontiers in immunology
Objective:Emerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM). Methods:We used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results. Results:It was showed that Class [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,FDR=0.0018], Order (OR=1.5651, 95%CI: 1.1810-2.0742, FDR=0.0018) and Family (OR=1.3956, 95%CI:1.0336-1.8844, FDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy. Conclusions:At the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.
10.3389/fimmu.2024.1332757
Causal relationship of gut microbiota and metabolites on cognitive performance: A mendelian randomization analysis.
Neurobiology of disease
Emerging evidence has indicated that the alterations in gut microbiota and metabolites are associated with cognitive performance. However, whether these associations imply a causal relationship remains to be definitively established. Here, we conducted two-sample mendelian randomization (MR) studies to explore the causal effects of gut microbiota and metabolites on cognitive performance, using large-scale genome-wide association studies (GWASs). We identified seven positive causalities between host genetic-driven gut microbiota and cognitive performance, including Class Clostridia (p = 0.0002), Order Clostridiales (p = 8.12E-05), Family Rhodospirillaceae (p = 0.042) and Ruminococcustorquesgroup (p = 0.030), Dialister (p = 0.027), Paraprevotella (p = 0.037) and RuminococcaceaeUCG003 (p = 0.007) at the genus level. Additionally, a total of four higher abundance of gut microbiota traits were identified to be negatively related to cognitive performance, including genus Blautia (p = 0.013), LachnospiraceaeFCS020group (p = 0.035), LachnospiraceaeNK4A136group (p = 0.034) and Roseburia (p = 0.00016). In terms of plasma metabolites, we discovered eight positive and six negative relationships between genetic liability in metabolites and cognitive performance (all p < 0.05). No evidence was detected across a series of sensitivity analyses, including pleiotropy and heterogeneity. Collectively, our MR analyses revealed that gut microbiota and metabolites were causally connected with cognitive performance, which holds significant potential for shedding light on the early detection and diagnosis of cognitive impairment, offering valuable insights into this area of research.
10.1016/j.nbd.2023.106395
Gut microbiota and polycystic ovary syndrome, focus on genetic associations: a bidirectional Mendelian randomization study.
Frontiers in endocrinology
Background:The contribution of gut microbiota to the pathogenesis of polycystic ovary syndrome (PCOS) is controversial. The causal relationship to this question is worth an in-depth comprehensive of known single nucleotide polymorphisms associated with gut microbiota. Methods:We conducted bidirectional Mendelian randomization (MR) utilizing instrumental variables associated with gut microbiota (N = 18,340) from MiBioGen GWAS to assess their impact on PCOS risk in the FinnGen GWAS (27,943 PCOS cases and 162,936 controls). Two-sample MR using inverse variance weighting (IVW) was undertaken, followed by the weighted median, weighted mode, and MR-Egger regression. In a subsample, we replicated our findings using the meta-analysis PCOS consortium (10,074 cases and 103,164 controls) from European ancestry. Results:IVWMR results suggested that six gut microbiota were causally associated with PCOS features. After adjusting BMI, SHBG, fasting insulin, testosterone, and alcohol intake frequency, the effect sizes were significantly reduced. Reverse MR analysis revealed that the effects of PCOS features on 13 gut microbiota no longer remained significant after sensitivity analysis and Bonferroni corrections. MR replication analysis was consistent and the results suggest that gut microbiota was likely not an independent cause of PCOS. Conclusion:Our findings did not support the causal relationships between the gut microbiota and PCOS features at the genetic level. More comprehensive genome-wide association studies of the gut microbiota and PCOS are warranted to confirm their genetic relationship. Declaration:This study contains 3533 words, 0 tables, and six figures in the text as well as night supplementary files and 0 supplementary figures in the Supplementary material.
10.3389/fendo.2024.1275419
Causal relationship between gut microbiota and kidney diseases: a two-sample Mendelian randomization study.
Frontiers in immunology
Background:The interplay between gut microbiome genera and inflammatory kidney-related diseases, such as nephrotic syndrome, glomerulonephritis, tubulo-interstitial nephritis, and chronic kidney disease, has been observed. However, the causal relationships between specific bacterial genera and these renal diseases have not been fully elucidated. Objective:To investigate the potential causal links between different genera of the gut microbiome and the susceptibility to various renal conditions utilizing two-sample Mendelian randomization (MR) analyses. Materials and methods:Genome-wide association study (GWAS) summary statistics of gut microbiota and inflammatory kidney-related diseases were obtained from published GWASs. Two-sample MR analyses were conducted using methods including inverse-variance weighted (IVW), MR Egger, and others to identify potential causal links between gut microbial genera and renal conditions. Sensitivity analyses, including Cochran's Q test and the MR-PRESSO global test, were performed to validate the robustness of the results and detect horizontal pleiotropy. In addition, a reverse MR analysis was conducted to assess reverse causation possibilities. Results:By synthesizing insights from both primary and sensitivity analyses, this study unveiled critical associations of 12 bacterial genera with nephrotic syndrome, 7 bacterial genera with membranous nephropathy, 3 bacterial genera with glomerulonephritis, 4 bacterial genera with acute tubulo-interstitial nephritis, 6 bacterial genera with chronic tubulo-interstitial nephritis, and 7 bacterial genera with chronic kidney disease. Various genera were pinpointed as having either positive or negative causal relationships with these renal conditions, as evidenced by specific ranges of IVW-OR values (all P< 0.05). The congruence of the sensitivity analyses bolstered the primary findings, displaying no marked heterogeneity or horizontal pleiotropy. Notably, the reverse MR analysis with nephritis as the exposure did not reveal any causal relationships, thereby strengthening the resilience and validity of the primary associations. Conclusion:This study explored the causal associations between several gut microbial genera and the risk of several inflammatory kidney-related diseases, uncovering several associations between specific gut microbial genera and nephrotic syndrome, membranous nephropathy, glomerulonephritis, tubulo-interstitial nephritis, and chronic kidney disease. These findings enhance our understanding of the complex interplay between the gut microbiome and kidney diseases, and they will be beneficial for early diagnosis and subsequent treatment.
10.3389/fimmu.2023.1277554
Identification of host gene-microbiome associations in colorectal cancer patients using mendelian randomization.
Journal of translational medicine
BACKGROUND:There are many studies indicating that alterations in the abundance of certain gut microbiota are associated with colorectal cancer (CRC). However, a causal relationship has not been identified due to confounding factors such as lifestyle, environmental, and possible reverse causal associations between the two. Furthermore, certain host gene mutations can also contribute to the development of CRC. However, the association between genes and gut microbes in patients with CRC has not been extensively studied. METHODS:We conducted a two-sample Mendelian randomization (MR) study to reveal the causal relationship between gut microbiota and CRC. We obtained SNPs associated with gut microbiome abundance as instrumental variables (IVs) from a large-scale, multi-ethnic GWAS study, and extracted CRC-related datasets from an East Asian Population genetic consortia GWAS (AGWAS) study and FinnGen consortium, respectively. We analyzed a total of 166 bacterial features at four taxonomic levels, including order, family, genus, and species. The inverse-variance-weighted (IVW), weighted median, MR-Egger, and simple median methods were applied to the MR analysis, and the robustness of the results were tested using a series of sensitivity analyses. We extracted IVs of gut microbiota with direct causal association with CRC for SNP annotation to identify the genes in which these genetic variants were located to reveal the possible host gene-microbiome associations in CRC patients. RESULTS:The findings from our MR analysis based on CRC-associated GWAS datasets from AGWAS revealed causal relationships between 6 bacterial taxa and CRC at a locus-wide significance level (P < 1 × 10). The IVW method found that family Porphyromonadaceae, genera Anaerotruncus, Intestinibacter, Slackia, and Ruminococcaceae UCG004, and species Eubacterium coprostanoligenes group were positively associated with CRC risk, which was generally consistent with the results of other complementary analyses. The results of a meta-analysis of the MR estimates from the AGWAS and the FinnGen datasets showed that family Porphyromonadaceae and genera Slackia, Anaerotruncus, and Intestinibacter replicated the same causal association. Sensitivity analysis of all causal associations did not indicate significant heterogeneity, horizontal pleiotropy, or reverse causal associations. We annotated the SNPs at a locus-wide significance level of the above intestinal flora and identified 24 host genes that may be related to pathogenic intestinal microflora in CRC patients. CONCLUSION:This study supported the causal relationship of gut microbiota on CRC and revealed a possible correlation between genes and pathogenic microbiota in CRC. These findings suggested that the study of the gut microbiome and its further multi-omics analysis was important for the prevention and treatment of CRC.
10.1186/s12967-023-04335-9
Causal relationship between gut microbiota and tuberculosis: a bidirectional two-sample Mendelian randomization analysis.
Respiratory research
BACKGROUND:Growing evidence from observational studies and clinical trials suggests that the gut microbiota is associated with tuberculosis (TB). However, it is unclear whether any causal relationship exists between them and whether causality is bidirectional. METHODS:A bidirectional two-sample Mendelian randomization (MR) analysis was performed. The genome-wide association study (GWAS) summary statistics of gut microbiota were obtained from the MiBioGen consortium, while the GWAS summary statistics of TB and its specific phenotypes [respiratory tuberculosis (RTB) and extrapulmonary tuberculosis (EPTB)] were retrieved from the UK Biobank and the FinnGen consortium. And 195 bacterial taxa from phylum to genus were analyzed. Inverse variance weighted (IVW), MR-Egger regression, maximum likelihood (ML), weighted median, and weighted mode methods were applied to the MR analysis. The robustness of causal estimation was tested using the heterogeneity test, horizontal pleiotropy test, and leave-one-out method. RESULTS:In the UK Biobank database, we found that 11 bacterial taxa had potential causal effects on TB. Three bacterial taxa genus.Akkermansia, family.Verrucomicrobiacea, order.Verrucomicrobiales were validated in the FinnGen database. Based on the results in the FinnGen database, the present study found significant differences in the characteristics of gut microbial distribution between RTB and EPTB. Four bacterial taxa genus.LachnospiraceaeUCG010, genus.Parabacteroides, genus.RuminococcaceaeUCG011, and order.Bacillales were common traits in relation to both RTB and TB, among which order.Bacillales showed a protective effect. Additionally, family.Bacteroidacea and genus.Bacteroides were identified as common traits in relation to both EPTB and TB, positively associating with a higher risk of EPTB. In reverse MR analysis, no causal association was identified. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found. CONCLUSION:Our study supports a one-way causal relationship between gut microbiota and TB, with gut microbiota having a causal effect on TB. The identification of characteristic gut microbiota provides scientific insights for the potential application of the gut microbiota as a preventive, diagnostic, and therapeutic tool for TB.
10.1186/s12931-023-02652-7
Association of nicotine dependence and gut microbiota: a bidirectional two-sample Mendelian randomization study.
Frontiers in immunology
Background:Nicotine dependence is a key factor influencing the diversity of gut microbiota, and targeting gut microbiota may become a new approach for the prevention and treatment of nicotine dependence. However, the causal relationship between the two is still unclear. This study aims to investigate the causal relationship between nicotine dependence and gut microbiota. Methods:A two-sample bidirectional Mendelian randomization (MR) study was conducted using the largest existing gut microbiota and nicotine dependence genome-wide association studies (GWAS). Causal relationships between genetically predicted nicotine dependence and gut microbiota abundance were examined using inverse variance weighted, MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO approaches. Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were performed as sensitivity analyses to assess the robustness of the results. Multivariable Mendelian randomization analysis was also conducted to eliminate the interference of smoking-related phenotypes. Reverse Mendelian randomization analysis was then performed to determine the causal relationship between genetically predicted gut microbiota abundance and nicotine dependence. Results:Genetically predicted nicotine dependence had a causal effect on (β: -0.52, 95% CI: -0.934-0.106, P = 0.014). The group (OR: 1.106, 95% CI: 1.004-1.218), (OR: 1.118, 95% CI: 1.001-1.249) and (OR: 1.08, 95% CI: 1.001-1.167) were risk factors for nicotine dependence. (OR: 0.905, 95% CI: 0.837-0.977), (OR: 0.014, 95% CI: 0.819-0.977), (OR: 0.841, 95% CI. 0.731-0.968), (OR: 0.831, 95% CI: 0.735-0.939) and (OR: 0.838, 95% CI: 0.739-0.951) were protective factor for nicotine dependence. The sensitivity analysis showed consistent results. Conclusion:The Mendelian randomization study confirmed the causal link between genetically predicted risk of nicotine dependence and genetically predicted abundance of gut microbiota. Gut microbiota may serve as a biomarker and offer insights for addressing nicotine dependence.
10.3389/fimmu.2023.1244272
Causal relationship between the gut microbiota and insomnia: a two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Changes in the gut microbiota are closely related to insomnia, but the causal relationship between them is not yet clear. Objective:To clarify the relationship between the gut microbiota and insomnia and provide genetic evidence for them, we conducted a two-sample Mendelian randomization study. Methods:We used a Mendelian randomized two-way validation method to discuss the causal relationship. First, we downloaded the data of 462,341 participants relating to insomnia, and the data of 18,340 participants relating to the gut microbiota from a genome-wide association study (GWAS). Then, we used two regression models, inverse-variance weighted (IVW) and MR-Egger regression, to evaluate the relationship between exposure factors and outcomes. Finally, we took a reverse MR analysis to assess the possibility of reverse causality. Results:The combined results show 19 gut microbiotas to have a causal relationship with insomnia (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.01, 1.05; p=0.000 for class. Negativicutes; OR: 1.03; 95% CI: 1.01, 1.05; p=0.000 for order.Selenomonadales; OR: 1.01; 95% CI: 1.00, 1.02; p=0.003 for genus.RikenellaceaeRC9gutgroup). The results were consistent with sensitivity analyses for these bacterial traits. In reverse MR analysis, we found no statistical difference between insomnia and these gut microbiotas. Conclusion:This study can provide a new direction for the causal relationship between the gut microbiota (class.Negativicutes, order.Selenomonadales, genus.Lactococcus) and insomnia and the treatment or prevention strategies of insomnia.
10.3389/fcimb.2024.1279218
Causal relationship between gut microbiota and immune thrombocytopenia: a Mendelian randomization study of two samples.
Frontiers in microbiology
Background:Some observational studies have shown that immune thrombocytopenia (ITP) is highly associated with the alteration-composition of gut microbiota. However, the causality of gut microbiota on ITP has not yet been determined. Methods:Based on accessible summary statistics of the genome-wide union, the latent connection between ITP and gut microbiota was estimated using bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Inverse variance weighted (IVW), weighted median analyses, and MR-Egger regression methods were performed to examine the causal correlation between ITP and the gut microbiota. Several sensitivity analyses verified the MR results. The strength of causal relationships was evaluated using the MR-Steiger test. MVMR analysis was undertaken to test the independent causal effect. MR analyses of reverse direction were made to exclude the potential of reverse correlations. Finally, GO enrichment analyses were carried out to explore the biological functions. Results:After FDR adjustment, two microbial taxa were identified to be causally associated with ITP ( < 0.10), namely ( = 7.31 × 10) and ( = 7.31 × 10). In addition, eight microbial taxa were considered as potentially causal features under the nominal significance ( < 0.05): , , , , , , , and . According to the reverse-direction MR study findings, the gut microbiota was not significantly affected by ITP. There was no discernible horizontal pleiotropy or instrument heterogeneity. Finally, GO enrichment analyses showed how the identified microbial taxa participate in ITP through their underlying biological mechanisms. Conclusion:Several microbial taxa were discovered to be causally linked to ITP in this MR investigation. The findings improve our understanding of the gut microbiome in the risk of ITP.
10.3389/fmicb.2023.1190866
Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study.
BMC pulmonary medicine
BACKGROUND:While several traditional observational studies have suggested associations between gut microbiota and asthma, these studies are limited by factors such as participant selection bias, confounders, and reverse causality. Therefore, the causal relationship between gut microbiota and asthma remains uncertain. METHODS:We performed two-sample bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota and asthma as well as its phenotypes. We also conducted MR analysis to evaluate the causal effect of gut metabolites on asthma. Genetic variants for gut microbiota were obtained from the MiBioGen consortium, GWAS summary statistics for metabolites from the TwinsUK study and KORA study, and GWAS summary statistics for asthma from the FinnGen consortium. The causal associations between gut microbiota, gut metabolites and asthma were examined using inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted model and further validated by MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis. RESULTS:We identified nine gut microbes whose genetically predicted relative abundance causally impacted asthma risk. After FDR correction, significant causal relationships were observed for two of these microbes, namely the class Bacilli (OR = 0.84, 95%CI = 0.76-0.94, p = 1.98 × 10) and the order Lactobacillales (OR = 0.83, 95%CI = 0.74-0.94, p = 1.92 × 10). Additionally, in a reverse MR analysis, we observed a causal effect of genetically predicted asthma risk on the abundance of nine gut microbes, but these associations were no longer significant after FDR correction. No significant causal effect of gut metabolites was found on asthma. CONCLUSIONS:Our study provides insights into the development mechanism of microbiota-mediated asthma, as well as into the prevention and treatment of asthma through targeting specific gut microbiota.
10.1186/s12890-024-02898-x
Genetically Predicted Causal Effects of Gut Microbiota and Gut Metabolites on Digestive Tract Cancer: A Two-Sample Mendelian Randomization Analysis.
World journal of oncology
Background:Evidence from numerous observational studies and clinical trials has linked gut microbiota and metabolites to digestive tract cancer. However, the causal effect between these factors remains uncertain. Methods:Data for this study were obtained from the MiBioGen, TwinsUK Registry, and FinnGen (version R8). Two-sample Mendelian randomization analysis with inverse variance weighting method was primarily used, and the results were validated by heterogeneity analysis, pleiotropy test, and sensitivity analysis. Results:At P < 5 × 10, our analysis identified four gut microbiotas as risk factors for digestive tract cancer and six as risk factors for colorectal cancer. Conversely, one gut microbiota exhibited protection against bile duct cancer, and two showed protective effects against stomach cancer. At P < 1 × 10, our investigation revealed five, six, three, eight, eight, and eight gut microbiotas as risk factors for esophageal, stomach, bile duct, liver, pancreatic, and colorectal cancers, respectively. In contrast, four, two, eight, two, two, and five gut microbiotas exhibited protective effects against these cancers. Additionally, , a metabolite of gut microbiota, displayed a significant protective effect against colorectal cancer. Conclusion:In conclusion, specific gut microbiota and metabolites play roles as risk factors or protective factors for digestive tract cancer, and a causal relationship between them has been established, offering novel insights into gut microbiota-mediated cancer development.
10.14740/wjon1737
Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals.
JAMA psychiatry
Importance:Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression. Objective:To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD. Design, Setting and Participants:This cohort study used data from participants in the UK Biobank cohort (n = 500 000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD = 59 851; control individuals = 113 154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n = 118 000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021. Main Outcomes and Measures:Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform. Results:The study included 6811 individuals with lifetime MDD compared with 51 446 control individuals and 4370 individuals with recurrent MDD compared with 62 508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (β [SE], -0.07 [0.02]; FDR = 4 × 10-04) and pyruvate was significantly increased (β [SE], 0.04 [0.02]; FDR = 0.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not. Conclusions and Relevance:The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.
10.1001/jamapsychiatry.2023.0685
Genetically predicted the causal relationship between gut microbiota and infertility: bidirectional Mendelian randomization analysis in the framework of predictive, preventive, and personalized medicine.
The EPMA journal
Objective:Several studies have reported the association between gut microbiota and infertility; however, the causal association between them remains unclear. This study aimed to explore the causal relationship between gut microbiota and infertility and evaluate how specific gut microbiota can support early monitoring and prevention of infertility in the context of predictive, preventive, and personalized medicine (PPPM/3PM). Methods:The gut microbiota GWAS data included 18,340 individuals. Female infertility (6481 cases and 68,969 controls) and male infertility data (680 cases and 72,799 controls) were obtained from the FinnGen consortium. The inverse variance weighting (IVW), MR-Egger, weighted median (WM), Cochran Q tests, MR-PRESSO, and leave-one-out were used as a supplement to Mendelian randomization (MR) results and sensitivity analysis. Results:The results of MR analysis indicated a significant causal association between Eubacterium oxidoreducens (OR = 2.048, = 0.008), Lactococcus (OR = 1.445, = 0.042), Eubacterium ventriosum (OR = 0.436, = 0.018), Eubacterium rectale (OR = 0.306, = 0.002), and Ruminococcaceae NK4A214 (OR = 0.537, = 0.045) and male infertility. Genetically predicted Eubacterium ventriosum (OR = 0.809, = 0.018), Holdemania (OR = 0.836, = 0.037), Lactococcus (OR = 0.867, = 0.020), Ruminococcaceae NK4A214 (OR = 0.830, < 0.050), Ruminococcus torques (OR = 0.739, = 0.022), and Faecalibacterium (OR = 1.311, = 0.007) were associated with female infertility. Sensitivity analysis did not detect heterogeneity and pleiotropy ( > 0.05). Conclusions:Our results provided evidence for the causal relationship between some gut microbiota and male and female infertility. These findings might be valuable in providing personalized treatment options for preventing infertility and improving reproductive function by monitoring and regulating the gut microbiota of infertility patients in the context of PPPM. Moreover, detecting the abundance of microbiota in feces can support preventive and personalized strategies, which may benefit more infertility patients. Supplementary Information:The online version contains supplementary material available at 10.1007/s13167-023-00332-6.
10.1007/s13167-023-00332-6
Causal associations between gut microbiota and regional cortical structure: a Mendelian randomization study.
Frontiers in neuroscience
Introduction:Observational studies have reported associations between gut microbiota composition and central nervous system diseases. However, the potential causal relationships and underlying mechanisms remain unclear. Here, we applied Mendelian randomization (MR) to investigate the causal effects of gut microbiota on cortical surface area (SA) and thickness (TH) in the brain. Methods:We used genome-wide association study summary statistics of gut microbiota abundance in 18,340 individuals from the MiBioGen Consortium to identify genetic instruments for 196 gut microbial taxa. We then analyzed data from 56,761 individuals from the ENIGMA Consortium to examine associations of genetically predicted gut microbiota with alterations in cortical SA and TH globally and across 34 functional brain regions. Inverse-variance weighted analysis was used as the primary MR method, with MR Egger regression, MR-PRESSO, Cochran's test, and leave-one-out analysis to assess heterogeneity and pleiotropy. Results:At the functional region level, genetically predicted higher abundance of class Mollicutes was associated with greater SA of the medial orbitofrontal cortex ( = 8.39 mm, 95% CI: 3.08-13.70 mm, = 0.002), as was higher abundance of phylum Tenericutes ( = 8.39 mm, 95% CI: 3.08-13.70 mm, = 0.002). Additionally, higher abundance of phylum Tenericutes was associated with greater SA of the lateral orbitofrontal cortex ( = 10.51 mm, 95% CI: 3.24-17.79 mm, = 0.0046). No evidence of heterogeneity or pleiotropy was detected. Conclusion:Specific gut microbiota may causally influence cortical structure in brain regions involved in neuropsychiatric disorders. The findings provide evidence for a gut-brain axis influencing cortical development, particularly in the orbitofrontal cortex during adolescence.
10.3389/fnins.2023.1296145
Convergent application of traditional Chinese medicine and gut microbiota in ameliorate of cirrhosis: a data mining and Mendelian randomization study.
Frontiers in cellular and infection microbiology
Objective:Traditional Chinese medicine (TCM) has been used for the treatment of chronic liver diseases for a long time, with proven safety and efficacy in clinical settings. Previous studies suggest that the therapeutic mechanism of TCM for hepatitis B cirrhosis may involve the gut microbiota. Nevertheless, the causal relationship between the gut microbiota, which is closely linked to TCM, and cirrhosis remains unknown. This study aims to utilize two-sample Mendelian randomization (MR) to investigate the potential causal relationship between gut microbes and cirrhosis, as well as to elucidate the synergistic mechanisms between botanical drugs and microbiota in treating cirrhosis. Methods:Eight databases were systematically searched through May 2022 to identify clinical studies on TCM for hepatitis B cirrhosis. We analyzed the frequency, properties, flavors, and meridians of Chinese medicinals based on TCM theories and utilized the Apriori algorithm to identify the core botanical drugs for cirrhosis treatment. Cross-database comparison elucidated gut microbes sharing therapeutic targets with these core botanical drugs. MR analysis assessed consistency between gut microbiota causally implicated in cirrhosis and microbiota sharing therapeutic targets with key botanicals. Results:Our findings revealed differences between the Chinese medicinals used for compensated and decompensated cirrhosis, with distinct frequency, dosage, properties, flavors, and meridian based on TCM theory. were the main botanicals. Botanical drugs and gut microbiota target MAPK1, VEGFA, STAT3, AKT1, RELA, JUN, and ESR1 in the treatment of hepatitis B cirrhosis, and their combined use has shown promise for cirrhosis treatment. MR analysis demonstrated a positive correlation between increased ClostridialesvadinBB60 and Ruminococcustorques abundance and heightened cirrhosis risk. In contrast, Eubacteriumruminantium, Lachnospiraceae, Eubacteriumnodatum, RuminococcaceaeNK4A214, Veillonella, and RuminococcaceaeUCG002 associated with reduced cirrhosis risk. Notably, Lachnospiraceae shares key therapeutic targets with core botanicals, which can treat cirrhosis at a causal level. Conclusion:We identified 6 core botanical drugs for managing compensated and decompensated hepatitis B cirrhosis, despite slight prescription differences. The core botanical drugs affected cirrhosis through multiple targets and pathways. The shared biological effects between botanicals and protective gut microbiota offer a potential explanation for the therapeutic benefits of these key herbal components in treating cirrhosis. Elucidating these mechanisms provides crucial insights to inform new drug development and optimize clinical therapy for hepatitis B cirrhosis.
10.3389/fcimb.2023.1273031
Association of the gut microbiota with coronary artery disease and myocardial infarction: A Mendelian randomization study.
Frontiers in genetics
Previous studies have indicated that the gut microbiota (GM) is associated with coronary artery disease (CAD), but the causality of these associations remains unestablished due to confounding factors and reverse causality. We conducted Mendelian randomization study (MR) to determine the causal effect of the specific bacterial taxa on CAD/myocardial infarction (MI) and identify the mediating factors involved. Two-sample MR, multivariable MR (MVMR) and mediation analysis were performed. Inverse-variance weighting (IVW) was the main method used to analyze causality, and sensitivity analysis was used to verify the reliability of the study. Causal estimates from CARDIoGRAMplusC4D and FinnGen databases were combined using the meta-analysis method, and repeated validation was conducted based on the UK Biobank (UKB) database. Confounders that may affect the causal estimates were corrected by MVMP and the potential mediation effects were investigated by using mediation analysis. The study suggested that increased abundance of the RuminococcusUCG010 genus leads to a lower risk of CAD (OR, 0.88; 95% CI, 0.78, 1.00; = 2.88 × 10) and MI (OR, 0.88; 95% CI, 0.79, 0.97; = 1.08 × 10), with consistent results in both meta-analysis (CAD: OR, 0.86; 95% CI, 0.78, 0.96; = 4.71 × 10; MI: OR, 0.82; 95% CI, 0.73, 0.92; = 8.25 × 10) and repeated analysis of the UKB dataset (CAD: OR, 0.99; 95% CI, 0.99, 1.00, = 2.53 × 10; MI: OR, 0.99; 95% CI, 0.99, 1.00, = 1.85 × 10-11). Based on multiple databases, T2DM was proved as a mediating factor in the causal effect of RuminococcusUCG010 and CAD/MI, with an average mediation effect proportion of 20% on CAD and 17% on MI, respectively. This MR study provided suggestive genetic evidence that the higher the RuminococcusUCG010 abundance is, the lower the risk of CAD and MI, with T2DM playing a mediating effect. This genus may become a novel target in strategies for treating and preventing CAD and MI.
10.3389/fgene.2023.1158293
Role of gut microbiota and inflammatory factors in acute respiratory distress syndrome: a Mendelian randomization analysis.
Frontiers in microbiology
Background:Acute respiratory distress syndrome (ARDS) is a serious lung ailment marked by significant inflammation and damage in the alveoli and capillaries of the lungs. Recent research suggests a strong correlation between the onset and advancement of ARDS and an imbalance in the gut microbiota (GM). Methods:In this investigation, Mendelian randomization (MR) analysis was utilized, drawing on data from publicly accessible genome-wide association studies. The primary focus was on examining the interplay between GM, inflammatory factors (IFs) and ARDS. Instrumental variables were established through genetic modifications of GM and IFs. Various statistical analysis methods including the inverse-variance weighted model, MR-Egger method and Wald ratio test were applied for comprehensive data analysis. Results:Eight bacterial taxa within the GM demonstrated a potential causal link with development of ARDS. Notably, the phylum Actinobacteria and the genus exhibited a negative association with the risk of ARDS. However, (id. 2,148), (id. 2,256), UCG014 (id. 11,371), group (id. 11,340), (id. 2,149) and (id. 2,147) demonstrated a positive association with ARDS risk. Additionally, the study identified a potential causal relationship between the inflammatory factors interleukin-16 and C-C motif chemokine 3 with the occurrence of ARDS. Conclusion:This study strongly suggests that the interaction between gut microbiota (GM) and inflammatory factors (IFs) significantly contributes to the pathogenesis of acute respiratory distress syndrome (ARDS). This underscores their crucial involvement in both the initiation and advancement of this severe lung disorder.
10.3389/fmicb.2023.1294692
A Two-Sample Mendelian Randomization Analysis Investigates Associations Between Gut Microbiota and Celiac Disease.
García-Santisteban Iraia,Cilleros-Portet Ariadna,Moyua-Ormazabal Elisabet,Kurilshikov Alexander,Zhernakova Alexandra,Garcia-Etxebarria Koldo,Fernandez-Jimenez Nora,Bilbao Jose Ramon
Nutrients
Celiac disease (CeD) is a complex immune-mediated inflammatory condition triggered by the ingestion of gluten in genetically predisposed individuals. Literature suggests that alterations in gut microbiota composition and function precede the onset of CeD. Considering that microbiota is partly determined by host genetics, we speculated that the genetic makeup of CeD patients could elicit disease development through alterations in the intestinal microbiota. To evaluate potential causal relationships between gut microbiota and CeD, we performed a two-sample Mendelian randomization analysis (2SMR). Exposure data were obtained from the raw results of a previous genome-wide association study (GWAS) of gut microbiota and outcome data from summary statistics of CeD GWAS and Immunochip studies. We identified a number of putative associations between gut microbiota single nucleotide polymorphisms (SNPs) associated with CeD. Regarding bacterial composition, most of the associated SNPs were related to Firmicutes phylum, whose relative abundance has been previously reported to be altered in CeD patients. In terms of functional units, we linked a number of SNPs to several bacterial metabolic pathways that seemed to be related to CeD. Overall, this study represented the first 2SMR approach to elucidate the relationship between microbiome and CeD.
10.3390/nu12051420
The causal role of gut microbiota in susceptibility and severity of COVID-19: A bidirectional Mendelian randomization study.
Journal of medical virology
Growing evidence has shown that altered gut microbiota is associated with the pathogenesis of COVID-19, but their causal effects are still unclear. We conducted a bidirectional Mendelian randomization (MR) study to assess the causal effects of gut microbiota on COVID-19 susceptibility or severity, and vice versa. The microbiome genome-wide association studies (GWAS) data of 18 340 individuals and GWAS statistics from the COVID-19 host genetics initiative (38 984 European patients and 1 644 784 controls) were used as exposure and outcomes. The inverse variance weighted (IVW) was used as the primary MR analysis. Sensitivity analyses were performed to validate the robustness, pleiotropy, and heterogeneity of results. In the forward MR, we identified several microbial genera with causal effects on COVID-19 susceptibility (p < 0.05 and FDR < 0.1): Alloprevotella (odds ratio [OR]: 1.088, 95% confidence interval [CI]: 1.021-1.160), Coprococcus (OR: 1.159, 95% CI: 1.030-1.304), Parasutterella (OR: 0.902, 95% CI: 0.836-0.973), and Ruminococcaceae UCG014 (OR: 0.878, 95% CI: 0.777-0.992). The Reverse MR identified that exposure to COVID-19 had causal effects on the depletion of the families Lactobacillaceae (Beta [SE]: -0.220 [0.101]) and Lachnospiraceae (-0.129 [0.062]), the genera Flavonifractor (-0.180 [0.081]) and Lachnoclostridium [-0.181 [0.063]). Our findings supported the causal effect of gut microbiota on the pathogenesis of COVID-19, and infection of COVID-19 might further causally induce gut microbiota dysbiosis.
10.1002/jmv.28880
Circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis: a two-step bidirectional Mendelian randomization study.
Frontiers in nutrition
Background:The relationship between gut microbiota and the occurrence of cholecystitis remains unclear. Existing research lacks a clear understanding of how circulating vitamin levels modulate this relationship. Therefore, our study aims to investigate whether circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis using a two-step bidirectional Mendelian randomization approach. Methods:In this study, we initially employed Linkage Disequilibrium Score Regression (LDSC) analysis to assess the genetic correlation of five circulating vitamin level genome-wide association study (GWAS) summary datasets, thereby avoiding potential sample overlap. Subsequently, we conducted a two-step analysis to investigate the causal effects between gut microbiota and cholecystitis. In the second step, we explored the causal relationship between circulating vitamin levels and cholecystitis and identified the mediating role of vitamin D. The primary method used for causal analysis was the inverse variance-weighted approach. We performed additional sensitivity analyses to ensure result robustness, including the cML-MA method and reverse Mendelian randomization (MR) analysis. Results:An increment of one standard deviation in was associated with a 25% increased risk of cholecystitis (OR = 1.25, 95%CI = 1.01-1.54, = 0.04), along with a 3% decrease in 25-hydroxyvitamin D levels (OR = 0.97, 95%CI = 0.944-0.998, = 0.04). However, following the rigorous Bonferroni correction, every one standard deviation decrease in circulating vitamin D levels was associated with a 33% increased risk of cholecystitis (OR = 0.67, 95%CI = 0.49-0.90, = 0.008, P = 0.04). Thus, the potential link between gut microbiota and cholecystitis risk might be mediated by circulating vitamin D levels (proportion mediated = 5.5%). Sensitivity analyses provided no evidence of pleiotropy. Conclusion:Our study results suggest that an elevated abundance of specific gut microbiota is associated with an increased susceptibility to cholecystitis, with the causal relationship being mediated by circulating vitamin D levels. Further large-scale randomized controlled trials are necessary to validate the causal effects of gut microbiota on cholecystitis risk. This study provides novel insights into cholecystitis prevention through the regulation of gut microbiota.
10.3389/fnut.2023.1268893
Causal link between gut microbiota and four types of pancreatitis: a genetic association and bidirectional Mendelian randomization study.
Frontiers in microbiology
Background:A number of recent observational studies have indicated a correlation between the constitution of gut microbiota and the incidence of pancreatitis. Notwithstanding, observational studies are unreliable for inferring causality because of their susceptibility to confounding, bias, and reverse causality, the causal relationship between specific gut microbiota and pancreatitis is still unclear. Therefore, our study aimed to investigate the causal relationship between gut microbiota and four types of pancreatitis. Methods:An investigative undertaking encompassing a genome-wide association study (GWAS) comprising 18,340 participants was undertaken with the aim of discerning genetic instrumental variables that exhibit associations with gut microbiota, The aggregated statistical data pertaining to acute pancreatitis (AP), alcohol-induced AP (AAP), chronic pancreatitis (CP), and alcohol-induced CP (ACP) were acquired from the FinnGen Consortium. The two-sample bidirectional Mendelian randomization (MR) approach was utilized. Utilizing the Inverse-Variance Weighted (IVW) technique as the cornerstone of our primary analysis. The Bonferroni analysis was used to correct for multiple testing, In addition, a number of sensitivity analysis methodologies, comprising the MR-Egger intercept test, the Cochran's Q test, MR polymorphism residual and outlier (MR-PRESSO) test, and the leave-one-out test, were performed to evaluate the robustness of our findings. Results:A total of 28 intestinal microflora were ascertained to exhibit significant associations with diverse outcomes of pancreatitis. Among them, (OR = 1.801, 95% CI: 1.288-2.519, = 0.008) has a strong causality with ACP after the Bonferroni-corrected test, in order to assess potential reverse causation effects, we used four types of pancreatitis as the exposure variable and scrutinized its impact on gut microbiota as the outcome variable, this analysis revealed associations between pancreatitis and 30 distinct types of gut microflora. The implementation of Cochran's Q test revealed a lack of substantial heterogeneity among the various single nucleotide polymorphisms (SNP). Conclusion:Our first systematic Mendelian randomization analysis provides evidence that multiple gut microbiota taxa may be causally associated with four types of pancreatitis disease. This discovery may contribute significant biomarkers conducive to the preliminary, non-invasive identification of Pancreatitis. Additionally, it could present viable targets for potential therapeutic interventions in the disease's treatment.
10.3389/fmicb.2023.1290202
Causal relationship between kidney stones and gut microbiota contributes to the gut-kidney axis: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Gut microbiota, particularly , has been previously reported to be associated with kidney stones. However, the conflicting results from both observational and intervention studies have created substantial uncertainty regarding the contribution of to the formation of kidney stone. Methods:We employed a two-sample MR analysis to investigate the causal relationship between gut microbiota and kidney stones using GWASs summary statistics obtained from the MiBioGen and FinnGen consortia. Moreover, we conducted a reserve MR analysis to assess the direction of the causal associations between gut microbiota and kidney stones. The inverse variance weighted (IVW) approach represents the primary method of Mendelian Randomization (MR) analysis. Results:Our analyses do not yield supportive evidence for a causal link between the genus r (OR = 0.99, 95% CI: 0.90-1.09, = 0.811) and the formation of kidney stones. The order (OR = 0.79, 95% CI: 0.65-0.96, = 0.020), family (OR = 0.79, 95% CI: 0.65-0.96, = 0.019), family (OR = 0.80, 95% CI: 0.67-0.96, = 0.015), genus (OR = 0.81, 95% CI: 0.67-0.98, = 0.030) and genus (OR = 0.86, 95% CI: 0.74-0.99, = 0.040) had protective effects on kidney stones, and the genus (OR = 1.16, 95% CI: 1.01-1.33, = 0.032), genus (OR = 1.38, 95% CI: 1.04-1.84, = 0.028), genus (OR = 1.27, 95% CI: 1.06-1.52, = 0.009) were risk factors for kidney stones. Differential abundance analysis provide no evidence of a association between and kidney stones, and showed genus Subdoligranulum were risk factors for kidney stones. Reverse MR analysis did not indicate any causal association of kidney stones on gut microbiota. No considerable heterogeneity of instrumental variables or horizontal pleiotropy was observed. Conclusion:Our two-sample MR study did not find any causal relationship between genus and kidney stones. The association between gut microbiota and kidney stones does not solely depend on the presence of genus /. A more integrated approach using multiple omics platforms is needed to better understand the pathogenesis of kidney stones in the context of complex gene-environment interactions over time.
10.3389/fmicb.2023.1204311
Dissecting the association between gut microbiota and liver cancer in European and East Asian populations using Mendelian randomization analysis.
Frontiers in microbiology
Background:Ample evidence suggests an important role of the gut microbiome in liver cancer, but the causal relationship between gut microbiome and liver cancer is unclear. This study employed Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiome and liver cancer in European and East Asian populations. Methods:We sourced genetic variants linked to gut microbiota from the MiBioGen consortium meta-analysis, and procured liver cancer genome-wide association study (GWAS) summary data from the FinnGen consortium and Biobank Japan. We employed the inverse variance weighted method for primary statistical analysis, fortified by several sensitivity analyses such as MR-PRESSO, MR-Egger regression, weighted median, weighted mode, and maximum likelihood methods for rigorous results. We also evaluated heterogeneity and horizontal pleiotropy. Results:The study examined an extensive set of gut microbiota, including 131 genera, 35 families, 20 orders, 16 classes, and 9 phyla. In Europeans, ten gut microbiota types displayed a suggestive association with liver cancer ( < 0.05). Notably, and exhibited a statistically significant positive association with liver cancer risk, with odds ratios (OR) of 2.59 (95% CI 1.36-4.95) and 2.03 (95% CI 1.21-3.40), respectively, after adjusting for multiple testing. In East Asians, while six microbial types demonstrated suggestive associations with liver cancer, only displayed a statistically significant positive association (OR = 1.56, 95% CI 1.11-2.19) with an FDR < 0.05. Sensitivity analyses reinforced these findings despite variations in -values. Conclusion:This study provides evidence for a causal relationship between specific gut microbiota and liver cancer, enhancing the understanding of the role of the gut microbiome in liver cancer and may offer new avenues for preventive and therapeutic strategies.
10.3389/fmicb.2023.1255650
Two-sample Mendelian randomization to study the causal association between gut microbiota and atherosclerosis.
Frontiers in immunology
Background:According to some recent observational studies, the gut microbiota influences atherosclerosis via the gut microbiota-artery axis. However, the causal role of the gut microbiota in atherosclerosis remains unclear. Therefore, we used a Mendelian randomization (MR) strategy to try to dissect this causative link. Methods:The biggest known genome-wide association study (GWAS) (n = 13,266) from the MiBioGen collaboration was used to provide summary data on the gut microbiota for a two-sample MR research. Data on atherosclerosis were obtained from publicly available GWAS data from the FinnGen consortium, including cerebral atherosclerosis (104 cases and 218,688 controls), coronary atherosclerosis (23,363 cases and 187,840 controls), and peripheral atherosclerosis (6631 cases and 162,201 controls). The causal link between gut microbiota and atherosclerosis was investigated using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode approaches, among which inverse variance weighting was the main research method. Cochran's Q statistic was used to quantify the heterogeneity of instrumental variables (IVs), and the MR Egger intercept test was used to assess the pleiotropy of IVs. Results:Inverse-variance-weighted (IVW) estimation showed that had a protective influence on cerebral atherosclerosis (OR = 0.10, 95% CI: 0.01-0.67, = 0.018), while (OR = 5.39, 95% CI: 1.50-19.37, = 0.010), (OR = 6.87, 95% CI: 1.60-29.49, = 0.010), (OR = 2.88, 95% CI: 1.18-7.05, = 0.021), and (OR = 5.26, 95% CI: 1.28-21.61, = 0.021) had pathogenic effects on cerebral atherosclerosis. For (OR = 0.87, 95% CI: 0.76-0.99, = 0.039), the (OR = 0.89, 95% CI: 0.80-1.00, = 0.048), the (OR = 0.80, 95% CI: 0.69-0.94, = 0.006), and the (OR = 0.87, 95% CI: 0.77-0.98, = 0.023) were protective against coronary atherosclerosis. However, the (OR = 1.12, 95% CI: 1.00-1.24, = 0.049) had a pathogenic effect on coronary atherosclerosis. Finally, (OR = 0.83, 95% CI: 0.69-0.99, = 0.036), (OR = 0.76, 95% CI: 0.61-0.94, = 0.013), (OR = 0.76, 95% CI: 0.60-0.96, = 0.022), and (OR = 0.65, 95% CI: 0.46-0.92, = 0.013), these four microbiota have a protective effect on peripheral atherosclerosis. However, for the (OR = 1.25, 95% CI: 1.01-1.56, = 0.040) and the (OR = 1.22, 95% CI: 1.04-1.42, = 0.016), there is a pathogenic role for peripheral atherosclerosis. No heterogeneity was found for instrumental variables, and no considerable horizontal pleiotropy was observed. Conclusion:We discovered that the presence of probiotics and pathogens in the host is causally associated with atherosclerosis, and atherosclerosis at different sites is causally linked to specific gut microbiota. The specific gut microbiota associated with atherosclerosis identified by Mendelian randomization studies provides precise clinical targets for the treatment of atherosclerosis. In the future, we can further examine the gut microbiota's therapeutic potential for atherosclerosis if we have a better grasp of the causal relationship between it and atherosclerosis.
10.3389/fimmu.2023.1282072
Dissecting the Association between Gut Microbiota and Brain Structure Change Rate: A Two-Sample Bidirectional Mendelian Randomization Study.
Nutrients
The connection between the gut microbiota and brain structure changes is still unclear. We conducted a Mendelian randomization (MR) study to examine the bidirectional causality between the gut microbiota (211 taxa, including 131 genera, 35 families, 20 orders, 16 classes and 9 phyla; N = 18,340 individuals) and age-independent/dependent longitudinal changes in brain structure across the lifespan (N = 15,640 individuals aged 4~99 years). We identified causal associations between the gut microbiota and age-independent/dependent longitudinal changes in brain structure, such as family with age-independent longitudinal changes of cortical gray matter (GM) volume and genus with age-independent average cortical thickness and cortical GM volume. Taking age-independent longitudinal changes in brain structure across the lifespan as exposures, there were causal relationships between the surface area and genus . Our findings may serve as fundamentals for further research on the genetic mechanisms and biological treatment of complex traits and diseases associated with the gut microbiota and the brain structure change rate.
10.3390/nu15194227
Unraveling the connection between gut microbiota and Alzheimer's disease: a two-sample Mendelian randomization analysis.
Frontiers in aging neuroscience
Purpose:Studies have shown a close relationship between gut microbiota (GM) and Alzheimer's disease (AD). However, the causal relationship between them remains unclear. Methods:We conducted a genome-wide association study (GWAS) using publicly available summary statistics data for GM and AD. We extracted independent genetic loci significantly associated with GM relative abundances as instrumental variables based on predefined thresholds ( < 1*e-5). The inverse variance-weighted (IVW) method was primarily used for causal relationship assessment. Additional analyses, including MR-Egger, weighted median, simple mode, and weighted mode, were performed as supplementary analyses. Results:IVW analysis revealed significant correlations between certain microbial taxa and the risk of AD. Higher abundances of at the class level, phylum. , class. , order. , genus. , and genus. UCG004 ( < 0.048) was found to be positively associated with an elevated risk of AD. However, within the genus-level taxa, ( = 0.030) demonstrated a protective effect on lowering the risk of AD. In addition, to ensure the robustness of the findings, we employed Cochrane's test and leave-one-out analysis for quality assessment, while the stability and reliability of the results were validated through MR-Egger intercept test, MR-PRESSO global test, and sensitivity analysis. Conclusion:This study provided a comprehensive analysis of the causal relationship between 211 GM taxa and AD. It discerned distinct GM taxa linked to the susceptibility of AD, thereby providing novel perspectives on the genetic mechanisms governing AD via the GM. Additionally, these discoveries held promise as valuable biomarkers, enabling the identification of potential therapeutic targets and guiding forthcoming AD investigations.
10.3389/fnagi.2023.1273104
The Causal Relationship between the Morning Chronotype and the Gut Microbiota: A Bidirectional Two-Sample Mendelian Randomization Study.
Nutrients
BACKGROUND:Numerous observational studies have documented an association between the circadian rhythm and the composition of the gut microbiota. However, the bidirectional causal effect of the morning chronotype on the gut microbiota is unknown. METHODS:A two-sample Mendelian randomization study was performed, using the summary statistics of the morning chronotype from the European Consortium and those of the gut microbiota from the largest available genome-wide association study meta-analysis, conducted by the MiBioGen consortium. The inverse variance-weighted (IVW), weighted mode, weighted median, MR-Egger regression, and simple mode methods were used to examine the causal association between the morning chronotype and the gut microbiota. A reverse Mendelian randomization analysis was conducted on the gut microbiota, which was identified as causally linked to the morning chronotype in the initial Mendelian randomization analysis. Cochran's Q statistics were employed to assess the heterogeneity of the instrumental variables. RESULTS:Inverse variance-weighted estimates suggested that the morning chronotype had a protective effect on Family ( = -0.072; 95% CI: -0.143, -0.001; = 0.047), Genus ( = -0.112; 95% CI: -0.184, -0.039; = 0.002), and Genus ( = -0.072; 95% CI: -0.143, -0.001; = 0.047). In addition, the gut microbiota (Family (OR = 0.925; 95% CI: 0.857, 0.999; = 0.047), Genus (OR = 0.915; 95% CI: 0.858, 0.975; = 0.007), and Genus (OR = 0.925; 95% CI: 0.857, 0.999; = 0.047)) demonstrated positive effects on the morning chronotype. No significant heterogeneity in the instrumental variables, or in horizontal pleiotropy, was found. CONCLUSION:This two-sample Mendelian randomization study found that Family , Genus , and Genus were causally associated with the morning chronotype. Further randomized controlled trials are needed to clarify the effects of the gut microbiota on the morning chronotype, as well as their specific protective mechanisms.
10.3390/nu16010046
The influence of gut microbiota on circulating inflammatory cytokines and host: A Mendelian randomization study with meta-analysis.
Life sciences
AIMS:The gut microbiota has been found to be altered in different inflammatory disorders, but its involvement in the regulation of inflammatory cytokines remains unclear. Therefore, this study aimed to investigate the impacts of gut microbiota on circulating inflammatory cytokines and their potential roles in host diseases. MAIN METHODS:Two-sample Mendelian randomization (MR) analyses were conducted using summary-level data from genome-wide association studies (GWAS) to identify significant causal associations between 196 gut microbiota and 41 inflammatory cytokines. Meta-analysis was applied to test the robustness of the results. Enrichment analyses of identified cytokines were further utilized to infer the effects of gut microbiota on the host. KEY FINDINGS:The MR analyses and meta-analyses identified the following significant causal associations: phylum Euryarchaeota on interleukin-2 (IL-2) (β = 0.085, P = 1.5 × 10) and interleukin-8 (IL-8) (β = 0.065, P = 4.1 × 10), phylum Tenericutes and class Mollicutes on macrophage inflammatory protein 1a (MIP1a) (β = -0.142, P = 7.0 × 10), class Bacilli on hepatocyte growth factor (HGF) (β = -0.106, P = 2.5 × 10), order Enterobacteriales on monocyte chemoattractant protein-1 (MCP1) (β = 0.182, P = 1.8 × 10), and genus Lachnospiraceae NC2004 group on TNF-related apoptosis-inducing ligand (TRAIL) (β = -0.207, P = 6.0 × 10). Enrichment analyses suggested that phylum Euryarchaeota and order Enterobacteriales might be risk factors for certain autoimmune diseases and neoplasms, while the phylum Tenericutes may have a protective effect. SIGNIFICANCE:This study represents the first evidence confirming the causal effect of specific gut microbial taxa on circulating inflammatory cytokines and sheds light on their potential roles in the development and progression of various host diseases.
10.1016/j.lfs.2023.122105
Association of gut microbiota with cerebral cortical thickness: A Mendelian randomization study.
Journal of affective disorders
BACKGROUND:The causal relationship between gut microbiota and cerebral cortex development remains unclear. We aimed to scrutinize the plausible causal impact of gut microbiota on cortical thickness via Mendelian randomization (MR) study. METHODS:Genome-wide association study (GWAS) data for 196 gut microbiota phenotypes (N = 18,340) were obtained as exposures, and GWAS data for cortical thickness-related traits (N = 51,665) were selected as outcomes. Inverse variance weighted was used as the main estimate method. A series of sensitivity analyses was used to test the robustness of the estimates including Cochran's Q test, MR-Egger intercept analysis, Steiger filtering, scatter plot funnel plot and leave-one-out analysis. RESULTS:Genetic prediction of high Bacillales (β = 0.005, P = 0.032) and Lactobacillales (β = 0.010, P = 0.012) abundance was associated with a potential increase in global cortical thickness. For specific functional brain subdivisions, genetically predicted order Lactobacillales would potentially increase the thickness of the fusiform (β = 0.014, P = 0.016) and supramarginal (β = 0.017, P = 0.003). Meanwhile, order Bacillales would increase the thickness of fusiform (β = 0.007, P = 0.039), insula (β = 0.011, P = 0.003), rostralanteriorcingulate (β = 0.014, P = 0.002) and supramarginal (β = 0.006, P = 0.043). No significant estimates of heterogeneity or pleiotropy were found. CONCLUSIONS:Through MR studies, we discovered genetic prediction of the Lactobacillales and Bacillales orders potentially linked to cortical thickness, affirming gut microbiota may enhance brain structure. Genetically predicted supramarginal and fusiform may be potential targets.
10.1016/j.jad.2024.02.063
Mendelian Randomisation Study on Association of Gut Microbiota and Periodontitis.
International dental journal
OBJECTIVE:Several studies have demonstrated the possible association between gut microbiota and periodontitis. The mechanism by which gut microbiota contribute to periodontitis remains unknown. METHODS:A 2-sample Mendelian randomisation (MR) study was conducted using publicly available Genome-Wide Association Studies (GWAS) data of European ancestry. The relationships between gut microbiota and tooth loss and periodontitis were assessed using summary-level data. Moreover, inverse variance weighted (IVW), MR-Egger, weighted median, and simple Mendelian were used. The results were further validated using sensitivity analyses. RESULTS:A total of 211 gut microbiota were studied, including 9 phyla, 16 classes, 20 orders, 35 families, and 131 genera. The IVW method identified 16 bacterial genera related to the risk of periodontitis and tooth loss. Lactobacillaceae was associated with an increased risk of periodontitis (odds ratio [OR], 1.40, 95% confidence interval [CI], 1.03-1.91, P<.001) and tooth loss (OR, 1.12; 95% CIs, 1.02-1.24, P = .002), whereas Lachnospiraceae UCG008 was linked to a lower risk of tooth loss (P = .041). There was no heterogeneity and horizontal pleiotropy in the sensitivity analysis. CONCLUSIONS:Several microorganisms were identified to be linked to the risk of periodontitis. Furthermore, the findings improved our understanding of gut microbiota and periodontitis pathology.
10.1016/j.identj.2023.05.002
Causal relationship between gut microbiota and gastrointestinal diseases: a mendelian randomization study.
Journal of translational medicine
BACKGROUND:Recent research increasingly highlights a strong correlation between gut microbiota and the risk of gastrointestinal diseases. However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between gut microbiota and prevalent gastrointestinal diseases. METHODS:Genome-wide association study (GWAS) summary statistics for gut microbiota, encompassing a diverse range of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla), were sourced from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were gathered from the UK Biobank, FinnGen study, and various extensive GWAS studies. MR analysis was meticulously conducted to assess the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. To validate the reliability of our findings, sensitivity analyses and tests for heterogeneity were systematically performed. RESULTS:The MR analysis yielded significant evidence for 251 causal relationships between genetically predicted gut microbiota and the risk of gastrointestinal diseases. This included 98 associations with upper gastrointestinal diseases, 81 with lower gastrointestinal diseases, 54 with hepatobiliary diseases, and 18 with pancreatic diseases. Notably, these associations were particularly evident in taxa belonging to the genera Ruminococcus and Eubacterium. Further sensitivity analyses reinforced the robustness of these results. CONCLUSIONS:The findings of this study indicate a potential genetic predisposition linking gut microbiota to gastrointestinal diseases. These insights pave the way for designing future clinical trials focusing on microbiome-related interventions, including the use of microbiome-dependent metabolites, to potentially treat or manage gastrointestinal diseases and their associated risk factors.
10.1186/s12967-024-04894-5
Causal effects of gut microbiota on appendicitis: a two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Previous research has posited a potential correlation between the gut microbiota and the onset of appendicitis; however, the precise causal connection between appendicitis and the gut microbiota remains an unresolved and contentious issue. Methods:In this investigation, we performed a Mendelian randomization (MR) analysis employing publicly accessible summary data extracted from genome-wide association studies (GWAS) to elucidate the potential causal nexus between the gut microbiota and the development of appendicitis. We initially identified instrumental variables (IVs) through a comprehensive array of screening methodologies, subsequently executing MR analyses using the Inverse Variance Weighted (IVW) technique as our primary approach, supplemented by several alternative methods such as MR Egger, weighted median, simple mode, and weighted mode. Additionally, we implemented a series of sensitivity analysis procedures, encompassing Cochran's Q test, MR-Egger intercept test, Mendelian Randomized Polymorphism Residual and Outlier (MR-PRESSO) test, and a leave-one-out test, to affirm the robustness and validity of our findings. Results:Our investigation indicates that an elevated prevalence of Deltaproteobacteria, Christensenellaceae, Desulfovibrionaceae, Eubacterium ruminantium group, Lachnospiraceae NK4A136 group, Methanobrevibacter, Desulfovibrionales, and Euryarchaeota is inversely associated with the risk of appendicitis. Conversely, we observed a positive correlation between an increased abundance of Family XIII, Howardella, and Veillonella and the susceptibility to appendicitis. Sensitivity analyses have corroborated the robustness of these findings, and Mendelian randomization analyses provided no indications of reverse causality. Conclusion:Our Mendelian randomization (MR) analysis has unveiled potential advantageous or detrimental causal associations between the gut microbiota and the occurrence of appendicitis. This study offers novel theoretical and empirical insights into the understanding of appendicitis pathogenesis, along with its implications for preventive and therapeutic strategies.
10.3389/fcimb.2023.1320992
Gut microbiota and sepsis and sepsis-related death: a Mendelian randomization investigation.
Frontiers in immunology
Background:It is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two. Methods:This study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis. Results:For sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that (OR = 0.86, 95% CI, 0.78-0.94, = 0.0017) was protective against sepsis, while (OR = 0.89, 95% CI, 0.80-0.99), (OR = 1.37, 95% CI, 1.08-1.73), (OR = 1.21, 95% CI, 1.04-1.40), (OR = 1.10, 95% CI, 1.01-1.20), (OR = 0.85, 95% CI, 0.74-0.97), and (OR = 0.81, 95% CI, 0.69-0.94) presented a suggestive association with the development of sepsis (all < 0.05). For sepsis (critical care), IVW estimates indicated that (OR = 0.70, 95% CI, 0.53-0.93), (OR = 0.67, 95% CI, 0.50-0.91), (OR = 0.49, 95% CI, 0.31-0.76), (OR = 0.51, 95% CI, 0.34-0.77), and (OR = 0.66, 95% CI, 0.44-0.99) showed a suggestive negative correlation with sepsis (critical care) (all < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including (OR = 0.54, 95% CI, 0.30-0.95), (OR = 0.34, 95% CI, 0.14-0.83), (OR = 0.43, 95% CI, 0.22-0.83), and (OR = 0.45, 95% CI, 0.21-0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, (OR = 2.03, 95% CI, 1.01-4.08) and (OR = 2.65, 95% CI, 1.18-5.96) (all < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses. Conclusion:This MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.
10.3389/fimmu.2024.1266230
Association between Gut Microbiota and Biological Aging: A Two-Sample Mendelian Randomization Study.
Microorganisms
Recent observational studies revealed an association between gut microbiota and aging, but whether gut microbiota are causally associated with the aging process remains unknown. We used a two-sample Mendelian randomization approach to investigate the causal association between gut microbiota and biological age acceleration using the largest available gut microbiota GWAS summary data from the MiBioGen consortium and GWAS data on biological age acceleration. We further conducted sensitivity analysis using MR-PRESSO, MR-Egger regression, Cochran Q test, and reverse MR analysis. (IVW, β = 0.16, = 0.0001) was causally associated with Bioage acceleration. () (IVW, β = 0.20, = 0.0190), (IVW, β = 0.06, = 0.019), and (IVW, β = -0.18, = 0.01) were suggestive of causal associations with Bioage acceleration, with the latter being protective. (IVW, β = 0.26, = 0.0083), (IVW, β = 0.21, = 0.0184), and () (IVW, β = 0.24, = 0.0194) were suggestive of causal associations with Phenoage acceleration. This Mendelian randomization study found that was causally associated with Bioage acceleration. Further randomized controlled trials are needed to investigate its role in the aging process.
10.3390/microorganisms12020370
Mendelian randomization suggests a causal relationship between gut dysbiosis and thyroid cancer.
Frontiers in cellular and infection microbiology
Background:Alterations in gut microbiota composition and function have been linked to the development and progression of thyroid cancer (TC). However, the exact nature of the causal relationship between them remains uncertain. Methods:A bidirectional two-sample Mendelian randomization (TSMR) analysis was conducted to assess the causal connection between gut microbiota (18,340 individuals) and TC (6,699 cases combined with 1,613,655 controls) using data from a genome-wide association study (GWAS). The primary analysis used the inverse-variance weighted (IVW) method to estimate the causal effect, with supplementary approaches including the weighted median, weighted mode, simple mode, and MR-Egger. Heterogeneity and pleiotropy were assessed using the Cochrane Q test, MR-Egger intercept test, and MR-PRESSO global test. A reverse TSMR analysis was performed to explore reverse causality. Results:This study identified seven microbial taxa with significant associations with TC. Specifically, the genus (OR: 1.127, 95% CI: 1.008-1.260, = 0.036) (OR: 1.313, 95% CI: 1.066-1.618, = 0.011) (OR: 1.240, 95% CI: 1.001-1.536, = 0.049) (OR: 1.408, 95% CI: 1.158-1.711, < 0.001) (OR: 1.241, 95% CI: 1.018-1.513, = 0.032) were identified as risk factors for TC, while The genus (OR: 0.882, 95% CI: 0.787-0.989, = 0.031) and (OR: 0.719, 95% CI: 0.566-0.914, = 0.007) were associated with reduced TC risk. The reverse MR analysis found no evidence of reverse causality and suggested that TC may lead to increased levels of the genus (β: 0.053, 95% CI: 0.012~0.094, = 0.011) and decreased levels of the order (β: -0.075, 95% CI: -0.143~-0.006, = 0.033). No significant bias, heterogeneity, or pleiotropy was detected in this study. Conclusion:This study suggests a potential causal relationship between gut microbiota and TC, providing new insights into the role of gut microbiota in TC. Further research is needed to explore the underlying biological mechanisms.
10.3389/fcimb.2023.1298443
Gut microbiota, circulating metabolites, and gallstone disease: a Mendelian randomization study.
Frontiers in microbiology
Background:The link between Gut microbiota (GM) and Gallstone disease (GSD) is well established, but it is not clear whether there is a causal relationship between the two associations. Methods:We conducted bidirectional Mendelian randomization (MR) analyses, leveraging aggregated data from the Genome-Wide Association Study (GWAS) of GM and Circulating Metabolites. Our primary objective was to investigate the causal interplay between intestinal flora and GSD. Additionally, we performed mediational analyses, two-step MR, and multivariate MR to uncover the potential mediating effect of circulating metabolites in this relationship. Result:Our study has revealed a causal relationship between GSD and six distinct bacterial groups. Genetically predicted Class Bacilli (Odds Ratio (OR): 0.901, 95% Confidence Interval (95% CI): 0.825-0.985; 0.021), Order Lactobacillales (OR: 0.895, 95% CI: 0.816-0.981; 0.017), and Genus Coprococcus 2 (OR: 0.884, 95% CI: 0.804-0.973; 0.011) were inversely associated with the risk of GSD. Conversely, the Genus Clostridiumsensustricto1 (OR: 1.158, 95% CI: 1.029-1.303; = 0.015), Genus Coprococcus3 (OR: 1.166, 95% CI: 1.024-1.327; = 0.020), and Genus Peptococcus (OR: 1.070, 95% CI: 1.017-1.125; 0.009) were positively associated with the risk of GSD. Moreover, our findings suggest that the positive influence of the Genus Peptococcus on GSD may be mediated through Omega-3 polyunsaturated fatty acids (PUFA). Conclusion:This study reinforces the connection between the gut microbiome and the risk of GSD while also unveiling the mediating role of Omega-3 PUFA in the causal relationship between these factors.
10.3389/fmicb.2024.1336673
Assessment of causal associations among gut microbiota, metabolites, and celiac disease: a bidirectional Mendelian randomization study.
Frontiers in microbiology
Background:A growing number of studies have implicated that gut microbial abundance and metabolite concentration alterations are associated with celiac disease (CD). However, the causal relationship underlying these associations is unclear. Here, we used Mendelian randomization (MR) to reveal the causal effect of gut microbiota and metabolites on CD. Methods:Genome-wide association study (GWAS) summary-level data for gut microbiota, metabolites, and CD were extracted from published GWASs. Causal bacterial taxa and metabolites for CD were determined by two-sample MR analyses. The robustness of the results was assessed with sensitivity analyses. Finally, reverse causality was investigated with a reverse MR analysis. Results:Genetically, increased genus was potentially associated with higher CD risk (odds ratio [OR] = 1.447, 95% confidence interval [CI]: 1.054-1.988, = 0.022) while phylum (OR = 0.798, 95% CI: 0.648-0.983, = 0.034) and genus (OR = 0.683, 95% CI: 0.531-0.880, = 0.003) were related to lower CD risk. Moreover, there were suggestive associations between CD and the following seven metabolites: 1-oleoylglycerophosphoethanolamine, 1-palmitoylglycerophosphoethanolamine, 1,6-anhydroglucose, phenylacetylglutamine, tryptophan betaine, 10-undecenoate, and tyrosine. Sensitivity analyses deemed the results reliable without pleiotropy. Conclusion:We investigated the causal relationships between gut microbiota, metabolites, and CD with two-sample MR. Our findings suggest several novel potential therapeutic targets for CD treatment. Further understanding of the underlying mechanism may provide insights into CD pathogenesis.
10.3389/fmicb.2023.1087622
Causal relationships between gut microbiota and hypothyroidism: a Mendelian randomization study.
Endocrine
BACKGROUND:Previous studies have shown that the gut microbiota plays an important role in the maintenance of thyroid homeostasis. We aimed to evaluate the causal relationships between gut microbiota and hypothyroidism. METHODS:Summary statistics for 211 gut microbiota taxa were obtained from the largest available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen consortium. Summary statistics for hypothyroidism were obtained from two distinct sources: the FinnGen consortium R9 release data (40,926 cases and 274,069 controls) and the UK Biobank data (22,687 cases and 440,246 controls), respectively. A two-sample Mendelian randomization (MR) design was employed, and thorough sensitivity analyses were carried out to ensure the reliability of the results. RESULTS:Based on the FinnGen consortium, we found increased levels of Intestinimonas (OR = 1.09; 95%CI = 1.02-1.16; P = 0.01) and Ruminiclostridium5 (OR = 1.11; 95%CI = 1.02-1.22; P = 0.02) may be associated with a higher risk of hypothyroidism, while increased levels of Butyrivibrio (OR = 0.95; 95%CI = 0.92-0.99; P = 0.02), Eggerthella (OR = 0.93; 95%CI = 0.88-0.98; P = 0.01), Lachnospiraceae UCG008 (OR = 0.92; 95%CI = 0.85-0.99; P = 0.02), Ruminococcaceae UCG011 (OR = 0.95; 95%CI = 0.90-0.99; P = 0.02), and Actinobacteria (OR = 0.88; 95%CI = 0.80-0.97; P = 0.01) may be associated with a lower risk. According to the UK Biobank data, Eggerthella and Ruminiclostridium5 remain causally associated with hypothyroidism. The sensitivity analysis demonstrates consistent results without evidence of heterogeneity or pleiotropy. CONCLUSION:This study highlights the impact of specific gut microbiota on hypothyroidism. Strategies to change composition of gut microbiota may hold promise as potential interventions.
10.1007/s12020-023-03538-w
Association between gut microbiota and glioblastoma: a Mendelian randomization study.
Frontiers in genetics
Glioblastoma (GBM) is the most prevalent malignant brain tumor, significantly impacting the physical and mental wellbeing of patients. Several studies have demonstrated a close association between gut microbiota and the development of GBM. In this investigation, Mendelian randomization (MR) was employed to rigorously evaluate the potential causal relationship between gut microbiota and GBM. We utilized summary statistics derived from genome-wide association studies (GWAS) encompassing 211 gut microbiota and GBM. The causal association between gut microbiota and GBM was scrutinized using Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median (WM) methods. Cochrane's Q statistic was employed to conduct a heterogeneity test. MR-Pleiotropic Residuals and Outliers (MR-PRESSO) were applied to identify and eliminate SNPs with horizontal pleiotropic outliers. Additionally, Reverse MR was employed to assess the causal relationship between GBM and pertinent gut microbiota. The MR study estimates suggest that the nine gut microbiota remain stable, considering heterogeneity and sensitivity methods. Among these, the and were associated with an increased risk of GBM, whereas , , , , , , and were associated with a reduced risk of GBM. Following Benjamini and Hochberg (BH) correction, (OR = 0.04, 95% CI: 0.01-0.19, FDR = 0.003) was identified as playing a protective role against GBM. This groundbreaking study is the first to demonstrate that is significantly associated with a reduced risk of GBM. The modulation of for the treatment of GBM holds considerable potential clinical significance.
10.3389/fgene.2023.1308263
Gut microbiota and common gastrointestinal diseases: a bidirectional two-sample Mendelian randomized study.
Frontiers in microbiology
Background:Several recent studies have shown an association between gut microbiota and gastrointestinal diseases. However, the causal relationship between gut microbiota and gastrointestinal disorders is unclear. Methods:We assessed causal relationships between gut microbiota and eight common gastrointestinal diseases using Mendelian randomization (MR) analyses. IVW results were considered primary results. Cochrane's Q and MR-Egger tests were used to test for heterogeneity and pleiotropy. Leave-one-out was used to test the stability of the MR results, and Bonferroni correction was used to test the strength of the causal relationship between exposure and outcome. Results:MR analyses of 196 gut microbiota and eight common gastrointestinal disease phenotypes showed 62 flora and common gastrointestinal diseases with potential causal relationships. Among these potential causal relationships, after the Bonferroni-corrected test, significant causal relationships remained between Genus Oxalobacter and CD (OR = 1.29, 95% CI: 1.13-1.48, = 2.5 × 10-4, = 4.20 × 10-4), and between Family Clostridiaceae1 and IBS (OR = 0.9967, 95% CI: 0.9944-0.9991, = 1.3 × 10-3, = 1.56 × 10-3). Cochrane's -test showed no significant heterogeneity among the various single nucleotide polymorphisms (SNPs). In addition, no significant level of pleiotropy was found according to the MR-Egger. Conclusion:This study provides new insights into the mechanisms of gut microbiota-mediated gastrointestinal disorders and some guidance for targeting specific gut microbiota for treating gastrointestinal disorders.
10.3389/fmicb.2023.1273269
Exploring the potential causal relationship between gut microbiota and heart failure: A two-sample mendelian randomization study combined with the geo database.
Current problems in cardiology
OBJECTIVE:In recent years, researchers have observed a potential association between alterations in gut microbiota and the onset and progression of heart failure. Nevertheless, the causal relationship between gut microbiota and heart failure remains a topic of controversy. This study employed a two-sample Mendelian randomization approach to investigate the causal link between gut microbiota and heart failure. METHOD:We extracted single nucleotide polymorphism (SNPs) data for heart failure (ebi-a-gcst009541) and gut microbiota from the publicly available genome-wide association analysis (GWAS) summary database. The primary analytical method employed was inverse variance weighting (IVW), complemented by validation using MR-PRESSO, weighted median, and MR pleiotropic residual methods. Additionally, gene pleiotropy (MR-Egger), heterogeneity testing, and a "leave-one-out" analysis were conducted to assess the robustness of the findings. Utilizing the limma package, differentially expressed genes (DEGs) from the Gut Microbiota datasets (GSE3586, GSE5406) and Heart Failure datasets (GSE47908, GSE87466) sourced from the Gene Expression Omnibus (GEO) were curated. Subsequent enrichment analysis was conducted using the Cluster Profiler and GO plot packages to validate the MR analysis outcomes. RESULTS:The results of our analysis revealed seven distinct bacterial groups in the intestines that exhibited associations.with.the.risk.of.heart.failure. These.included.class.negativicutes (P = 0.02,OR:1.11,95%CI:1.02,1.21), gene.eubacterium.eligensgroup (P = 0.02,OR:1.10,95%CI:1.01,1.20),gene.eubacteriummoxidoreducensgroup (P = 0.01,OR:1.10,95%CI:1.02,1.19),Order.selenium (P = 0.02,OR:1.11,95%CI:1.02,1.21), gene.familyxiiiucg001 (P = 0.03,OR=1.09.95%CI:1.01,1.19), gene.familyxiiiad3011group (P = 0.03,OR:0.92,95%CI:0.86,0.99), and.gene.anaerostipes (P = 0.00,OR:0.87,95%CI:0.80,0.94). Nevertheless, upon conducting reverse causal MR analysis, no evidence of a causal relationship between heart failure and the aforementioned seven gut microbiota groups was found.Bioinformatics analysis reveals shared DEGs between gut microbiota and heart failure. CONCLUSION:This Mendelian randomization study represents the first endeavor to explore the causal relationship between specific gut microbiota and heart failure. The findings suggest a significant correlation between these seven specific gut microbiota groups and the risk of heart failure, potentially offering valuable insights for heart failure prevention and control efforts.
10.1016/j.cpcardiol.2023.102235
Causal relationship between Gut Microbiota and Obstructive sleep apnea.
Archives of gerontology and geriatrics
OBJECTIVE:Although observational studies have identified relations between gut microbiota and obstructive sleep apnea (OSA), their causal links remain elusive. Hence, we aimed to investigate this causal relation using the Mendelian randomization (MR) approach. METHODS:Summary-level gut microbiota data were acquired using the maximum available genome-wide association study (GWAS) from the MiBioGen consortium while obtaining summary-level OSA data using publicly available GWAS from the FinnGen Consortium. A two-sample MR analysis was used for assessing gut microbiota and OSA causal effect, using the inverse variance-weighted (IVW) approach as the primary analysis method. The results were further examined for pleiotropy and heterogeneity. Moreover, the reverse MR analysis did not find a causal relationship. RESULTS:Four gut microbiota were found to have nominally significant association to OSA according to the IVW method. Among them, the family Peptostreptococcaceae (OR = 1.171, 95% CI: 1.027-1.334) and genus Coprococcus3 (OR = 1.163, 95% CI: 1.007-1.343), these two florae that may increase the risk of OSA. Family Acidaminococcaceae (OR = 0.843, 95% CI: 0.729-0.975) and genus Blautia (OR = 0.830, 95% CI: 0.708-0.972) may have an ameliorative effect on OSA. No evidence of pleiotropy or heterogeneity was found. CONCLUSIONS:MR analysis indicated that a causal relation is existed between specific gut microbiota and OSA at the genetic prediction level, offering innovative perspectives into the mechanisms underlying gut microbiota-mediated OSA development.
10.1016/j.archger.2023.105052
Application of Mendelian randomization to assess host gene-gut microbiota correlations in patients with esophageal cancer.
Frontiers in microbiology
Background:Increasing evidence suggests that esophageal cancer (ESCA) may be correlated with gut flora. However, their causal connection remains unclear. This study aimed to evaluate potential causal linkages and gene-gut microbiome associations between the gut microbiota and ESCA using Mendelian randomization (MR). Methods:We analyzed the data using genome-wide association studies. The exposure factor and outcome variable were the gut microbiota and ESCA, respectively. The MR-Egger method, weighted median, inverse-variance weighted method, heterogeneity test, sensitivity analysis, and multiplicity analysis were used for the MR analysis. And it was validated using an external dataset. Further meta-analysis was performed to validate the robustness of this relationship. Finally, we annotated single nucleotide polymorphisms in the gut microbiota that were causally associated with ESCA to explore possible host gene-gut microbiota correlations in patients with ESCA. Results:We identified four species with potential associations with ESCA. Three of these species had a negative causal relationship with ESCA (odds ratio (OR): 0.961; 95% confidence interval (CI): 0.923-0.971; = 0.047 for ; OR: 0.972; 95% CI: 0.921-0.961; = 0.018 for ; OR: 0.948; 95% CI: 0.912-0.970; = 0.032 for ). A positive causal relationship was observed between one bacterial group and ESCA (OR: 1.105; 95% CI: 1.010-1.072; = 0.018 for ). External datasets show the same trend. This is further supported by meta-analysis. None of the data showed pleiotropy, and leave-one-out analysis indicated the reliability of these findings. The gut microbiomes of patients with ESCA may correlate with the 19 identified genes. Conclusion:Our data indicate a potential causal link between these four gut bacteria and ESCA and identify a correlation between host genes and gut microbiota in ESCA, offering novel therapeutic options.
10.3389/fmicb.2023.1309596
Causal effects of specific gut microbiota on bone mineral density: a two-sample Mendelian randomization study.
Frontiers in endocrinology
Background:Recent studies have reported that the gut microbiota is essential for preventing and delaying the progression of osteoporosis. Nonetheless, the causal relationship between the gut microbiota and the risk of osteoporosis has not been fully revealed. Methods:A two-sample Mendelian randomization (MR) analysis based on a large-scale genome-wide association study (GWAS) was conducted to investigate the causal relationship between the gut microbiota and bone mineral density (BMD). Instrumental variables for 211 gut microbiota taxa were obtained from the available GWAS meta-analysis (n = 18,340) conducted by the MiBioGen consortium. The summary-level data for BMD were from the Genetic Factors for Osteoporosis (GEFOS) Consortium, which involved a total of 32,735 individuals of European ancestry. The inverse variance-weighted (IVW) method was performed as a primary analysis to estimate the causal effect, and the robustness of the results was tested sensitivity analyses by using multiple methods. Finally, a reverse MR analysis was applied to evaluate reverse causality. Results:According to the IVW method, we found that nine, six, and eight genetically predicted gut microbiota were associated with lumbar spine (LS) BMD, forearm (FA) BMD, and femoral neck (FN) BMD, respectively. Among them, the higher genetically predicted level was correlated with increased LS-BMD [β = 0.125, 95% confidence interval (CI): 0.050-0.200, = 0.001] and FA-BMD (β = 0.129, 95% CI: 0.007-0.251, = 0.039). The higher level of genetically predicted was associated with increased FA-BMD (β = 0.154, 95% CI: 0.020-0.288, = 0.025) and FN-BMD (β = 0.080, 95% CI: 0.015-0.145, = 0.016). Consistent directional effects for all analyses were observed in both the MR-Egger and weighted median methods. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on BMD ( > 0.05). In reverse MR analysis, there was no evidence of reverse causality between LS-BMD, FA-BMD, and FN-BMD and gut microbiota ( > 0.05). Conclusion:Genetic evidence suggested a causal relationship between the gut microbiota and BMD and identified specific bacterial taxa that regulate bone mass variation. Further exploration of the potential microbiota-related mechanisms of bone metabolism might provide new approaches for the prevention and treatment of osteoporosis.
10.3389/fendo.2023.1178831
The causal role of gut microbiota in development of osteoarthritis.
Yu X-H,Yang Y-Q,Cao R-R,Bo L,Lei S-F
Osteoarthritis and cartilage
OBJECTIVE:There is considerable evidence for relationship between gut microbiota and osteoarthritis (OA), but no studies have investigated their causal relationship. METHOD:This study utilized large-scale genome-wide association studies (GWAS) summary statistics to evaluate the causal association between gut microbiota and OA risk. Specifically, two-sample Mendelian randomization (MR) approach was used to identify the causal microbial taxa for OA. Comprehensively sensitive analyses were performed to validate the robustness of results and novel multivariable MR analyses were further conducted to ensure the independence of causal association. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations. Finally, enrichment analyses were used to investigate the biofunction. RESULTS:After correction, three microbial taxa were identified to be causally associated with diverse joint OA (P < 0.100), namely Methanobacteriaceae family for knee OA (P = 0.043) and any OA (P = 0.028), Desulfovibrionales order for knee OA (P = 0.045) and Ruminiclostridium5 genus for knee OA (P = 0.063). In addition, we also identified five suggestive microbial taxa that were significant with three different methods under the nominal significance (P < 0.05). Sensitive analysis excluded the influence of heterogeneity and horizontal pleiotropy and multivariable MR analysis ruled out the possibility of horizontal pleiotropy of BMI. GO enrichment analysis illustrates the protective mechanism of the identified taxa against OA. CONCLUSIONS:This study found that several microbial taxa were causally associated with diverse joint OA. The results enhanced our understanding of gut microbiota in the pathology of OA.
10.1016/j.joca.2021.08.003
Association between the gut microbiota and nonalcoholic fatty liver disease: A two-sample Mendelian randomization study.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
BACKGROUND:Increasing studies have shown that there is a significant association between gut microbiota and non-alcoholic fatty liver disease. AIMS:To show the potential association between gut microbiota and non-alcoholic fatty liver disease, we performed a two-sample Mendelian randomization analysis. METHODS:We analyzed summary statistics from genome-wide association studies of gut microbiota and non-alcoholic fatty liver disease and conducted Mendelian randomization studies to evaluate relationships between these factors. RESULTS:Of the 211 gut microbiota taxa examined, the inverse variance weighted method identified Lactobacillaceae (OR = 0.83, 95% CI = 0.72 - 0.95, P = 0.007), Christensenellaceae (OR = 0.74, 95% CI = 0.59 - 0.92, P = 0.007), and Intestinibacter (OR = 0.85, 95% CI = 0.73 - 0.99, P = 0.035) were negatively correlated with non-alcoholic fatty liver disease. And Coriobacteriia (OR = 1.22, 95% CI = 1.01 - 1.42, P = 0.038), Actinomycetales (OR = 1.25, 95% CI = 1.02 - 1.53, P = 0.031), Oxalobacteraceae (OR = 1.10, 95% CI = 1.01 - 1.21, P = 0.036), Ruminococcaceae_UCG005 (OR = 1.18, 95% CI = 1.01 - 1.38, P = 0.033) are positively associated with non-alcoholic fatty liver disease. CONCLUSIONS:Our study found that the abundance of certain strains was associated with the progression of nonalcoholic fatty liver disease.
10.1016/j.dld.2023.07.014
The relationship between gut microbiota and insomnia: a bi-directional two-sample Mendelian randomization research.
Frontiers in cellular and infection microbiology
Introduction:Insomnia is the second most common mental health issue, also is a social and financial burden. Insomnia affects the balance between sleep, the immune system, and the central nervous system, which may raise the risk of different systemic disorders. The gut microbiota, referred to as the "second genome," has the ability to control host homeostasis. It has been discovered that disruption of the gut-brain axis is linked to insomnia. Methods:In this study, we conducted MR analysis between large-scale GWAS data of GMs and insomnia to uncover potential associations. Results:Ten GM taxa were detected to have causal associations with insomnia. Among them, class , genus , genus , genus , genus , and order were linked to a higher risk of insomnia. In reverse MR analysis, we discovered a causal link between insomnia and six other GM taxa. Conclusion:It suggested that the relationship between insomnia and intestinal flora was convoluted. Our findings may offer beneficial biomarkers for disease development and prospective candidate treatment targets for insomnia.
10.3389/fcimb.2023.1296417
Causal associations between gut microbiota, gut microbiota-derived metabolites, and cerebrovascular diseases: a multivariable Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Mounting evidence has demonstrated the associations between gut microbiota, gut microbiota-derived metabolites, and cerebrovascular diseases (CVDs). The major categories of CVD are ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). However, the causal relationship is still unclear. Methods:A two-sample Mendelian randomization (MR) study was conducted leveraging the summary data from genome-wide association studies. The inverse variance-weighted, maximum likelihood, weighted median, and MR.RAPS methods were performed to detect the causal relationship. Several sensitivity analyses were carried out to evaluate potential horizontal pleiotropy and heterogeneity. Finally, reverse MR analysis was conducted to examine the likelihood of reverse causality, and multivariable MR was performed to adjust the potential confounders. Results:We collected 1,505 host single nucleotide polymorphisms (SNPs) linked to 119 gut microbiota traits and 1,873 host SNPs associated with 81 gut metabolite traits as exposure data. Among these, three gut bacteria indicated an elevated risk of IS, two of ICH, and one of SAH. In contrast, five gut bacteria were associated with a reduced risk of IS, one with ICH, and one with SAH. Our study also demonstrated the potential causal associations between 11 gut microbiota-derived metabolites and CVD. Conclusions:This study provided evidence of the causal relationship between gut microbiota, gut microbiota-derived metabolites, and CVD, thereby offering novel perspectives on gut biomarkers and targeted prevention and treatment for CVD.
10.3389/fcimb.2023.1269414
Association of Gut Microbiota with Age-Related Macular Degeneration and Glaucoma: A Bidirectional Mendelian Randomization Study.
Nutrients
The objective of this study was to examine the correlation between gut microbiota and both age-related macular degeneration (AMD) and glaucoma. Mendelian randomization studies were conducted utilizing the data sourced from the genome-wide association study (GWAS) database for the gut microbiome, AMD, and glaucoma. Single nucleotide polymorphism (SNP) estimates were summarized through five Mendelian randomization (MR) methods. We utilized Cochran's Q statistic to evaluate the heterogeneity of the instrumental variables (IVs). Additionally, we employed a "leave-one-out" approach to verify the stability of our findings. Inverse variance weighted (IVW) suggests that Eubacterium (oxidoreducens group) and Parabacteroides had a protective effect on AMD. Both weighted median and IVW suggest that Lachnospiraceae (NK4A136 group) and Ruminococcaceae (UCG009) had a protective effect on AMD. However, both weighted median and IVW suggest that Dorea had a risk effect on AMD. Similarly, The IVW of Eubacterium (ventriosum group) showed a risk effect on AMD. The weighted median of Eubacterium (nodatum group), Lachnospiraceae (NC2004 group), and Roseburia had a risk effect on glaucoma. IVW suggested that Ruminococcaceae (UCG004) had a risk effect on glaucoma. Reverse MR analysis found a causal link between Eubacterium (nodatum group) and glaucoma. No causal relationships were found between AMD or glaucoma and the other mentioned bacterial groups. No significant heterogeneity or evidence of horizontal pleiotropy was detected. This study found that certain gut bacteria had protective effects on AMD, while others may be risk factors for AMD or glaucoma. Likewise, reverse MR found that glaucoma led to an increased abundance of certain gut bacteria. Further trials are needed to clarify the specific mechanisms involved.
10.3390/nu15214646
Causal associations between gut microbiota and primary biliary cholangitis: a bidirectional two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Previous studies have suggested an association between gut microbiota and primary biliary cholangitis (PBC). Nonetheless, the causal relationship between gut microbiota and PBC risk remains unclear. Methods:A bidirectional two-sample Mendelian Randomization (MR) study was employed using summary statistical data for gut microbiota and PBC from the MiBioGen consortium and Genome-Wide Association Studies (GWAS) database to investigate causal relationships between 211 gut microbiota and PBC risk. Inverse variance weighted (IVW) method was the primary analytical approach to assess causality, and the pleiotropy and heterogeneity tests were employed to verify the robustness of the findings. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association. Results:The IVW method identified five gut microbiota that demonstrated associations with the risk of PBC. Order [odds ratio (OR) 2.13, 95% confidence interval (CI) 1.10-4.14, = 0.03], Order (OR 1.58, 95% CI 1.07-2.33, = 0.02), and Genus (OR 1.64, 95%CI 1.06-2.55, = 0.03) were correlated with a higher risk of PBC, while Family (OR 0.65, 95%CI 0.43-0.98, = 0.04) and Family (OR 0.33, 95%CI 0.15-0.72, = 0.01) had a protective effect on PBC. The reverse MR analysis demonstrated no statistically significant relationship between PBC and these five specific gut microbial taxa. Conclusion:This study revealed that there was a causal relationship between specific gut microbiota taxa and PBC, which may provide novel perspectives and a theoretical basis for the clinical prevention, diagnosis, and treatment of PBC.
10.3389/fmicb.2023.1273024
Causal Associations between Gut Microbiota and Different Types of Dyslipidemia: A Two-Sample Mendelian Randomization Study.
Nutrients
The determination of a causal association between gut microbiota and a range of dyslipidemia remains uncertain. To clarify these associations, we employed a two-sample Mendelian randomization (MR) analysis utilizing the inverse-variance weighted (IVW) method. This comprehensive analysis investigated the genetic variants that exhibited a significant association ( < 5 × 10) with 129 distinct gut microbiota genera and their potential link to different types of dyslipidemia. The results indicated a potential causal association between 22 gut microbiota genera and dyslipidemia in humans. Furthermore, these findings suggested that the impact of gut microbiota on dyslipidemia regulation is dependent on the specific phylum, family, and genus. Bacillota phylum demonstrated the greatest diversity, with 15 distinct genera distributed among eight families. Notably, gut microbiota-derived from the Lachnospiraceae and Lactobacillaceae families exhibit statistically significant associations with lipid levels that contribute to overall health ( < 0.05). The sensitivity analysis indicated that our findings possess robustness ( > 0.05). The findings of our investigation provide compelling evidence that substantiates a causal association between the gut microbiota and dyslipidemia in the human body. It is noteworthy to highlight the significant influence of the Bacillota phylum as a crucial regulator of lipid levels, and the families Lachnospiraceae and Lactobacillaceae should be recognized as probiotics that significantly contribute to this metabolic process.
10.3390/nu15204445
Causal Effects of Gut Microbiota on Age-Related Macular Degeneration: A Mendelian Randomization Study.
Investigative ophthalmology & visual science
Purpose:Recently, the association between gut microbiota and age-related macular degeneration (AMD) through the gut-retina axis has attracted great interest. However, the causal relationship between them has not been elucidated. Using publicly available genome-wide association study summary statistics, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between the gut microbiota and the occurrence of AMD. Methods:The study used a variety of quality control techniques to select instrumental single nucleotide polymorphisms (SNPs) with strong exposure associations. We used a set of SNPs as instrumental variable that were below the genome-wide statistical significance threshold (5 × 10-8). Additionally, a separate group of SNPs below the locus-wide significance level (1 × 10-5) were selected as instrumental variables to ensure a comprehensive conclusion. Inverse variance-weighted (IVW) analysis was the primary technique we used to examine causality in order to confirm the validity of our findings. The MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis were used to evaluate the horizontal pleiotropy, heterogeneities, and stability of the genetic variants. Results:IVW results showed that genus Anaerotruncus (P = 5.00 × 10-3), genus Candidatus Soleaferrea (P = 1.83 × 10-2), and genus unknown id.2071 (P = 3.12 × 10-2) were protective factors for AMD. The Eubacterium oxidoreducens group (P = 3.17 × 10-2), genus Faecalibacterium (P = 2.67 × 10-2), and genus Ruminococcaceae UCG-011 (P = 4.04 × 10-2) were risk factors of AMD. No gut microbiota (GM) taxa were found to be causally related to AMD at the phylum, class, order, and family levels (P > 0.05). The robustness of MR results were confirmed by heterogeneity and pleiotropy analysis. (P > 0.05). We also performed a bidirectional analysis, which showed that genus Anaerotruncus, genus Candidatus Soleaferrea, genus unknown id.2071 and the Eubacterium oxidoreducens group had an interaction with AMD, whereas genus Faecalibacterium showed only a unilateral unfavorable effect on AMD. Conclusions:We confirmed a causal relationship between AMD and GM taxa, including the Eubacterium oxidoreducens group, Faecalibacterium, Ruminococcaceae UCG-011, Anaerotruncus, and Candidatus Soleaferrea. These strains have the potential to serve as new biomarkers, offering valuable insights into the treatment and prevention of AMD.
10.1167/iovs.64.12.32
Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?
International journal of molecular sciences
Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which-at least in part-could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.
10.3390/ijms24031940
Causal Link between Gut Microbiota, Neurophysiological States, and Bone Diseases: A Comprehensive Mendelian Randomization Study.
Nutrients
Increasing evidence highlights a robust correlation between the gut microbiota and bone diseases; however, the existence of a causal relationship between them remains unclear. In this study, we thoroughly examined the correlation between gut microbiota and skeletal diseases using genome-wide association studies. Linkage disequilibrium score regression and Mendelian randomization were used to probe genetic causality. Furthermore, the potential mediating role of neuropsychological states (i.e., cognition, depression, and insomnia) between the gut microbiota and bone diseases was evaluated using mediation analysis, with genetic colocalization analysis revealing potential targets. These findings suggest a direct causal relationship between Ruminococcaceae and knee osteoarthritis (OA), which appears to be mediated by cognitive performance and insomnia. Similarly, a causal association was observed between Burkholderiales and lumbar pelvic fractures, mediated by cognitive performance. Colocalization analysis identified a shared causal variant (rs2352974) at the TRAF-interacting protein locus for cognitive ability and knee OA. This study provides compelling evidence that alterations in the gut microbiota can enhance cognitive ability, ameliorate insomnia, and potentially reduce the risk of site-specific fractures and OA. Therefore, strategies targeting gut microbiota optimization could serve as novel and effective preventive measures against fractures and OA.
10.3390/nu15183934
Effects of gut microbiota on prostatic cancer: a two-sample Mendelian randomization study.
Frontiers in microbiology
Aim:Recent observational and small-sample case-control studies have shown a relationship between gut microbiota composition and prostatic cancer (PCa). Nevertheless, the causal association between gut microbiota and PCa is still unclear. Herein, we used the Mendelian randomization (MR) method to explore the potential causal relationship between gut microbiota and PCa. Methods:In this two-sample MR study, data were extracted from the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis conducted by the MiBioGen consortium ( = 14,306) and the Dutch Microbiome Project ( = 8,208). Summary statistics for PCa were obtained from the FinnGen consortium release data ( = 95,213). Inverse variance weighted (IVW), MR-Egger, strength test (F), and MR-PRESSO were used to examine the potential causal association between gut microbiota and PCa. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. Results:IVW estimates suggested that the relative abundance of (odds ratio [OR] = 0.7926, 95% confidence interval [CI]: 0.6655-0.9440) and (OR = 0.9023, 95% CI: 0.8262-0.9853) were negatively associated with the odds of PCa, while that of (OR = 1.1629, 95% CI: 1.0110-1.3376) was positively associated with the odds of PCa. In addition, we explored these relationships among patients without other cancers and similarly found that the relative abundance of , and were linked to PCa (all < 0.05). Conclusion:Gut microbiota potentially influenced the occurrence of PCa. Our findings may provide some new ideas for researching the methods of PCa prevention. In addition, further studies are needed to explore the causal association and specific underlying mechanisms between gut microbiota and PCa.
10.3389/fmicb.2023.1250369
Causal relationship between gut microbiota and polycystic ovary syndrome: a literature review and Mendelian randomization study.
Frontiers in endocrinology
Introduction:Numerous studies have suggested an association between gut microbiota and polycystic ovarian syndrome (PCOS). However, the causal relationship between these two factors remains unclear. Methods:A review of observational studies was conducted to compare changes in gut microbiota between PCOS patients and controls. The analysis focused on four levels of classification, namely, phylum, family, genus, and species/genus subgroups. To further investigate the causal relationship, Mendelian randomization (MR) was employed using genome-wide association study (GWAS) data on gut microbiota from the MiBioGen consortium, as well as GWAS data from a large meta-analysis of PCOS. Additionally, a reverse MR was performed, and the results were verified through sensitivity analyses. Results:The present review included 18 observational studies that met the inclusion and exclusion criteria. The abundance of 64 gut microbiota taxa significantly differed between PCOS patients and controls. Using the MR method, eight bacteria were identified as causally associated with PCOS. The protective effects of the genus on PCOS remained significant after applying Bonferroni correction. No significant heterogeneity or horizontal pleiotropy was found in the instrumental variables (IVs). Reverse MR analyses did not reveal a significant causal effect of PCOS on gut microbiota. Conclusion:The differences in gut microbiota between PCOS patients and controls vary across observational studies. However, MR analyses identified specific gut microbiota taxa that are causally related to PCOS. Future studies should investigate the gut microbiota that showed significant results in the MR analyses, as well as the underlying mechanisms of this causal relationship and its potential clinical significance.
10.3389/fendo.2024.1280983
Association between gut microbiota and benign prostatic hyperplasia: a two-sample mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Recent researches have shown a correlation between the gut microbiota (GM) and various diseases. However, it remains uncertain whether the relationship between GM and benign prostatic hyperplasia (BPH) is causal. Methods:We carried out a two-sample Mendelian randomization (MR) analysis, utilizing data from the most extensive GM-focused genome-wide association study by the MiBioGen consortium, with a sample size of 13,266. Data for BPH, encompassing 26,358 cases and 110,070 controls, were obtained from the R8 release of the FinnGen consortium. We employed multiple techniques, such as inverse variance weighted (IVW), constrained maximum likelihood and model averaging methods, maximum likelihood, MR-Pleiotropy RESidual Sum and Outlier (MRPRESSO),MR-Egger, and weighted median methods, to investigate the causal relationship between GM and BPH. To evaluate the heterogeneity among the instrumental variables, Cochran's Q statistics were employed. Additionally, the presence of horizontal pleiotropy was assessed through the application of both MR-Egger and MR-PRESSO tests. The direction of causality was scrutinized for robustness using the MR-Steiger directionality test. A reverse MR analysis examined the GM previously linked to BPH through a causal relationship in the forward MR assessment. Results:According to the analysis conducted using IVW,Eisenbergiella (odds ratio [OR]=0.92, 95% confidence interval [CI]: 0.85-0.99,P=0.022) and Ruminococcaceae (UCG009) (OR=0.88, 95% CI: 0.79-0.99, P=0.027) were found to reduce the risk of BPH, while Escherichia shigella (OR=1.19, 95% CI: 1.05-1.36, P=0.0082) appeared to increase it. The subsequent reverse MR analysis revealed that the three GM were not significantly influenced by BPH, and there was no noticeable heterogeneity or horizontal pleiotropy among the instrumental variables.Conclusion: These results indicated a causal relationship between Eisenbergiella, Ruminococcaceae (UCG009), and Escherichia shigella and BPH. Further randomized controlled trials are needed to explore more comprehensively the roles and operational mechanisms of these GM in relation to BPH.
10.3389/fcimb.2023.1248381
Exploring the Association between Gut Microbiota and Inflammatory Skin Diseases: A Two-Sample Mendelian Randomization Analysis.
Microorganisms
Emerging research underscores the substantial link between gut flora and various inflammatory skin diseases. We hypothesize that there exists a complex gut-skin axis, possibly affecting the progression of conditions such as eczema, acne, psoriasis, and rosacea. However, the precise nature of the causal connection between gut flora and skin diseases remains unestablished. In this study, we started by compiling summary data from genome-wide association studies (GWAS) featuring 211 unique gut microbiota and four types of skin conditions. We scrutinized these data across different taxonomic strata. Subsequently, we leveraged Mendelian randomization (MR) to ascertain if there is a causal link between gut microbiota and these skin conditions. We also performed a bidirectional MR analysis to identify the causality's direction. By utilizing Mendelian randomization, we identified 26 causal connections between the gut microbiome and four recognized inflammatory skin conditions, including 9 positive and 17 negative causal directions. Additional sensitivity analyses of these results revealed no evidence of pleiotropy or heterogeneity. Our MR analysis suggests a causal connection between gut microbiota and skin diseases, potentially providing groundbreaking perspectives for future mechanistic and clinical studies on microbiota-affected skin conditions.
10.3390/microorganisms11102586
Mendelian randomization analyses reveal causal relationships between the human microbiome and longevity.
Scientific reports
Although recent studies have revealed the association between the human microbiome especially gut microbiota and longevity, their causality remains unclear. Here, we assess the causal relationships between the human microbiome (gut and oral microbiota) and longevity, by leveraging bidirectional two-sample Mendelian randomization (MR) analyses based on genome-wide association studies (GWAS) summary statistics of the gut and oral microbiome from the 4D-SZ cohort and longevity from the CLHLS cohort. We found that some disease-protected gut microbiota such as Coriobacteriaceae and Oxalobacter as well as the probiotic Lactobacillus amylovorus were related to increased odds of longevity, whereas the other gut microbiota such as colorectal cancer pathogen Fusobacterium nucleatum, Coprococcus, Streptococcus, Lactobacillus, and Neisseria were negatively associated with longevity. The reverse MR analysis further revealed genetically longevous individuals tended to have higher abundances of Prevotella and Paraprevotella but lower abundances of Bacteroides and Fusobacterium species. Few overlaps of gut microbiota-longevity interactions were identified across different populations. We also identified abundant links between the oral microbiome and longevity. The additional analysis suggested that centenarians genetically had a lower gut microbial diversity, but no difference in oral microbiota. Our findings strongly implicate these bacteria to play a role in human longevity and underscore the relocation of commensal microbes among different body sites that would need to be monitored for long and healthy life.
10.1038/s41598-023-31115-8
Specific gut microbiota may increase the risk of erectile dysfunction: a two-sample Mendelian randomization study.
Frontiers in endocrinology
Objective:Studies have found that gut microbiota may be associated with the development of erectile dysfunction (ED); however, the exact link between the two remains unclear. This study aimed to elucidate the relationship between the gut microbiota and the risk of ED from a genetic perspective. Methods:We investigated the relationship between the gut microflora and ED using two-sample Mendelian randomization. GWAS-pooled data for ED were obtained from 223805 participants in Europe. GWAS summary data for ED were obtained from 223805 subjects in Europe and that for the gut microbiota were obtained from 18340 participants in 24 cohorts. We used the inverse-variance weighted (IVW) estimator as the primary method for the preliminary analysis, and the MR-Egger, weighted median (WM), simple model, and weighted model as secondary methods. We used Cochrane's Q-test, to detect heterogeneity, MREgger to detect pleiotropy, and the leave-one-out method to test the stability of the MR results. Ultimately, we genetically predicted a causal relationship between 211 gut microbiota and ED. Results:A total of 2818 SNPs associated with gut microflora were screened in the ED correlation analysis based on the assumption of instrumental variables. The results of MR analysis showed a causal relationship between the six gut microbes and ED occurrence. The results of the fixed effects IVW method revealed five gut microflora, including Lachnospiraceae (OR, 1.265; P = 0.008), Lachnospiraceae NC2004 group (OR, 1.188; P = 0.019), Oscillibacter (OR, 1.200; P = 0.015), Senegalimassilia (OR, 1.355; P = 0.002), Tyzzerella3 (OR, 1.133; P = 0.022), to be negatively associated with ED. In addition, the IVW method revealed Ruminococcaceae UCG-013 (OR, 0.827; P = 0.049) to be positively associated with ED. Quality control results showed no heterogeneity or horizontal pleiotropy in the MR analysis (P > 0.05). Conclusions:Six gut microbes were genetically associated with ED; of which, Ruminococcaceae UCG-013 was causally associated with a reduced risk of ED development. Our findings provide a new direction for research on the prevention and treatment of ED; however, the mechanisms and details require further investigation.
10.3389/fendo.2023.1216746
Investigating causal relationships between the gut microbiota and allergic diseases: A mendelian randomization study.
Frontiers in genetics
Observational studies revealed altered gut microbial composition in patients with allergic diseases, which illustrated a strong association between the gut microbiome and the risk of allergies. However, whether such associations reflect causality remains to be well-documented. Two-sample mendelian randomization (2SMR) was performed to estimate the potential causal effect between the gut microbiota and the risk of allergic diseases. 3, 12, and 16 SNPs at the species, genus, and family levels respectively of 15 microbiome features were obtained as the genetic instruments of the exposure dataset from a previous study. GWAS summary data of a total of 17 independent studies related to allergic diseases were collected from the IEU GWAS database for the outcome dataset. Significant causal relationships were obtained between gut microbiome features including , , , , and and the risk of allergic diseases. Furthermore, our results also pointed out a number of putative associations between the gut microbiome and allergic diseases. Taken together, this study was the first study using the approach of 2SMR to elucidate the association between gut microbiome and allergic diseases.
10.3389/fgene.2023.1153847
Causal effect between gut microbiota and pancreatic cancer: a two-sample Mendelian randomization study.
BMC cancer
BACKGROUND:Gut microbiota (GM) comprises a vast and diverse community of microorganisms, and recent studies have highlighted the crucial regulatory roles of various GM and their secreted metabolites in pancreatic cancer (PC). However, the causal relationship between GM and PC has yet to be confirmed. METHODS:In the present study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal effect between GM and PC, with genome-wide association study (GWAS) from MiBioGen consortium as an exposure factor and PC GWAS data from FinnGen as an outcome factor. Inverse variance weighted (IVW) was used as the primary method for this study. RESULTS:At the genus level, we observed that Senegalimassilia (OR: 0.635, 95% CI: 0.403-0.998, P = 0.049) exhibited a protective effect against PC, while Odoribacter (OR:1.899, 95%CI:1.157-3.116, P = 0.011), Ruminiclostridium 9(OR:1.976,95%CI:1.128-3.461, P = 0.017), Ruminococcaceae (UCG011)(OR:1.433, 95%CI:1.072-1.916, P = 0.015), and Streptococcus(OR:1.712, 95%CI:1.071-1.736, P = 0.025) were identified as causative factors for PC. Additionally, sensitivity analysis, Cochran's Q test, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger regression indicated no heterogeneity, horizontal pleiotropy, or reverse causality between GM and PC. CONCLUSIONS:Our analysis establishes a causal effect between specific GM and PC, which may provide new insights into the potential pathogenic mechanisms of GM in PC and the assignment of effective therapeutic strategies.
10.1186/s12885-023-11493-y
Investigating the causal impact of gut microbiota on glioblastoma: a bidirectional Mendelian randomization study.
BMC genomics
BACKGROUND:Currently, the influence of microbiota on the occurrence, progression, and treatment of cancer is a topic of considerable research interest. Therefore, based on the theory of the gut-brain axis proved by previous studies, our objective was to uncover the causal relationship between glioblastoma and the gut microbiome using Mendelian randomization analysis. METHODS:We conducted a bidirectional Mendelian randomization study using summary statistics of gut microbiota derived from the MiBioGen consortium, the largest database of gut microbiota. Summary statistics for glioblastoma were obtained from IEU OpenGWAS project, which included 91 cases and 218,701 controls. We assessed the presence of heterogeneity and horizontal pleiotropy in the analyzed data. We primarily employed the inverse variance weighting method to investigate the causal relationship between gut microbiota and glioblastoma after excluding cases of horizontal pleiotropy. Four other analysis methods were employed as supplementary. Excluding abnormal results based on leave-one-out sensitivity analysis. Finally, reverse Mendelian randomization analysis was performed. RESULTS:Four genus-level taxa and one family-level taxa exhibited causal associations with glioblastoma. And these results of reverse Mendelian randomization analysis shown glioblastoma exhibited causal associations with three genus-level taxa and one family-level taxa. However, the Prevotella7(Forward, P=0.006, OR=0.34, 95%CI:0.158-0.732; Reverse, P=0.004, OR=0.972, 95%CI:0.953-0.991) shown the causal associations with glioblastoma in the bidirectional Mendelian randomization. CONCLUSIONS:In this bidirectional Mendelian randomization study, we identified five gut microbiota species with causal associations to glioblastoma. However, additional randomized controlled trials are required to clarify the impact of gut microbiota on glioblastoma and to reveal its precise mechanisms.
10.1186/s12864-023-09885-2
Elucidating the causal association between gut microbiota and intrahepatic cholangiocarcinoma through Mendelian randomization analysis.
Frontiers in microbiology
Background:Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver cancer with poor prognosis. The gut microbiota has been linked to ICC, but evidence for causality is lacking. Elucidating causal gut microbiota-ICC links could inform prevention and treatment strategies. Materials and methods:We performed a bidirectional two-sample Mendelian randomization (MR) study to investigate causal associations between gut microbiota and ICC risk. Genome-wide significant single nucleotide polymorphisms (SNPs) associated with gut microbiota abundances were utilized as instrumental variables (IVs). Multiple methods assessed causality and sensitivity analyses evaluated result robustness. Bioinformatics analysis of genetic loci linked to gut microbiota and ICC examined potential mechanisms. Results:Genetically predicted increases in , , , and were suggestively associated with higher ICC risk, while increases in , , , and appeared protective. Bioinformatics analysis revealed differentially expressed genes near gut microbiota-associated loci may influence ICC through regulating pathways and tumor immune microenvironment. Conclusion:Our findings provide suggestive evidence for causal links between specific gut microbiota and ICC risk.
10.3389/fmicb.2023.1288525
Genetic association and bidirectional Mendelian randomization for causality between gut microbiota and six lung diseases.
Frontiers in medicine
Purposes:Increasing evidence suggests that intestinal microbiota correlates with the pathological processes of many lung diseases. This study aimed to investigate the causality of gut microbiota and lung diseases. Methods:Genetic information on intestinal flora and lung diseases [asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), lower respiratory tract infection (LRTI), pulmonary arterial hypertension (PAH)] and lung function was obtained from UK Biobank, FinnGen, and additional studies. A Mendelian randomization (MR) analysis was conducted to explore the causal association between gut microbiota and lung diseases. Results:The genetic liability to lung diseases may be associated with the abundance of certain microbiota taxa. Specifically, the genus ( = 0.041) was related to a higher risk of asthma; the family Defluviitaleaceae ( = 0.002) and its child taxon were identified as a risk factor for chronic bronchitis; the abundance of the genus ( = 0.020) was related to a higher risk of ILD; the family Coriobacteriaceae ( = 0.011) was identified to have a positive effect on the risk of LRTI; the genus ( = 0.0297) has been identified to be associated with an increased risk of PAH, whereas the genus ( = 0.0154) presented a causal decrease in COPD risk; the order Selenomonadales was identified to have a positive effect on the risk of FEV1( = 0.011). The reverse TSMR analysis also provided genetic evidence of reverse causality from lung diseases to the gut microbiota. Conclusion:This data-driven MR analysis revealed that gut microbiota was causally associated with lung diseases, providing genetic evidence for further mechanistic and clinical studies to understand the crosstalk between gut microbiota and lung diseases.
10.3389/fmed.2023.1279239
Causal relationship between gut microbiota and type 2 diabetes: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Studies showed that development of gut microbial dysbiosis has a close association with type 2 diabetes (T2D). It is not yet clear if there is a causal relationship between gut microbiota and T2D. Methods:The data collected from the published genome-wide association studies (GWASs) on gut microbiota and T2D were analyzed. Two-sample Mendelian randomization (MR) analyses were performed to identify causal relationship between bacterial taxa and T2D. Significant bacterial taxa were further analyzed. To confirm the findings' robustness, we performed sensitivity, heterogeneity, and pleiotropy analyses. A reverse MR analysis was also performed to check for potential reverse causation. Results:By combining the findings of all the MR steps, we identified six causal bacterial taxa, namely, and . The risk of T2D might be positively associated with a high relative abundance of and but negatively associated with and The results of MR analyses revealed that there were causal relationships between the six different genera and T2D. And the reverse MR analysis did not reveal any evidence of a reverse causality. Conclusion:This study implied that and might have anti-protective effect on T2D, whereas , and genera might have protective effect on T2D. Our study revealed that there was a causal relationship between specific gut microbiota genera and T2D.
10.3389/fmicb.2023.1184734
Systematic Mendelian randomization study of the effect of gut microbiome and plasma metabolome on severe COVID-19.
Frontiers in immunology
Background:COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear. Methods:Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships. Results:MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of and with severe COVID-19, respectively. and could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95). Conclusions:Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.
10.3389/fimmu.2023.1211612
The causal relationship between gut microbiota and type 2 diabetes: a two-sample Mendelian randomized study.
Frontiers in public health
Background:Type 2 diabetes mellitus (T2DM) is a commonly observed metabolic anomaly globally, and as of the present time, there's no recognized solution. There is an increasing body of evidence from numerous observational studies indicating a significant correlation between gut flora and metabolic disease progression, particularly in relation to T2DM. Despite this, the direct impact of gut microbiota on T2DM isn't fully understood yet. Methods:The summary statistical figures for intestinal microbiota were sourced from the MiBioGen consortium, while the summary statistical data for T2DM were gathered from the Genome-Wide Association Studies (GWAS) database. These datasets were used to execute a two-sample Mendelian randomization (MR) investigation. The Inverse Variance Weighted (IVW), Maximum Likelihood, MR-Egger, Weighted Median, and Weighted Models strategies were employed to assess the impact of gut microbiota on T2DM. Findings were primarily obtained using the IVW technique. Techniques like MR-Egger were employed to identify the occurrence of horizontal pleiotropy among instrumental variables. Meanwhile, Cochran's Q statistical measures were utilized to assess the variability or heterogeneity within these instrumental variables. Results:The outcomes from the IVW analysis demonstrated that the genus (OR = 0.998, 95% confidence interval: 0.996-1.000, and = 0.038), genus (OR = 0.998, 95% confidence interval: 0.997-0.999, = 0.033), genus (OR = 0.995, 95% confidence interval: 0.993-0.998, = 3.78 × 10), and genus (OR = 0.995, 95% confidence interval: 0.993-0.998, = 8.08 × 10) all acted as defense elements against type 2 diabetes. Family (OR = 1.003, 95% confidence interval: 1.001-1.005, = 0.012), family (OR = 1.0025, 95% confidence interval: 1.000-1.005, = 0.043), genus (OR = 1.003,95% confidence interval: 1.001-1.005, = 4.38 × 10), genus (OR = 1.001,95% confidence interval: 1.000-1.002 = 0.012) were risk factors for type 2 diabetes. False Discovery Rate correction was performed with finding that genus., genus, family and T2DM no longer displayed a significant causal association. In addition, no significant heterogeneity or horizontal pleiotropy was found for instrumental variable. Conclusion:This MR study relies on genetic variation tools to confirm the causal effect of genus , genus , family , genus and genus on T2DM in the gut microbiome, providing new directions and strategies for the treatment and early screening of T2DM, which carries significant clinical relevance. To develop new biomarkers and better understand targeted prevention strategies for T2DM, further comprehensive investigations are required into the protective and detrimental mechanisms exerted by these five genera against T2DM.
10.3389/fpubh.2023.1255059
Large-scale association analyses identify host factors influencing human gut microbiome composition.
Nature genetics
To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
10.1038/s41588-020-00763-1
Mendelian Randomization Analysis Reveals Causal Effects of the Human Gut Microbiota on Abdominal Obesity.
The Journal of nutrition
BACKGROUND:Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined. OBJECTIVES:The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity. METHODS:Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis. RESULTS:Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; β = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; β = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; β = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004). CONCLUSIONS:Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity.
10.1093/jn/nxab025
Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.
Frontiers in immunology
Background:Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. Objective:To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. Materials and Methods:We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. Results:We identified several bacteria from and families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of family might be causal in the development of CeD, while alterations in family might be a consequence of the disease itself. Conclusion:Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.
10.3389/fimmu.2023.1082862
Mendelian randomization analyses support causal relationship between gut microbiota and childhood obesity.
Frontiers in pediatrics
Background:Childhood obesity (CO) is an increasing public health issue. Mounting evidence has shown that gut microbiota (GM) is closely related to CO. However, the causal association needs to be treated with caution due to confounding factors and reverse causation. Methods:Data were obtained from the Microbiome Genome Consortium for GM as well as the Early Growth Genetics Consortium for childhood obesity and childhood body mass index (CBMI). Inverse variance weighted, maximum likelihood, weighted median, and MR.RAPS methods were applied to examine the causal association. Then replication dataset was used to validate the results and reverse Mendelian randomization analysis was performed to confirm the causal direction. Additionally, sensitivity analyses including Cochran's statistics, MR-Egger intercept, MR-PRESSO global test, and the leave-one-out analysis were conducted to detect the potential heterogeneity and horizontal pleiotropy. Results:Our study found suggestive causal relationships between eight bacterial genera and the risk of childhood obesity (five for CO and four for CBMI). After validating the results in the replication dataset, we finally identified three childhood obesity-related GM including the genera , , and . Amongst these, the genus was both negatively associated with the risk of CO (OR = 0.574; 95% CI: 0.417, 0.789) and CBMI ( = -0.172; 95% CI: -0.306, -0.039). Conclusions:In this study, we employed the MR approach to investigate the causal relationship between GM and CO, and discovered that the genus has a protective effect on both childhood obesity and BMI. Our findings may provide a potential strategy for preventing and intervening in CO, while also offering novel insights into the pathogenesis of CO from the perspective of GM.
10.3389/fped.2023.1229236
Complex relationship between gut microbiota and thyroid dysfunction: a bidirectional two-sample Mendelian randomization study.
Frontiers in endocrinology
Background:Many studies have reported the link between gut microbiota and thyroid dysfunction. However, the causal effect of gut microbiota on thyroid dysfunction and the changes in gut microbiota after the onset of thyroid dysfunction are not clear. Methods:A two-sample Mendelian randomization (MR) study was used to explore the complex relationship between gut microbiota and thyroid dysfunction. Data on 211 bacterial taxa were obtained from the MiBioGen consortium, and data on thyroid dysfunction, including hypothyroidism, thyroid-stimulating hormone alteration, thyroxine deficiency, and thyroid peroxidase antibodies positivity, were derived from several databases. Inverse variance weighting (IVW), weighted median, MR-Egger, weighted mode, and simple mode were applied to assess the causal effects of gut microbiota on thyroid dysfunction. Comprehensive sensitivity analyses were followed to validate the robustness of the results. Finally, a reverse MR study was conducted to explore the alteration of gut microbiota after hypothyroidism onset. Results:Our bidirectional two-sample MR study revealed that the genera , , , and were the risk factors for decreased thyroid function, whereas the genera and and phyla Actinobacteria and Verrucomicrobia were protective. The abundance of eight bacterial taxa varied after the onset of hypothyroidism. Sensitivity analysis showed that no heterogeneity or pleiotropy existed in the results of this study. Conclusion:This novel MR study systematically demonstrated the complex relationship between gut microbiota and thyroid dysfunction, which supports the selection of more targeted probiotics to maintain thyroid-gut axis homeostasis and thus to prevent, control, and reverse the development of thyroid dysfunction.
10.3389/fendo.2023.1267383
The causal relationship between gut microbiota and bone mineral density: a Mendelian randomization study.
Frontiers in microbiology
Background:The gut microbiota has emerged as an intriguing and potentially influential factor in regulating bone health. However, the causal effect of the gut microbiota on bone mineral density (BMD) appears to differ throughout various life stages. Methods:We conducted a Mendelian randomization (MR) analysis to investigate the potential causal relationship between gut microbiota and BMD in five distinct age groups: 0-15, 15-30, 30-45, 45-60, and 60 years and older. The analysis employed three different methods, namely MR-Egger, weighted median, and Inverse-variance weighting, to ensure the robustness of our findings, a series of sensitivity analyses were also conducted, such as horizontal pleiotropy tests, heterogeneity tests, and leave-one-out sensitivity tests. Results:In the age group of 0-15 years, _group and _group were identified as risk factors for BMD. During the 15-30 age group, , , and _UCG_003 were found to be protective factors for BMD. In the 30-45 age group, genus demonstrated a protective effect on BMD, while and were identified as risk factors for BMD. Moving on to the 45-60 age group, _group, _UCG_004, and were observed to be protective factors for BMD, while _group, , and were associated with an increased risk of BMD. In individuals aged 60 years and older, and _UCG_002 were also noted as risk factors for BMD. Conversely, _group, _group, , and _3 were found to be protective factors for BMD, whereas and were identified as risk factors for BMD. Conclusion:A robust causal relationship between gut microbiota and bone mineral density (BMD) exists throughout all stages of life, with Firmicutes phylum being the primary group associated with BMD across age groups. Gut microbiota linked with BMD primarily belong to the Firmicutes phylum across age groups. The diversity of gut microbiota phyla associated with BMD depicts relatively stable patterns during the ages of 0-45 years. However, for individuals aged 45 years and above, there is an observed increase in the number of gut microbiota species linked with BMD, and by the age of 60 years, a trend toward an increase in the Bacteroidetes phylum categories is proposed.
10.3389/fmicb.2023.1268935
The association between gut microbiome and PCOS: evidence from meta-analysis and two-sample mendelian randomization.
Frontiers in microbiology
Background:Increasing evidence from observational studies and clinical experimentation has indicated a link between the gut microbiotas (GMs) and polycystic ovary syndrome (PCOS), however, the causality and direction of causality between gut microbiome and PCOS remains to be established. Methods:We conducted a comprehensive search of four databases-PubMed, Cochrane Library, Web of Science, and Embase up until June 1, 2023, and subjected the results to a meta-analysis. In this study, a bidirectional two-sample Mendelian randomization (MR) analysis was employed to investigate the impact of gut microbiota on polycystic ovary syndrome (PCOS). The genome-wide association study (GWAS) data for PCOS comprised 113,238 samples, while the GWAS data for gut microbiota were derived from the MiBioGen consortium, encompassing a total sample size of 18,340 individuals. As the largest dataset of its kind, this study represents the most comprehensive genome-wide meta-analysis concerning gut microbiota composition to date. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables at various taxonomic levels, including Phylum, Class, Order, Family, and Genus. The causal associations between exposures and outcomes were assessed using four established MR methods. To correct for multiple testing, the false discovery rate (FDR) method was applied. The reliability and potential biases of the results were evaluated through sensitivity analysis and F-statistics. Results:The meta-analysis incorporated a total of 20 studies that met the criteria, revealing a close association between PCOS and specific gut microbiota species. As per the results from our MR analysis, we identified six causal associations between the gut microbiome and polycystic ovary syndrome (PCOS). At the genus level, (OR = 1.369, = 0.040), (OR = 1.548, = 0.027), and (OR = 1.488, = 0.028) were identified as risk factors for PCOS. Conversely, (OR = 0.723, = 0.040), (OR = 0.580, = 0.032), and (OR = 0.732, = 0.030) were found to be protective factors against PCOS. Furthermore, the MR-PRESSO global test and MR-Egger regression indicated that our study results were not affected by horizontal pleiotropy ( > 0.05). Finally, the leave-one-out analysis corroborated the robustness of the MR findings. Conclusion:Both our meta-analysis and MR study indicates that there is a causal relationship between the gut microbiome and PCOS, which may contribute to providing novel insights for the development of new preventive and therapeutic strategies for PCOS.
10.3389/fmicb.2023.1203902
A bidirectional Mendelian randomization study investigating the causal role between gut microbiota and insomnia.
Frontiers in neurology
Background:It has emerged that disturbances of the gut microbiota (GM) are linked to insomnia. However, the causality of the observed associations remains uncertain. Methods:We conducted a two-sample Mendelian randomization analysis based on genome-wide association study data to explore the possible causal link between GM and insomnia. The GM data were from the MiBioGen consortium, while the summary statistics of insomnia were obtained from the FinnGen consortium R9 release data. Cochran's Q statistics were used to analyze instrumental variable heterogeneity. Results:According to the inverse variance weighted estimates, the family Ruminococcaceae (odds ratio = 1.494, 95% confidence interval:1.004-2.223, = 0.047) and the genus Lachnospiraceae (odds ratio = 1.726, 95% confidence interval: 1.191-2.501, = 0.004) play a role in insomnia risk. In contrast, the genus Flavonifractor (odds ratio = 0.596, 95% confidence interval: 0.374-0.952, = 0.030) and the genus Olsenella (odds ratio = 0.808, 95% confidence interval: 0.666-0.980, = 0.031) tended to protect against insomnia. According to the reverse MR analysis, insomnia can also alter GM composition. Instrumental variables were neither heterogeneous nor horizontal pleiotropic. Conclusion:In conclusion, our Mendelian randomization study provides evidence of a causal relationship between GM and insomnia. The identified GM may be promising gut biomarkers and new therapeutic targets for insomnia. This investigation also provides a foundation for future studies examining the influence of GM on sleep disorders beyond insomnia, with potential implications for redefining the mechanisms governing sleep regulation.
10.3389/fneur.2023.1277996
Causal Effects of Gut Microbiota on Sleep-Related Phenotypes: A Two-Sample Mendelian Randomization Study.
Clocks & sleep
Increasing evidence suggests a correlation between changes in the composition of gut microbiota and sleep-related phenotypes. However, it remains uncertain whether these associations indicate a causal relationship. The genome-wide association study summary statistics data of gut microbiota ( = 18,340) was downloaded from the MiBioGen consortium and the data of sleep-related phenotypes were derived from the UK Biobank, the Medical Research Council-Integrative Epidemiology Unit, Jones SE, the FinnGen consortium. To test and estimate the causal effect of gut microbiota on sleep traits, a two-sample Mendelian randomization (MR) approach using multiple methods was conducted. A series of sensitive analyses, such as horizontal pleiotropy analysis, heterogeneity test, MR Steiger directionality test and "leave-one-out" analysis as well as reverse MR analysis, were conducted to assess the robustness of MR results. The genus has a negative causal effect on getting up in the morning (odd ratio = 0.977, 95% confidence interval: 0.965-0.988, = 7.28 × 10). A higher abundance of order Enterobacteriales and family Enterobacteriaceae contributed to becoming an "evening person". Six and two taxa were causally associated with longer and shorter sleep duration, respectively. Specifically, two SCFA-produced genera including (odd ratio = 1.029, 95% confidence interval = 1.012-1.046, = 6.11 × 10) and contribute to extending sleep duration. Two obesity-related genera such as (odd ratio = 1.024, 95% confidence interval: 1.011-1.036, = 1.74 × 10) and were found to be increased and decreased risk of snoring, respectively. In addition, we found two risk taxa of insomnia such as the order Selenomonadales and one of its classes called Negativicutes. All of the sensitive analysis and reverse MR analysis results indicated that our MR results were robust. Our study revealed the causal effect of gut microbiota on sleep and identified causal risk and protective taxa for chronotype, sleep duration, snoring and insomnia, which has the potential to provide new perspectives for future mechanistic and clinical investigations of microbiota-mediated sleep abnormal patterns and provide clues for developing potential microbiota-based intervention strategies for sleep-related conditions.
10.3390/clockssleep5030037
Causal effects of gut microbiota on scoliosis: A bidirectional two-sample mendelian randomization study.
Heliyon
Background:Recent studies have shown altered gut microbiome composition in patients with scoliosis. However, the causal effect of gut microbiota on scoliosis remains unknown. Methods:A Mendelian randomization (MR) study was conducted to quantify the impact of 191 gut microbiome taxa's instrumental variables from the MibioGen Genome-wide association study (GWAS) on scoliosis risk using data from the FinnGen GWAS (1168 cases and 16,4682 controls). Inverse variance weighted (IVW) was the main method, and MR results were verified by sensitive analysis. Results: (eligens group), 9, and 2 were discovered to have a protective effect on the risk of scoliosis. UCG009, , 2, (ventriosum group), (FCS020 group), 6, and RF9 may increase the occurrence of scoliosis. Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analysis confirmed the robustness of the MR results. Conclusion:Our study identified four protective bacteria taxa on scoliosis and seven microbiota that may increase scoliosis occurrence. Further MR analysis is required to corroborate our findings, using a more sophisticated technique to obtain estimates with less bias and greater precision or GWAS summary data with more gut microbiome and scoliosis patients.
10.1016/j.heliyon.2023.e21654
Causal relationships between gut metabolites and Alzheimer's disease: a bidirectional Mendelian randomization study.
Zhuang Zhenhuang,Gao Meng,Yang Ruotong,Liu Zhonghua,Cao Weihua,Huang Tao
Neurobiology of aging
Observational studies have shown that gut microbiota-dependent metabolites are associated with the risk of Alzheimer's disease (AD). However, whether such association reflects a causality remains unclear. We conducted a bidirectional Mendelian randomization analysis to examine the causal relationships between gut microbiota-dependent metabolites trimethylamine N-oxide (TMAO) or its predecessors and AD. We observed that genetically predicted TMAO (odds ratio: 0.99, 95% confidence interval: 0.89 to 1.09 per 10 units, p = 0.775) or its predecessors including betaine (1.06, 1.00 to 1.12 per 10 units, p = 0.056), carnitine (1.05, 0.98 to 1.12 per 10 units, p = 0.178), and choline (1.01, 0.92 to 1.10 per 10 units, p = 0.905) were not associated with the risk of AD. Our Mendelian randomization estimates from AD to metabolites showed that genetically predicted higher risk of AD was also not causally associated with TMAO, betaine, carnitine, and choline levels. Our findings support that gut microbiota-dependent metabolites TMAO or its predecessors do not play causal roles in the development of AD.
10.1016/j.neurobiolaging.2020.10.022
Gut microbiota and cognitive performance: A bidirectional two-sample Mendelian randomization.
Journal of affective disorders
PURPOSE:Previous studies have suggested a potential association between gut microbiota and neurological and psychiatric disorders. However, the causal relationship between gut microbiota and cognitive performance remains uncertain. METHODS:A two-sample Mendelian randomization (MR) study used SNPs linked to gut microbiota (n = 18,340) and cognitive performance (n = 257,841) from recent GWAS data. Inverse-variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode were employed. Heterogeneity was assessed via Cochran's Q test for IVW. Results were shown with funnel plots. Outliers were detected through leave-one-out method. MR-PRESSO and MR-Egger intercept tests were conducted to address horizontal pleiotropy influence. LIMITATIONS:Limited to European populations, generic level, and potential confounding factors. RESULTS:IVW analysis revealed detrimental effects on cognitive perfmance associated with the presence of genus Blautia (P = 0.013, 0.966[0.940-0.993]), Catenibacterium (P = 0.035, 0.977[0.956-0.998]), Oxalobacter (P = 0.043, 0.979[0.960-0.999]). Roseburia (P < 0.001, 0.935[0.906-0.965]), in particular, remained strongly negatively associated with cognitive performance after Bonferroni correction. Conversely, families including Bacteroidaceae (P = 0.043, 1.040[1.001-1.081]), Rikenellaceae (P = 0.047, 1.026[1.000-1.053]), along with genera including Paraprevotella (P = 0.044, 1.020[1.001-1.039]), Ruminococcus torques group (P = 0.016, 1.062[1.011-1.115]), Bacteroides (P = 0.043, 1.040[1.001-1.081]), Dialister (P = 0.027, 1.039[1.004-1.074]), Paraprevotella (P = 0.044, 1.020[1.001-1.039]) and Ruminococcaceae UCG003 (P = 0.007, 1.040[1.011-1.070]) had a protective effect on cognitive performance. CONCLUSIONS:Our results suggest that interventions targeting specific gut microbiota may offer a promising avenue for improving cognitive function in diseased populations. The practical application of these findings has the potential to enhance cognitive performance, thereby improving overall quality of life.
10.1016/j.jad.2024.02.083
Two-sample Mendelian randomization analysis investigates causal associations between gut microbiota and attention deficit hyperactivity disorder.
Frontiers in microbiology
Previous research has suggested a link between gut microbiota and attention deficit hyperactivity disorder (ADHD), but their causal relationship has not been elucidated. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for ADHD, we conducted a two-sample Mendelian randomization (MR) analysis. Instrumental variables of 211 gut microbiota taxa were obtained from gene wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on ADHD risk from PGC GWAS (20,183 ADHD cases and 35,191 controls) and FinnGen GWAS (830 ADHD cases and 215,763 controls). Wald ratio (WR), inverse variance weighted (IVW), MR-Egger, and weighted median were the main methods to analyze causality, and MR results are verified by several sensitivity analysis analyses. At locus-wide significance level ( < 1 × 10), IVW results confirmed that genus ( = 0.013) and genus ( = 0.049) were correlated with the risk of ADHD and genus ( = 0.009), genus ( = 0.009), genus ( = 0.015), genus ( = 0.026), genus ( = 0.028) and family ( = 0.048) were protective factors of ADHD. Weighted median results indicated that genus ( = 0.018) was negatively correlated with the risk of ADHD. At genome-wide statistical significance level ( < 5 × 10), Wald ratio results demonstrated that genus ( = 0.003) was a risk factor for ADHD, while genus ( = 0.006) and family ( = 0.006) had a negative correlation with the risk of ADHD. In reverse MR analysis, IVW results showed that ADHD may lead to an increase in the abundance of genus ( = 0.020). Analysis of heterogeneity ( > 0.05) and pleiotropy ( > 0.05) confirmed the robustness of MR results. We demonstrated that there was a potential causal relationship between gut microbiota and ADHD. Our research provides a foundation for understanding the causal relationship between gut microbiota and ADHD, and the several gut bacteria found in this study that may reduce the occurrence of ADHD may have potential in the prevention and treatment of ADHD.
10.3389/fmicb.2023.1144851
Causal relationship between gut microbiota and urticaria: a bidirectional two-sample mendelian randomization study.
Frontiers in microbiology
Background:Cumulative evidence showed an association between gut microbiota and urticaria, but the causal relationship between them is unclear. We aimed to verify whether there is a causal relationship between the composition of gut microbiota and urticaria and explore whether the causal effect was bidirectional. Methods:We obtained genome-wide association studies (GWAS) summary data of 211 gut microbiota and urticaria from the most extensive available GWAS database. A bidirectional two-sample mendelian randomization (MR) study was used to test the causal relationship between the gut microbiota and urticaria. The MR analysis was primarily performed with the inverse variance weighted (IVW) method, and MR-Egger, weighted median (WM), and MR-PRESSO were performed as sensitivity analyses. Results:The Phylum Verrucomicrobia (OR 1.27, 95%CI 1.01 to 1.61; = 0.04), Genus Defluviitaleaceae UCG011 (OR 1.29, 95%CI 1.04 to 1.59; = 0.02), and Genus Coprococcus 3 (OR 1.44, 95%CI 1.02 to 2.05; = 0.04) was a risk effect against urticaria. And Order Burkholderiales (OR 0.68, 95%CI 0.49 to 0.99; = 0.04) and Genus group (OR 0.78, 95%CI 0.62 to 0.99; = 0.04) were negatively associated with urticaria, suggesting a protective effect. At the same time, urticaria had a positively causal effect on gut microbiota (Genus group) (OR 1.08, 95%CI 1.01 to 1.16; = 0.02). These findings showed no influence by heterogeneity or horizontal pleiotropy. Moreover, most sensitivity analyses showed results consistent with those of IVW analysis. Conclusion:Our MR study confirmed the potential causal relationship between gut microbiota and urticaria, and the causal effect was bidirectional. Nevertheless, these findings warrant further examination owing to the unclear mechanisms.
10.3389/fmicb.2023.1189484
Causal effects of gut microbiota on erectile dysfunction: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Several observational studies have reported the correlation between gut microbiota and the risk of erectile dysfunction (ED). However, the causal association between them remained unestablished owing to intrinsic limitations, confounding factors, and reverse causality. Therefore, the two-sample Mendelian randomization (MR) study was performed to determine the causal effect of gut microbiota on the risk of ED. Methods:The MR analysis utilized the publicly available genome-wide association study (GWAS) summary-level data to explore the causal associations between gut microbiota and ED. The gut microbiota data were extracted from the MiBioGen study ( = 18,340), and the ED data were extracted from the IEU Open GWAS (6,175 ED cases and 217,630 controls). The single nucleotide polymorphisms (SNPs) served as instrumental variables (IVs) by two thresholds of -values, the first -value setting as <1e-05 (locus-wide significance level) and the second -value setting as <5e-08 (genome-wide significance level). The inverse variance weighted approach was used as the primary approach for MR analysis, supplemented with the other methods. In addition, sensitivity analyses were performed to evaluate the robustness of the MR results, including Cochran's Q test for heterogeneity, the MR-Egger intercept test for horizontal pleiotropy, the Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) global test for outliers, and the forest test and leave-one-out test for strong influence SNPs. Results:Our results presented that the increased abundance of at family level (OR: 1.265, 95% CI: 1.054-1.519), (OR: 1.320, 95% CI: 1.064-1.638), group (OR: 1.197, 95% CI: 1.018-1.407), (OR: 1.138, 95% CI: 1.017-1.273), and (OR: 1.201, 95% CI: 1.035-1.393) at genus level may be risk factors for ED, while the increased abundance of (OR: 0.770, 95% CI: 0.615-0.965) at genus level may have a protective effect on ED. No heterogeneity or pleiotropy was found based on the previously described set of sensitivity analyses. Conclusion:Our MR analysis demonstrated that the gut microbiota had inducing and protective effects on the risk of ED. The results provide clinicians with novel insights into the treatment and prevention of ED in the future. Furthermore, our study also displays novel insights into the pathogenesis of microbiota-mediated ED.
10.3389/fmicb.2023.1257114
The causal relationship between gut microbiota and leukemia: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:The association between gut microbiota and leukemia has been established, but the causal relationship between the two remains unclear. Methods:A bidirectional two-sample Mendelian randomization (MR) was used to analyze the causal relationship between gut microbiota and leukemia. Microbiome data ( = 14,306) and leukemia ( = 1,145) data were both sourced from European populations. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on several criteria. We employed various MR methods, such as the inverse variance weighted (IVW) method, to evaluate the causal effect between exposure and outcomes and conducted sensitivity analyses to validate the heterogeneity and pleiotropy of the instrumental variables. Results:5,742 qualified instrumental variables were included. In the primary MR results, a total of 10 gut microbial taxa were associated with leukemia risk. Genus Blautia and genus Lactococcus are risk factors for acute lymphoblastic leukemia [genus Blautia odds ratio (OR): 1.643, 95% confidence interval (CI): 1.592 ~ 1.695, Adjusted < 0.001; genus Lactococcus OR: 2.152, 95% CI: 1.447 ~ 3.199, Adjusted = 0.011]. Genus Rikenellaceae RC9 gut group, genus Anaerostipes, genus Slackia, and genus Lachnospiraceae ND3007 group are risk factors for acute myeloid leukemia [genus Rikenellaceae RC9 gut group OR: 1.964, 95% CI: 1.573 ~ 2.453, Adjusted < 0.001; genus Anaerostipes OR: 2.515, 95% CI: 1.503 ~ 4.209, Adjusted = 0.017; genus Slackia OR: 2.553, 95% CI: 1.481 ~ 4.401, Adjusted = 0.022; genus Lachnospiraceae ND3007 group OR: 3.417, 95% CI: 1.960 ~ 5.959, Adjusted = 0.001]. Genus Ruminococcaceae UCG011 and genus Ruminococcaceae UCG014 were risk factors for chronic myeloid leukemia (genus Ruminococcaceae UCG011 OR: 2.010, 95% CI: 1.363 ~ 2.963, Adjusted = 0.044; genus Ruminococcaceae UCG014 OR: 3.101, 95% CI: 1.626 ~ 5.915, Adjusted = 0.044). Genus Slackia was a protective factor for acute lymphoblastic leukemia (genus Slackia OR: 0.166, 95% CI: 0.062 ~ 0.443, Adjusted = 0.017). Family Acidaminococcaceae was a protective factor for acute myeloid leukemia (family Acidaminococcaceae OR: 0.208, 95% CI: 0.120 ~ 0.361, Adjusted 0.001). Genus Desulfovibrio was a protective factor for chronic lymphoblastic leukemia (genus Desulfovibrio OR: 0.581, 95% CI: 0.440 ~ 0.768, Adjusted = 0.020). Sensitivity analysis revealed no heterogeneity or pleiotropy between SNPs. Conclusion:This study revealed the causal relationship between the gut microbiota and leukemia, and identified potential pathogenic bacteria and probiotic taxa associated with the onset of leukemia. This research may aid in the early detection of various types of leukemia and offer a new direction for the prevention and treatment of leukemia.
10.3389/fmicb.2023.1293333
A two-sample mendelian randomization analysis investigates associations between gut microbiota and infertility.
Scientific reports
Observational studies have provided evidence of a correlation between alterations in gut microbiota composition and infertility. However, concrete proof supporting the causal relationship is still lacking. We performed a Mendelian randomization study to assess whether genetically gut microbiota composition influences the risk of infertility. The genetic data pertaining to gut microbiota were obtained from a genome-wide association study meta-analysis, which was conducted among 24 cohorts (18,340 participants) from the international MiBioGen consortium. By the primary method of assessing causality, we have identified 2 family taxa, 2 genus taxa, and 1 order taxa that were linked to a low risk of male infertility, while 1 genus taxa were associated with a high risk of male infertility. Furthermore, we have discovered 6 genus taxa, 1 phylum taxa, 1 class taxa, 1 order taxa, and 1 family taxa that were associated with a low risk of female infertility, while 1 genus taxa were linked to a high risk of female infertility. This study successfully confirmed that there was a causal link between gut microbiota and infertility. The identification of these specific strains through genetic prediction offers a valuable insight for early diagnosis, prevention, and treatment of infertility.
10.1038/s41598-023-38624-6
Causal effect of gut microbiota on Gastroduodenal ulcer: a two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Gastroduodenal ulcers are associated with infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs). However, the causal relationship between gastroduodenal ulcers and gut microbiota, especially specific gut microbiota, remains unclear. Methods:We conducted an analysis of published data on the gut microbiota and Gastroduodenal ulcer using genome-wide association studies (GWAS). Two-sample Mendelian randomization (MR) analysis was performed to determine the causal relationship between gut microbiota and Gastroduodenal ulcer. Sensitivity, heterogeneity, and pleiotropy analyses were conducted to confirm the accuracy of the research findings. Results:Our study showed that the abundance of , , , , , and was negatively correlated with the risk of Gastroduodenal ulcer. Conversely, the abundance of , , , , , , and was positively correlated with the risk of Gastroduodenal ulcer. MR analysis revealed causal relationships between 13 bacterial genera and Gastroduodenal ulcer. Conclusion:This study represents a groundbreaking endeavor by furnishing preliminary evidence regarding the potentially advantageous or detrimental causal link between the gut microbiota and Gastroduodenal ulcer, employing Mendelian Randomization (MR) analysis for the first time. These discoveries have the potential to yield fresh perspectives on the prevention and therapeutic approaches concerning Gastroduodenal ulcer, with a specific focus on the modulation of the gut microbiota.
10.3389/fcimb.2023.1322537
Causal relationship between gut microbiota and myasthenia gravis: a bidirectional mendelian randomization study.
Cell & bioscience
BACKGROUND:Observational studies have demonstrated an association between gut microbiota and myasthenia gravis; however, the causal relationship between the two still lacks clarity. Our goals are to ascertain the existence of a bidirectional causal relationship between gut microbiota composition and myasthenia gravis, and to investigate how gut microbiota plays a role in reducing the risk of myasthenia gravis. METHODS:We acquired gut microbiota data at the phylum, class, order, family, and genus levels from the MiBioGen consortium (N = 18,340) and myasthenia gravis data from the FinnGen Research Project (426 cases and 373,848 controls). In the two-sample Mendelian randomization analysis, we assessed the causal relationship between the gut microbiota and myasthenia gravis. We also conducted bidirectional MR analysis to determine the direction of causality. The inverse variance weighted, mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to test the causal relationship between the gut microbiota and severe myasthenia gravis. We used MR-Egger intercept and Cochran's Q test to assess for pleiotropy and heterogeneity, respectively. Furthermore, we utilized the MR-PRESSO method to evaluate horizontal pleiotropy and detect outliers. RESULTS:In the forward analysis, the inverse-variance weighted method revealed that there is a positive correlation between the genus Lachnoclostridium (OR = 2.431,95%CI 1.047-5.647, p = 0.039) and the risk of myasthenia gravis. Additionally, the family Clostridiaceae1 (OR = 0.424,95%CI 0.202-0.889, p = 0.023), family Defluviitaleaceae (OR = 0.537,95%CI 0.290-0.995, p = 0.048), family Enterobacteriaceae (OR = 0.341,95%CI 0.135-0.865, p = 0.023), and an unknown genus (OR = 0.407,95%CI 0.209-0.793, p = 0.008) all demonstrated negative correlation with the risk of developing myasthenia gravis. Futhermore, reversed Mendelian randomization analysis proved a negative correlation between the risk of myasthenia gravis and genus Barnesiella (OR = 0.945,95%CI 0.906-0.985, p = 0.008). CONCLUSION:Our research yielded evidence of a causality connection in both directions between gut microbiota and myasthenia gravis. We identified specific types of microbes associated with myasthenia gravis, which offers a fresh window into the pathogenesis of this disease and the possibility of developing treatment strategies. Nonetheless, more studies, both basic and clinical, are necessary to elucidate the precise role and therapeutic potential of the gut microbiota in the pathogenesis of myasthenia gravis.
10.1186/s13578-023-01163-8
The causality between intestinal flora and allergic diseases: Insights from a bi-directional two-sample Mendelian randomization analysis.
Frontiers in immunology
Background:Growing evidence shows a significant association between intestinal flora and allergic diseases, specifically atopic dermatitis (AD), allergic rhinitis (AR), and allergic asthma (AA). However, the causality has not yet been clarified. Objective:We conducted a bidirectional two-sample Mendelian randomization (TSMR) analysis to study the causal relationships between intestinal flora classification and AD, AR, or AA. Materials and methods:We obtained summary data of intestinal flora, AD, AR, and AA from a genome-wide association research. The inverse-variance weighted method is the primary method for analyzing causality in the TSMR analysis. Several sensitivity analyses were conducted to examine the stability of TSMR results. Reverse TSMR analysis was also performed to assess whether there was a reverse causality. Results:A total of 7 bacterial taxa associated with AD, AR, and AA were identified by the current TSMR analysis. Specifically, the genus Dialister(=0.034)and genus Prevotella(=0.047)were associated with a higher risk of AD, whereas class Coriobacteriia (=0.034) and its child taxon, order Coriobacteriales (=0.034) and family Coriobacteriaceae (=0.034), all had a protective effect on AR. In addition, the family Victivallaceae (=0.019) was identified as a risk factor for AR. We also noticed a positive association between the genus Holdemanella (=0.046) and AA. The reverse TSMR analysis didn't suggest any evidence of reverse causality from allergic diseases to the intestinal flora. Conclusion:We confirmed the causal relationship between intestinal flora and allergic diseases and provided an innovative perspective for research on allergic diseases: targeted regulation of dysregulation of specific bacterial taxa to prevent and treat AD, AR, and AA.
10.3389/fimmu.2023.1121273
Causal association between gut microbiota and intrahepatic cholestasis of pregnancy: mendelian randomization study.
BMC pregnancy and childbirth
BACKGROUND:Previous observational cohort studies have shown that the composition of the gut microbiota is related to the risk of intrahepatic cholestasis of pregnancy (ICP), although it is unclear if the association is causative. This study used Mendelian randomization (MR) to systematically examine whether the gut microbiota was causally linked to ICP. METHODS:We obtained the genome-wide association study (GWAS) summary statistics of gut microbiota and ICP from published GWASs. Maximum likelihood (ML), MR-Egger regression, weighted median, inverse variance weighted (IVW), and weighted model were used to investigate the causal association between gut microbiota and ICP. We further conducted a series of sensitivity analyses to confirm the robustness of the primary results of the MR analyses. Reverse MR analysis was performed on the bacterial taxa that were reported to be causally linked to ICP risk in forwarding MR analysis to evaluate the possibility of reverse causation. RESULTS:MR analysis revealed that phylum Tenericutes (OR: 1.670, 95%CI: 1.073-2.598, P = 0.023), class Bacteroidia (OR: 1.644, 95%CI: 1.031-2.622, P = 0.037), class Mollicutes (OR: 1.670, 95%CI: 1.073-2.598, P = 0.023), and order Bacteroidales (OR: 1.644, 95%CI: 1.031-2.622, P = 0.037), and were positively associated with the risk of ICP. And we identified that the relative abundance of genus Dialister (OR: 0.562, 95%CI: 0.323-0.977, P = 0.041), genus Erysipelatoclostridium (OR: 0.695, 95%CI: 0.490-0.987, P = 0.042), genus Eubacterium (brachy group) (OR: 0.661, 95%CI: 0.497-0.880, P = 0.005), genus Eubacterium (hallii group) (OR: 0.664, 95%CI: 0.451-0.977, P = 0.037), genus Holdemania (OR: 0.590, 95%CI: 0.414-0.840, P = 0.003), genus Ruminococcus (torques group) (OR: 0.448, 95%CI: 0.235-0.854, P = 0.015), and genus Veillonella (OR: 0.513, 95%CI: 0.294-0.893, P = 0.018) were related to a lower risk of ICP. Additional sensitivity analyses confirmed the robustness of the association between specific gut microbiota composition and ICP. No evidence of reverse causality from ICP to identified bacterial taxa was found in the findings of the reverse MR analyses. CONCLUSIONS:Under MR assumptions, our findings propose new evidence of the relationship between gut microbiota and ICP risk. Our results show that the gut microbiota may be useful target of intervention for ICP.
10.1186/s12884-023-05889-8
The gut microbiome and hypertension.
Nature reviews. Nephrology
A large body of evidence has emerged in the past decade supporting a role for the gut microbiome in the regulation of blood pressure. The field has moved from association to causation in the last 5 years, with studies that have used germ-free animals, antibiotic treatments and direct supplementation with microbial metabolites. The gut microbiome can regulate blood pressure through several mechanisms, including through gut dysbiosis-induced changes in microbiome-associated gene pathways in the host. Microbiota-derived metabolites are either beneficial (for example, short-chain fatty acids and indole-3-lactic acid) or detrimental (for example, trimethylamine N-oxide), and can activate several downstream signalling pathways via G protein-coupled receptors or through direct immune cell activation. Moreover, dysbiosis-associated breakdown of the gut epithelial barrier can elicit systemic inflammation and disrupt intestinal mechanotransduction. These alterations activate mechanisms that are traditionally associated with blood pressure regulation, such as the renin-angiotensin-aldosterone system, the autonomic nervous system, and the immune system. Several methodological and technological challenges remain in gut microbiome research, and the solutions involve minimizing confounding factors, establishing causality and acting globally to improve sample diversity. New clinical trials, precision microbiome medicine and computational methods such as Mendelian randomization have the potential to enable leveraging of the microbiome for translational applications to lower blood pressure.
10.1038/s41581-022-00654-0
Gut microbiome and reproductive endocrine diseases: a Mendelian randomization study.
Frontiers in endocrinology
Background:Observation studies have confirmed the association between the gut microbiome and reproductive endocrine diseases (REDs), namely, polycystic ovary syndrome (PCOS), endometriosis, and female infertility. However, their association has never been confirmed by a two-sample Mendelian randomization (MR) analysis. Methods:We conducted a two-sample MR analysis to evaluate the relationship between the gut microbiome and the three aforementioned REDs. In order to get more comprehensive results, two different thresholds were adopted to select instrumental variables (IVs): one was a locus-wide significance threshold (1.0×10) and the other was a genome-wide significance level (< 5×10). Summary-level statistics for the gut microbiome and REDs were collected from public databases. Inverse-variance weighted (IVW) was the main method used to estimate causality, and sensitivity analyses were conducted to validate the MR results. Results:At the locus-wide significance level, we identified that the genera Streptococcus (OR=1.52, 95%CI: 1.13-2.06, =0.006) and RuminococcaceaeUCG005 (OR=1.39, 95%CI: 1.04-1.86, =0.028) were associated with a high risk of PCOS, while Sellimonas (OR= 0.69, 95%CI: 0.58-0.83, =0.0001) and RuminococcaceaeUCG011(OR=0.76, 95%CI: 0.60-0.95, =0.017) were linked to a low PCOS risk. The genus Coprococcus2 (OR=1.20, 95%CI: 1.01-1.43, =0.039) was correlated with an increased risk of female infertility, while Ruminococcus torques (OR=0.69, 95%CI: 0.54-0.88, =0.002) were negatively associated with the risk of female infertility. The genera Olsenella (OR= 1.11, 95%CI: 1.01-1.22, =0.036), Anaerotruncus (OR= 1.25, 95%CI: 1.03-1.53, =0.025), and Oscillospira (OR= 1.21, 95%CI: 1.01-1.46, =0.035) were linked to a high risk of endometriosis. However, the results showed that the gut microbiome did not possess a causal link with REDs risk based on the genome-wide significance level. Sensitivity analyses further confirmed the robustness of the MR results. Conclusion:Our study provides evidence that gut microbiome is closely related with REDs. Subsequent studies should be conducted to promote microbiome-orientated therapeutic strategies for managing REDs.
10.3389/fendo.2023.1164186
Roles of gut microbiome in epilepsy risk: A Mendelian randomization study.
Frontiers in microbiology
Background:Recent studies have suggested an association between gut microbiomes (GMs) and epilepsy. However, the GM taxa identified in different studies are variable. In addition, observational studies cannot indicate causality. Therefore, our study aimed to explore the causal association of GMs with epilepsy and identify the most influential GM taxa. Methods:We conducted a Mendelian randomization (MR) study using summary statistics from genome-wide association studies (GWAS) of 211 GM taxa and epilepsy. The GWAS summary statistics for 211 GM taxa (from phylum to genus level) were generated by the MiBioGen consortium, while the FinnGen consortium provided the GWAS summary statistics for epilepsy. The primary analytical method to assess causality was the inverse-variance weighted (IVW) approach. To complement the IVW method, we also applied four additional MR methods: MR-Egger, weighted median, simple mode, and weighted. In addition, we conducted sensitivity analyses using Cochrane's -test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results:We evaluated the causal effect of 211 GM taxa (from phylum to genus level) on epilepsy, generalized epilepsy, and focal epilepsy. After using the Bonferroni method for multiple testing correction, [odds ratio (OR) = 1.357, 95% confidence interval (CI): 1.126-1.635, = 0.001] and (OR = 1.336, 95% CI: 1.112-1.606, = 0.002). In addition, 21 nominally significant causal relationships were also identified. Further, the MR-Egger intercept test and MR-PRESSO global test suggested that our MR analysis was unaffected by horizontal pleiotropy ( > 0.05). Finally, the leave-one-out analysis suggested the robustness of the results. Conclusion:Through the MR study, we analyzed the causal relationship of 211 GM taxa with epilepsy and determined the specific intestinal flora associated with increased epilepsy risk. Our findings may provide helpful biomarkers for disease progression and potential candidate therapeutic targets for epilepsy. In addition, in-depth analysis of large-scale microbiome GWAS datasets based on metagenomics sequencing is necessary for future studies.
10.3389/fmicb.2023.1115014
Causal relationship in gut microbiota and upper urinary urolithiasis using Mendelian randomization.
Frontiers in microbiology
Background:Several reports in recent years have found an association between gut microbiota and upper urinary urolithiasis. However, the causal relationship between them remains to be clarified. Methods:Genetic variation is used as a tool in Mendelian randomization for inference of whether exposure factors have a causal effect on disease outcomes. We selected summary statistics from a large genome-wide association study of the gut microbiome published by the MiBioGen consortium with a sample size of 18,340 as an exposure factor and upper urinary urolithiasis data from FinnGen GWAS with 4,969 calculi cases and 213,445 controls as a disease outcome. Then, a two-sample Mendelian randomization analysis was performed by applying inverse variance-weighted, MR-Egger, maximum likelihood, and weighted median. In addition, heterogeneity and horizontal pleiotropy were excluded by sensitivity analysis. Results:IVW results confirmed that class (OR = 0.814, 95% CI: 0.666-0.995, = 0.045), order (OR = 0.833, 95% CI: 0.737-0.940, = 3.15 × 10), family (OR = 0.729, 95% CI: 0.581-0.916, = 6.61 × 10), genus (OR = 0.695, 95% CI: 0.551-0.877, = 2.20 × 10), genus (OR = 0.777, 95% CI: 0.612-0.986, = 0.0380), genus (OR = 0.711, 95% CI: 0.536-0.944, = 0.0181), genus (OR = 0.829, 95% CI: 0.690-0.995, = 0.0444), and genus (OR = 0.758, 95% CI: 0.577-0.996, = 0.0464) had a protective effect on upper urinary urolithiasis, while (OR =1.26, 95% CI: 1.010-1.566, = 0.0423) had the opposite effect. Sensitivity analysis did not find outlier SNPs. Conclusion:In summary, a causal relationship was found between several genera and upper urinary urolithiasis. However, we still need further randomized controlled trials to validate.
10.3389/fmicb.2023.1170793
Association between gut microbiota and NAFLD/NASH: a bidirectional two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Recent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links. Methods:Summary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations. Results:Our analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales ( =0.04), ( =0.04), ( =0.02), and ( =0.04) and increased risk of NAFLD. ( =0.03) and ( =0.04) could increase the risks of NASH while ( =0.04) and (=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in ( =0.007) and ( =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH. Conclusion:This study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.
10.3389/fcimb.2023.1294826
Association between gut microbiota and endometriosis: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Recent studies have shown that an imbalance in gut microbiota (GM) may not always be associated with endometriosis (EMS). To investigate this further, we conducted a two-sample Mendelian randomization study. Methods:MR analysis was performed on genome-wide association study (GWAS) summary statistics of GM and EMS. Specifically, the MiBioGen microbiota GWAS ( = 18,340) was used as exposure. The FinnGen study GWAS (8,288 EMS cases and 68,969 controls) was used as outcome. We primarily used the inverse variance weighted (IVW) method to analyze the correlation and conducted a sensitivity analysis to verify its reliability. Results:(1) MR analysis: The results of the IVW method confirmed that a total of 8 GM taxa were related to the risk of EMS. Class- ( = 0.036), family- ( = 0.037), and genus- ( = 0.015) had a protective effect on EMS, whereas order ( = 0.046), family ( = 0.027), genus ( = 0.025), genus ( = 0.036) and genus- ( = 0.035) could increase the risk of EMS. (2) Sensitivity analysis: Cochrane's Q test ( > 0.05), MR-Egger intercept method ( > 0.05), and leave-one-out method confirmed the robustness of MR results. Conclusion:This study performed a MR analysis on two large national databases and identified the association between 8 GM taxa and EMS. These taxa could potentially be utilized for indirectly diagnosing EMS and could lead to novel perspectives in research regarding the pathogenesis, diagnosis, and treatment of EMS.
10.3389/fmicb.2023.1188458
Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort.
Nature genetics
Human genetic variation affects the gut microbiota through a complex combination of environmental and host factors. Here we characterize genetic variations associated with microbial abundances in a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial metagenomes, and dietary and health records (prevalent and follow-up). We identified 567 independent SNP-taxon associations. Variants at the LCT locus associated with Bifidobacterium and other taxa, but they differed according to dairy intake. Furthermore, levels of Faecalicatena lactaris associated with ABO, and suggested preferential utilization of secreted blood antigens as energy source in the gut. Enterococcus faecalis levels associated with variants in the MED13L locus, which has been linked to colorectal cancer. Mendelian randomization analysis indicated a potential causal effect of Morganella on major depressive disorder, consistent with observational incident disease analysis. Overall, we identify and characterize the intricate nature of host-microbiota interactions and their association with disease.
10.1038/s41588-021-00991-z
Association between gut microbiota and influenza: a bidirectional two-sample mendelian randomization study.
BMC infectious diseases
BACKGROUND:Previous observational studies have indicated a correlation between the gut microbiota and influenza; however, the exact nature of the bidirectional causal connection remains uncertain. METHOD:A two-way, two-sample Mendelian randomization (MR) study was conducted to evaluate the possible causal connection between the gut microbiota and the two outcomes of influenza (pneumonia without influenza and influenza pneumonia). The statistical analysis of gut microbiota is derived from the information of the most extensive meta-analysis (GWAS) conducted by the MiBioGen Alliance, encompassing a sample size of 18,340.The summary statistical data for influenza (not pneumonia, n = 291,090) and influenza pneumonia (n = 342,499) are from GWAS data published by FinnGen consortium R8.Estimate and summarize Single-nucleotide polymorphisms (SNPs) using Inverse variance weighted (IVW), MR Egger, and Weighted median (WM) in bidirectional MR analysis. To assess the heterogeneity, horizontal pleiotropy, and stability of SNPs, we employed Cochran's Q test, MR Egger intercept test, and sensitivity analysis. RESULT:The IVW analysis indicated that there was a significant association between influenza infection and five bacterial taxa. Additionally, the abundance changes of seven gut microbiota were found to be causally related to influenza infection. In addition, seven bacterial taxa showed a significant association with the occurrence of influenza pneumonia. The findings from the WM analysis largely support the outcomes of IVW, however, the results of MR egger analysis do not align with IVW. Furthermore, there is no proof to substantiate the cause-and-effect relationship between influenza pneumonia and the composition of gut microbiota. CONCLUSION:This analysis demonstrates a possible bidirectional causal connection between the prevalence of particular gut microbiota and the occurrence of influenza infection. The presence of certain gut microbiota may potentially contribute to the development of pneumonia caused by influenza. Additional investigation into the interaction between particular bacterial communities and influenza can enhance efforts in preventing, monitoring, and treating influenza.
10.1186/s12879-023-08706-x
Mendelian randomization analysis reveals causal relationships between gut microbiome and optic neuritis.
Human genetics
BACKGROUND:It is unclear whether gut microbiota (GM) affects the risk of optic neuritis (ON) through the "gut-brain" axis and the "gut-retina" axis. To examine the causal relationship between GM and ON, we conducted Mendelian randomization (MR) study. METHODS:Up to 18,340 samples of 24 population-based cohorts were included in genome-wide association study (GWAS) of 196 GM taxa. ON outcomes were selected from the FinnGen GWAS (951 ON cases and 307,092 controls). In addition, the GWAS based on UK Biobank (UKB) (105 ON cases and 456,243 controls) was used for further exploration. Inverse variance weighted (IVW) was carried out to estimate their effects on ON risk and the MR assumptions were evaluated in sensitivity analyses. RESULTS:Among the 196 GM taxa, the IVW results confirmed that Family -Peptococcaceae (P = 2.17 × 10), Genus- Hungatella (P = 4.57 × 10) and genus-Eubacterium_rectale_group (P = 0.02) were correlated with the risk of ON based on Finngen GWAS. Based on data from UKB, Genus- Eubacterium_hallii_group (P = 1.50 × 10) and Genus- Ruminococcaceae_UCG_002 (P = 0.02) were correlated with the risk of ON. At the phylum, class and order levels, no GM taxa were causally related to ON (P > 0.05). Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analysis confirmed the robustness of the MR results. CONCLUSION:Our MR findings support the causal effect of specific GM taxa on ON. GM may affect the risk of ON through the "gut-brain" axis and the "gut-retina" axis. However, further research is needed to confirm the relevant mechanism of the relationship between GM and ON.
10.1007/s00439-022-02514-0
Relationship between gut microbiota and thyroid function: a two-sample Mendelian randomization study.
Frontiers in endocrinology
Background:Numerous observational studies have indicated a link between the composition of gut microbiota and thyroid function. Nevertheless, the precise causal relationship between gut microbiota and thyroid function remains uncertain. Methods:In this two-sample Mendelian randomization study, we utilized summary data from a genome-wide association study of gut microbiota composition in 18,340 participants from 24 cohorts, as well as summary statistics on thyroid hormones and thyroid-stimulating hormone from the ThyroidOmics Consortium and summary statistics on hypothyroidism and hyperthyroidism from the FinnGen R8 release. Five different methods, including inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode, were employed to examine the causal relationship between gut microbiota and thyroid function. Reverse Mendelian randomization analysis was conducted for taxa identified as having a causal relationship with thyroid function in the Mendelian randomization analysis. To assess the robustness of the results, sensitivity analyses were conducted employing Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis. Results:Through MR analysis of 211 microbial taxa and 4 phenotypes, we identified a total of 34 gut microbiota taxa that were associated with the outcomes. After using the bonferroni method for multiple testing correction, phylum (id.400) had a protective effect on hypothyroidism (OR=0.883, 95% CI: 0.817-0.955, =0.002), and class (id.3087) had a protective effect on hyperthyroidism (OR=0.549, 95% CI: 0.374-0.805, =0.002). According to the results of reverse MR analysis, no significant causal effect of the four phenotypes was found on gut microbiota. No significant horizontal pleiotropy was detected based on MR-Egger intercept test and MR-PRESSO global test. Conclusion:Through two-sample MR analysis, we identified specific gut microbiota taxa at the genetic level that are predicted to have a causal relationship with thyroid function, which may serve as useful biomarkers for early disease diagnosis.
10.3389/fendo.2023.1240752
Associations between gut microbiota and sleep: a two-sample, bidirectional Mendelian randomization study.
Frontiers in microbiology
Introduction:Previous research has reported that the gut microbiota performs an essential role in sleep through the microbiome-gut-brain axis. However, the causal association between gut microbiota and sleep remains undetermined. Methods:We performed a two-sample, bidirectional Mendelian randomization (MR) analysis using genome-wide association study summary data of gut microbiota and self-reported sleep traits from the MiBioGen consortium and UK Biobank to investigate causal relationships between 119 bacterial genera and seven sleep-associated traits. We calculated effect estimates by using the inverse-variance weighted (as the main method), maximum likelihood, simple model, weighted model, weighted median, and MR-Egger methods, whereas heterogeneity and pleiotropy were detected and measured by the MR pleiotropy residual sum and outlier method, Cochran's Q statistics, and MR-Egger regression. Results:In forward MR analysis, inverse-variance weighted estimates concluded that the genetic forecasts of relative abundance of 42 bacterial genera had causal effects on sleep-associated traits. In the reverse MR analysis, sleep-associated traits had a causal effect on 39 bacterial genera, 13 of which overlapped with the bacterial genera in the forward MR analysis. Discussion:In conclusion, our research indicates that gut microbiota may be involved in the regulation of sleep, and conversely, changes in sleep-associated traits may also alter the abundance of gut microbiota. These findings suggest an underlying reciprocal causal association between gut microbiota and sleep.
10.3389/fmicb.2023.1236847
Causal association of gut microbiota and esophageal cancer: a Mendelian randomization study.
Frontiers in microbiology
Introduction:Despite the growing body of evidence, the link between the gut microbiota and different types of tumors, such as colorectal, gastric, and liver cancer, is becoming more apparent. The gut microbiota can be used as a reference for evaluating various diseases, including cancer, and can also act as risk factors or preventive factors. However, the specific connection between the gut microbiota and the advancement of esophageal cancer has yet to be investigated. Therefore, the aim of this research is to clarify the possible causal influence of intestinal microorganisms on the vulnerability to esophageal cancer through the utilization of Mendelian randomization (MR) studies. Methods:In this study, we employed a two-sample Mendelian randomization approach to evaluate the unbiased causal association between 150 different gut microbiota types and the occurrence of esophageal cancer. Following the selection from the IEU GWAS database and SNP filtration, we utilized various MR statistical techniques on the suitable instrumental variables. These included IVW methods, employing inverse variance weighting. Additionally, we performed a range of sensitivity analyses to confirm the heterogeneity and pleiotropy of the instrumental variables, thus ensuring the reliability of the outcomes. Results:The increased likelihood of developing esophageal cancer is linked to the genetically predicted high levels of , and . Conversely, a decreased risk of esophageal cancer is associated with the high abundance of , and . No heterogeneity and pleiotropy were detected in the sensitivity analysis. Discussion:We found that 11 types of gut microbial communities are associated with esophageal cancer, thereby confirming that the gut microbiota plays a significant role in the path.
10.3389/fmicb.2023.1286598
A cause-effect relationship between Graves' disease and the gut microbiome contributes to the thyroid-gut axis: A bidirectional two-sample Mendelian randomization study.
Frontiers in immunology
Background:An association between Graves' disease (GD) and the gut microbiome has been identified, but the causal effect between them remains unclear. Methods:Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between GD and the gut microbiome. Gut microbiome data were derived from samples from a range of different ethnicities (18,340 samples) and data on GD were obtained from samples of Asian ethnicity (212,453 samples). Single nucleotide polymorphisms (SNPs) were selected as instrumental variables according to different criteria. They were used to evaluate the causal effect between exposures and outcomes through inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode methods. -statistics and sensitivity analyses were performed to evaluate bias and reliability. Results:In total, 1,560 instrumental variables were extracted from the gut microbiome data (< 1 × 10). The classes [odds ratio (OR) = 3.603] and , as well as the genera group, , and UCG 011 were identified as risk factors for GD. The family and the genus (OR = 0.489) were protective factors for GD. In addition, 13 instrumental variables were extracted from GD (< 1 × 10), causing one family and eight genera to be regulated. The genus group ( = 0.024, OR = 0.918) and ( = 0.049, OR = 1.584) had the greatest probability of being regulated. Significant bias, heterogeneity, and horizontal pleiotropy were not detected. Conclusion:A causal effect relationship exists between GD and the gut microbiome, demonstrating regulatory activity and interactions, and thus providing evidence supporting the involvement of a thyroid-gut axis.
10.3389/fimmu.2023.977587
Correlations between gut microbiota and lichen planus: a two-sample Mendelian randomization study.
Frontiers in immunology
Purpose:Several existing studies have revealed that the occurrence of lichen planus (LP) is relevant to the gut microbiota, and the causal relationship between gut microbiota and LP was analyzed using the Mendelian randomization (MR) method. Methods:Through the two-sample MR method, single nucleotide polymorphisms (SNPs) relevant to gut microbiota were selected as instrument variables (IVs) to evaluate the causal association between gut microbiota and the risk of LP. Results:According to the selection criteria of inverse-variance weighted (IVW), six bacterial genera were found to be significantly linked to the initiation of LP; The IVW results suggested that Oxalobacteraceae, Victivallaceae, and Actinobacteria could restrain the initiation of LP, showing protective effects against LP. Desulfovibrio, Veillonella, and Ruminococcus gauvreauii groups were demonstrated to have casual correlations with the onset of LP. Conclusion:The relationship between gut microbiota and LP was not a single positive or inverse relationship. Investigation of the causal relationship of these gut microbiota with LP could further provide evidence for the intestine-skin axis theory. However, the specific mechanism of microorganisms affecting the skin remains to be clarified. In this paper, the protective effects and mechanisms of Oxalobacteraceae, Victivallaceae, and Actinobacteria on LP require further exploration.
10.3389/fimmu.2023.1235982
The interactions between host genome and gut microbiome increase the risk of psychiatric disorders: Mendelian randomization and biological annotation.
Brain, behavior, and immunity
BACKGROUND:The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association studies on human genome and gut microbiome (mbGWAS) have revealed important host-microbiome interactions. However, establishing causal relationships between specific gut microbiome features and psychological conditions remains challenging due to insufficient sample sizes of previous studies of mbGWAS. METHODS:Cross-cohort meta-analysis (via METAL) and multi-trait analysis (via MTAG) were used to enhance the statistical power of mbGWAS for identifying genetic variants and genes. Using two large mbGWAS studies (7,738 and 5,959 participants respectively) and12 disease-specific studies from the Psychiatric Genomics Consortium (PGC), we performed bidirectional two-sample mendelian randomization (MR) analyses between microbial features and psychiatric diseases (up to 500,199 individuals). Additionally, we conducted downstream gene- and gene-set-based analyses to investigate the shared biology linking gut microbiota and psychiatric diseases. RESULTS:METAL and MTAG conducted in mbGWAS could boost power for gene prioritization and MR analysis. Increases in the number of lead SNPs and mapped genes were witnessed in 13/15 species and 5/10 genera after using METAL, and MTAG analysis gained an increase in sample size equivalent to expanding the original samples from 7% to 63%. Following METAL use, we identified a positive association between Bacteroides faecis and ADHD (OR, 1.09; 95 %CI, 1.02-1.16; P = 0.008). Bacteroides eggerthii and Bacteroides thetaiotaomicron were observed to be positively associated with PTSD (OR, 1.11; 95 %CI, 1.03-1.20; P = 0.007; OR, 1.11; 95 %CI, 1.01-1.23; P = 0.03). These findings remained stable across statistical models and sensitivity analyses. No genetic liabilities to psychiatric diseases may alter the abundance of gut microorganisms.Using biological annotation, we identified that those genes contributing to microbiomes (e.g., GRIN2A and RBFOX1) are expressed and enriched in human brain tissues. CONCLUSIONS:Our statistical genetics strategy helps to enhance the power of mbGWAS, and our genetic findings offer new insights into biological pleiotropy and causal relationship between microbiota and psychiatric diseases.
10.1016/j.bbi.2023.08.003
Gut microbiota and hypertensive disorders in pregnancy: evidence from the Mendelian randomization study.
Aging
BACKGROUND:Recent studies have shown that gut microbiota (GM) is related to hypertensive disorders in pregnancy (HDP). However, the causal relationship needs to be treated with caution due to confounding factors and reverse causation. METHODS:We obtained genetic variants from genome-wide association studies including GM (N = 18,340) in MiBioGen Consortium as well as HDP (7,686 cases/115,893 controls) and specific subtypes in FinnGen Consortium. Then, Inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS methods were applied to examine the causal association. Reverse Mendelian randomization (RMR) and multivariable MR were performed to confirm the causal direction and adjust the potential confounders, respectively. Furthermore, sensitivity analyses including Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and the leave-one-out analysis were conducted to detect the potential heterogeneity and horizontal pleiotropy. RESULTS:The present study found causalities between eight gut microbial genera and HDP. The HDP-associated gut microbial genera identified by MR analyses varied in different subtypes. Specifically, our study found causal associations of , , , , and with GH, of (), (), , , and with PE, and of and with eclampsia, respectively. CONCLUSIONS:This study first applied the MR approach to detect the causal relationships between GM and specific HDP subtypes. Our findings may promote the prevention and treatment of HDP targeted on GM and provide valuable insights to understand the mechanism of HDP in different subtypes from the perspective of GM.
10.18632/aging.205019
Causality of gut microbiome and hypertension: A bidirectional mendelian randomization study.
Frontiers in cardiovascular medicine
Background & Aims:The pathogenesis of hypertension involves a diverse range of genetic, environmental, hemodynamic, and more causative factors. Recent evidence points to an association between the gut microbiome and hypertension. Given that the microbiota is in part determined by host genetics, we used the two-sample Mendelian randomization (MR) analysis to address the bidirectional causal link between gut microbiota and hypertension. Methods:We selected genetic variants ( < 1 × 10) for gut microbiota ( = 18,340) from the MiBioGen study. Genetic association estimates for hypertension were extracted from genome-wide association study (GWAS) summary statistics on 54,358 cases and 408,652 controls. Seven complementary MR methods were implemented, including the inverse-variance weighted (IVW) method, followed by sensitivity analyses to verify the robustness of the results. Reverse-direction MR analyses were further conducted to probe if there was a reverse causative relationship. Bidirectional MR analysis then examines a modulation of gut microbiota composition by hypertension. Results:At the genus level, our MR estimates from gut microbiome to hypertension showed that there were 5 protective factors , , , and (id.1000000073), while 6 genera , , , , , and (id.2041) are risk factors. The and were detrimental and beneficial at the family level, respectively. In contrast, the MR results of hypertension-gut flora showed hypertensive states can lead to an increased abundance of E, , and and a lower abundance of , , , and . Conclusion:Altered gut microbiota is a causal factor in the development of hypertension, and hypertension causes imbalances in the intestinal flora. Substantial research is still needed to find the key gut flora and explore the specific mechanisms of their effects so that new biomarkers can be found for blood pressure control.
10.3389/fcvm.2023.1167346
Causal Associations Between Gut Microbiota and Psoriasis: A Mendelian Randomization Study.
Dermatology and therapy
INTRODUCTION:Previous studies have proposed a possible gut-skin axis, and linked gut microbiota to psoriasis risks. However, there is heterogeneity in existing evidence. Observational research is prone to bias, and it is hard to determine causality. Therefore, this study aims to evaluate possible causal associations between gut microbiota (GM) and psoriasis. METHODS:With published large-scale GWAS (genome-wide association study) summary datasets, two-sample Mendelian randomization (MR) was performed to sort out possible causal roles of GM in psoriasis and arthropathic psoriasis (PsA). The inverse variance weighted (IVW) method was taken as the primary evaluation of causal association. As complements to the IVW method, we also applied MR-Egger, weighted median. Sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept test, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global test, and leave-one-out analysis. RESULTS:By primary IVW analysis, we identified nominal protective roles of Bacteroidetes (odds ratio, OR 0.81, P = 0.033) and Prevotella9 (OR 0.87, P = 0.045) in psoriasis risks. Bacteroidia (OR 0.65, P = 0.03), Bacteroidales (OR 0.65, P = 0.03), and Ruminococcaceae UCG002 (OR 0.81, P = 0.038) are nominally associated with lower risks for PsA. On the other hand, Pasteurellales (OR 1.22, P = 0.033), Pasteurellaceae (OR 1.22, P = 0.033), Blautia (OR 1.46, P = 0.014), Methanobrevibacter (OR 1.27, P = 0.026), and Eubacterium fissicatena group (OR 1.21, P = 0.028) are nominal risk factors for PsA. Additionally, E. fissicatena group is a possible risk factor for psoriasis (OR 1.22, P = 0.00018). After false discovery rate (FDR) correction, E. fissicatena group remains a risk factor for psoriasis (P = 0.03798). CONCLUSION:We comprehensively evaluated possible causal associations of GM with psoriasis and arthropathic psoriasis, and identified several nominal associations. E. fissicatena group remains a risk factor for psoriasis after FDR correction. Our results offer promising therapeutic targets for psoriasis clinical management.
10.1007/s13555-023-01007-w
Associations between gut microbiota and Alzheimer's disease, major depressive disorder, and schizophrenia.
Zhuang Zhenhuang,Yang Ruotong,Wang Wenxiu,Qi Lu,Huang Tao
Journal of neuroinflammation
BACKGROUND:Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer's disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ). METHODS:A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively. RESULTS:We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79-0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92-1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00-1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83-0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00-1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02-1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition. CONCLUSIONS:These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.
10.1186/s12974-020-01961-8
Association between gut microbiota and sensorineural hearing loss: a Mendelian randomization study.
Frontiers in microbiology
Background:Several recent studies speculated that the gut microbiota is associated with sensorineural hearing loss (SNHL) and proposed the concept of the gut-inner ear axis. However, the causal effect of gut microbiota on SNHL is still unknown. In this study, we performed a two-sample Mendelian randomization (MR) analysis to estimate the causal effect of gut microbiota on SNHL. Methods:Gut microbiota data were obtained from the largest available genome-wide association study ( = 18,340) conducted by the MiBioGen consortium. The summary statistics of SNHL were obtained from the FinnGen consortium R8 release data (28,310 cases and 302,750 controls). The causal effects were estimated with inverse-variance weighted, MR-Egger, and weighted median. Reverse Mendelian randomization analysis was performed on the bacteria that were found to be associated with SNHL in forward Mendelian randomization analysis. We then performed sensitivity analyses, including Cochran's test, MR-Egger intercept test, MR-PRESSO, cML-MA-BIC, and leave-one-out analysis, to detect heterogeneity and pleiotropy. Results:The inverse-variance weighted results suggested that had a significant protective effect against SNHL (odds ratio = 0.85, 95% confidence interval: 0.78-0.93, = 6.99 × 10). In addition, (odds ratio = 0.89, 95% confidence interval: 0.82-0.97, = 8.53 × 10) presented a suggestively protective effect on SNHL. (odds ratio = 1.08, 95% confidence interval: 1.02-1.15, = 0.01) and (odds ratio = 1.12, 95% confidence interval: 1.00-1.24, = 0.048) suggestively increase the risk of SNHL. The results of the reverse MR analysis showed that there is no significant causal effect of SNHL on the gut microbiota. No significant heterogeneity of instrumental variables or pleiotropy was detected. Conclusion:The evidence that the four genera mentioned above are associated with SNHL supports the hypothesis of a gut-inner ear axis. Our study provides microbial markers for the prevention and treatment of SNHL, and further studies are needed to explore the mechanisms of the gut microbiome-inner ear axis in health and diseases.
10.3389/fmicb.2023.1230125
Psoriasis and gut microbiota: A Mendelian randomization study.
Journal of cellular and molecular medicine
In recent years, an increasing number of observational studies have revealed an association between gut microbiota composition and psoriasis patients. However, whether this association reflects a causal relationship remains unclear. This study aimed to identify the causal relationship between gut microbiota and psoriasis through relevant research. In order to determine whether gut microbiota and psoriasis are causally related, we conducted a Mendelian randomization analysis using summary statistics from genome-wide association studies (GWAS). As the exposure factor, we used summary statistics data from a GWAS study conducted by the MiBioGen Consortium, including 18,340 individuals with whole-genome gut microbiota composition, and data from the FinnGen GWAS study on psoriasis, including 9267 patients and 364,071 controls as the disease outcome. Two-sample Mendelian randomization analysis was subsequently performed with inverse variance weighted, MR-Egger and weighted median, while sensitivity analyses were conducted to address heterogeneity and horizontal pleiotropy. The IVW results confirmed the causal relationship between certain gut microbiota groups and psoriasis. Specifically, family Veillonellaceae (OR = 1.162, 95% CI: 1.038-1.301, p = 0.009), genus Candidatus Soleaferrea (OR = 1.123, 95% CI: 1.011-1.247, p = 0.030) and genus Eubacterium fissicatena group (OR = 0.831, 95% CI: 0.755-0.915, p = 0.00016) showed significant associations. Sensitivity analysis did not reveal any abnormalities in SNPs. Currently, we have found some causal relationship between the gut microbiota and psoriasis. However, the study needs further RCTs for further validation.
10.1111/jcmm.18023
Causal relationships between the gut microbiome, blood lipids, and heart failure: a Mendelian randomization analysis.
European journal of preventive cardiology
AIMS:Studies have linked gut microbiome and heart failure (HF). However, their causal relationships and potential mediating factors have not been well defined. To investigate the causal relationships between the gut microbiome and HF and the mediating effect of potential blood lipids by using genetics. METHODS AND RESULTS:We performed a bidirectional and mediation Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of gut microbial taxa (Dutch Microbiome Project, n = 7738), blood lipids (UK Biobank, n = 115 078), and a meta-analysis of HF (115 150 cases and 1550 331 controls). We applied the inverse-variance weighted estimation method as the primary method, with several other estimators as complementary methods. The multivariable MR approach based on Bayesian model averaging (MR-BMA) was used to prioritize the most likely causal lipids. Six microbial taxa are suggestively associated with HF causally. The most significant taxon was the species Bacteroides dorei [odds ratio = 1.059, 95% confidence interval (CI) = 1.022-1.097, P-value = 0.0017]. The MR-BMA analysis showed that apolipoprotein B (ApoB) was the most likely causal lipid for HF (the marginal inclusion probability = 0.717, P-value = 0.005). The mediation MR analysis showed that ApoB mediated the causal effects of species B. dorei on HF (proportion mediated = 10.1%, 95% CI = 0.2-21.6%, P-value = 0.031). CONCLUSION:The study suggested a causal relationship between specific gut microbial taxa and HF and that ApoB might mediate this relationship as the primary lipid determinant of HF.
10.1093/eurjpc/zwad171
Genome-wide Mendelian randomization identifies putatively causal gut microbiota for multiple peptic ulcer diseases.
Frontiers in immunology
Objective:The pathogenesis of peptic ulcer diseases (PUDs) involves multiple factors, and the contribution of gut microbiota to this process remains unclear. While previous studies have associated gut microbiota with peptic ulcers, the precise nature of the relationship, whether causal or influenced by biases, requires further elucidation. Design:The largest meta-analysis of genome-wide association studies was conducted by the MiBioGen consortium, which provided the summary statistics of gut microbiota for implementation in the Mendelian randomization (MR) analysis. Summary statistics for five types of PUDs were compiled using the FinnGen Consortium R8 release data. Various statistical techniques, including inverse variance weighting (IVW), MR-Egger, weighted median (WM), weighted mode, and simple mode, were employed to assess the causal relationships between gut microbiota and these five PUDs. Result:In the intestinal microbiome of 119 known genera, we found a total of 14 causal associations with various locations of PUDs and reported the potential pathogenic bacteria of et al. Among them, four had causal relationships with esophageal ulcer, one with gastric ulcer, three with gastroduodenal ulcer, four with duodenal ulcer, and two with gastrojejunal ulcer. Conclusion:In this study, the pathogenic bacterial genera in the gut microbiota that promote the occurrence of PUDs were found to be causally related. There are multiple correlations between intestinal flora and PUDs, overlapping PUDs have overlapping associated genera. The variance in ulcer-related bacterial genera across different locations underscores the potential influence of anatomical locations and physiological functions.
10.3389/fimmu.2023.1260780
Gut microbiota and sepsis: bidirectional Mendelian study and mediation analysis.
Frontiers in immunology
Background:There is a growing body of evidence that suggests a connection between the composition of gut microbiota and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between gut microbiota, C-reactive protein (CRP), and sepsis, we conducted several Mendelian randomization (MR) analyses. Methods:In this study, publicly available genome-wide association study (GWAS) summary statistics were examined to determine the correlation between gut microbiota and sepsis, including various sepsis subgroups (such as under 75, 28-day death, Critical Care Units (ICU), 28-day death in ICU). Initially, two-sample and reverse Mendelian randomization (MR) analyses were conducted to identify causality between gut microbiota and sepsis. Subsequently, multivariable and two-step MR analyses revealed that the relationship between microbiota and sepsis was mediated by CRP. The robustness of the findings was confirmed through several sensitivity analyses. Findings:In our study, we revealed positive correlations between 24 taxa and different sepsis outcomes, while 30 taxa demonstrated negative correlations with sepsis outcomes. Following the correction for multiple testing, we found that the Phylum Lentisphaerae (OR: 0.932, = 2.64E-03), class Lentisphaeria, and order Victivallales (OR: 0.927, = 1.42E-03) displayed a negative relationship with sepsis risk. In contrast, Phylum Tenericutes and class Mollicutes (OR: 1.274, = 2.89E-03) were positively related to sepsis risk and death within 28 days. It is notable that Phylum Tenericutes and class Mollicutes (OR: 1.108, = 1.72E-03) also indicated a positive relationship with sepsis risk in individuals under 75. From our analysis, it was shown that C-reactive protein (CRP) mediated 32.16% of the causal pathway from Phylum Tenericutes and class Mollicutes to sepsis for individuals under 75. Additionally, CRP was found to mediate 31.53% of the effect of the genus Gordonibacter on sepsis. Despite these findings, our reverse analysis did not indicate any influence of sepsis on the gut microbiota and CRP levels. Conclusion:The study showcased the connection between gut microbiota, CRP, and sepsis, which sheds new light on the potential role of CRP as a mediator in facilitating the impact of gut microbiota on sepsis.
10.3389/fimmu.2023.1234924
Gut microbiota and risk of polycystic ovary syndrome: Insights from Mendelian randomization.
Heliyon
Background:Polycystic ovary syndrome (PCOS) is a multifaceted endocrine and metabolic syndrome with complex origins and pathogenesis that has not yet been fully elucidated. Recently, the interconnection between gut microbiota and metabolic diseases has gained prominence in research, generating new insights into the correlation between PCOS and gut microbiota composition. However, the causal link between PCOS and gut microbiota remains relatively unexplored, indicating a crucial gap in current research. Methods:We conducted a two-sample Mendelian randomization analysis using summary statistics obtained from the MiBioGen Consortium's extensive genome-wide association studies (GWAS) meta-analysis, focusing on the gut microbiota. Summary statistics for PCOS were acquired from the FinnGen Consortium R7 release data. Various statistical approaches, including inverse variance weighted, MR-Egger, maximum likelihood, weighted model, and weighted median, have been employed to investigate the causal association between the gut microbiota and PCOS. Additionally, we performed a reverse causal analysis. Cochran's Q statistic was used to assess the heterogeneity of the instrumental variables. Regarding the relationships between PCOS and specific genera within the gut microbiota, a significance level of P < 0.05 was observed, but only when q ≥ 0.1. Results:Our analysis revealed that specific microbial genera, namely Bilophila (P = 4.62 × 10), Blautia (P = 0.02), and Holdemania (P = 0.04), displayed a protective effect against PCOS. Conversely, the presence of the Lachnospiraceae family of bacteria was associated with a detrimental effect on PCOS (P = 0.04). Furthermore, reverse Mendelian randomization analysis confirmed the significant influence of Lachnospiraceae on PCOS. No significant variations in instrumental variables or evidence of horizontal pleiotropy were observed. Conclusions:The results revealed a definitive causal link between PCOS and the presence of Bilophila, Blautia, Holdemania, and Lachnospiraceae in the gut microbiota. This discovery could provide pivotal insights, leading to novel preventive and therapeutic approaches for PCOS.
10.1016/j.heliyon.2023.e22155
Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.
Ecotoxicology and environmental safety
Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (β = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (β = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (β = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (β = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (β = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (β = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (β = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (β = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (β = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (P = 0.836) and E. hallii (P = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.
10.1016/j.ecoenv.2023.115660
Male infertility risk and gut microbiota: a Mendelian randomization study.
Frontiers in microbiology
Background:In recent decades, the decline of male sperm quality has become a worldwide phenomenon, with sperm quality of critical importance for the ability to conceive naturally. Recent studies suggest that male fertility function is closely linked to the gut microbiota, however, the cause-and-effect association between the gut microbiota and male infertility risk is currently unclear. Methods:We performed one two-sample Mendelian randomization (MR) study, which uses summary data on human gut microbiota from the MiBioGen consortium as factors of exposure. FinnGen Consortium R8 data was used to obtain GWAS data for male infertility. To evaluate cause-and-effect associations linking gut microbiota and male infertility risk with multiple Mendelian randomization methods, we included inverse variance weighted (IVW), MR-Egger, and Maximum Likelihood (ML) Ratio. The heterogeneity of instrumental variables was evaluated through Cochran's Q, Rucker's Q, and leave-one-out analysis methods. Results:We found a positive association between Allisonella, Anaerotruncus, Barnesiella, Intestinibacter, and Lactococcus with male infertility risk according to the MR analysis results. Bacteroides Romboutsia, Ruminococcaceae (NK4A2140group), and Ruminococcaceae (UCG011) play a protective function in male infertility pathogenesis. Conclusion:It was found that gut microbiota and infertility are causally related in this study. In subsequent studies, there is a need to build a larger and more comprehensive GWAS database on male infertility, which will reveal the underlying mechanisms for gut microbiota and male infertility. There is a need for randomized controlled trials for validating the protective effect of the associated gut microbiota against male infertility risk, and for exploring the associated mechanisms.
10.3389/fmicb.2023.1228693
Exploring the interplay of gut microbiota, inflammation, and LDL-cholesterol: a multiomics Mendelian randomization analysis of their causal relationship in acute pancreatitis and non-alcoholic fatty liver disease.
Journal of translational medicine
BACKGROUND:Acute pancreatitis and non-alcoholic fatty liver disease are both serious diseases in the digestive system. The pathogenesis of both diseases is extremely complex closely and it related to gut microbiota, inflammation, and blood fat. There is a close relationship between gut microbiota and blood lipids. METHODS:In this study, we used three types of exposure: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls), with LDL-C as an intermediary and acute pancreatitis and non-alcoholic fatty liver disease as outcomes. We mainly used MR-IVW, co-localization analysis, and reverse MR analysis methods for analysis. RESULTS:7 gut microbiota, 21 inflammatory cells, and 3 inflammatory proteins can affect LDL-C levels. LDL-C is associated with acute pancreatitis and non-alcoholic fatty liver disease. CONCLUSIONS:Three omics were used: 412 gut microbiota, 731 inflammatory cells, and 91 inflammatory proteins (pqtls). It explains the causal relationship between multiomics, LDL- cholesterol, acute pancreatitis, and non-alcoholic fatty liver disease.
10.1186/s12967-024-04996-0
Gut microbiota and immune mediation: a Mendelian randomization study on granulomatosis with polyangiitis.
Frontiers in immunology
Background:The gut microbiota plays a pivotal role in influencing various health outcomes, including immune-mediated conditions. Granulomatosis with Polyangiitis (GPA) is one such condition, and its potential associations with gut microbiota remain underexplored. Method:Using a two-sample Mendelian randomization approach, we investigated the causal links between gut microbiota and GPA. We sourced our data from multiple cohorts and consortiums, including the MiBioGen consortium. Our study design incorporated both direct associations and mediation effects of immune traits on the relationship between gut microbiota and GPA. Results:Our analysis revealed significant associations between 1 phylum, 1 family 9 genus microbiota taxa and GPA. Furthermore, we identified several immune cell traits that mediated the effects of gut microbiota on GPA. For instance, the family Defluviitaleaceae and genus Defluviitaleaceae UCG011 influenced GPA through CD11c in granulocytes. The mediation effect proportions further elucidated the complex dynamics between gut microbiota exposures, immune markers, and their combined influence on GPA. Conclusion:Our findings underscore the intricate relationship between gut microbiota, immune markers, and GPA. The identified associations and mediation effects provide valuable insights into the potential therapeutic avenues targeting gut microbiota to manage GPA.
10.3389/fimmu.2023.1296016
Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis.
Jia Jinzhu,Dou Pan,Gao Meng,Kong Xuejun,Li Changwei,Liu Zhonghua,Huang Tao
Diabetes
We examined the causal direction between gut microbiota-dependent metabolite trimethylamine -oxide (TMAO) or its predecessors and cardiometabolic diseases, such as risk of type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), myocardial infarction (MI), stroke, atrial fibrillation (AF), and chronic kidney disease (CKD). We used genetic variants as instruments to test the causal associations. Genetically predicted higher TMAO and carnitine were not associated with higher odds of T2DM, AF, CAD, MI, stroke, and CKD after Bonferroni correction ( ≤ 0.0005). However, we observed that genetically increased choline showed a suggestive association with higher risk of T2DM (odds ratio 1.84 [95% CI 1.00-3.42] per 10 units, = 0.05). In contrast, genetically predicted higher betaine (0.68 [0.48-0.95] per 10 units, = 0.023) was suggestively associated with a lower risk of T2DM. We observed a suggestive association of genetically increased choline with a lower level of body fat percentage (β ± SE -0.28 ± 0.11, = 0.013) but a higher estimated glomerular filtration rate (0.10 ± 0.05, = 0.034). We further found that T2DM (0.130 ± 0.036, < 0.0001) and CKD (0.483 ± 0.168, = 0.004) were causally associated with higher TMAO levels. Our Mendelian randomization findings support that T2DM and kidney disease increase TMAO levels and that observational evidence for cardiovascular diseases may be due to confounding or reverse causality.
10.2337/db19-0153
Gut microbiota and autism spectrum disorders: a bidirectional Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:In recent years, observational studies have provided evidence supporting a potential association between autism spectrum disorder (ASD) and gut microbiota. However, the causal effect of gut microbiota on ASD remains unknown. Methods:We identified the summary statistics of 206 gut microbiota from the MiBioGen study, and ASD data were obtained from the latest Psychiatric Genomics Consortium Genome-Wide Association Study (GWAS). We then performed Mendelian randomization (MR) to determine a causal relationship between the gut microbiota and ASD using the inverse variance weighted (IVW) method, simple mode, MR-Egger, weighted median, and weighted model. Furthermore, we used Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis to identify heterogeneity and pleiotropy. Moreover, the Benjamin-Hochberg approach (FDR) was employed to assess the strength of the connection between exposure and outcome. We performed reverse MR analysis on the gut microbiota that were found to be causally associated with ASD in the forward MR analysis to examine the causal relationships. The enrichment analyses were used to analyze the biological function at last. Results:Based on the results of IVW results, genetically predicted and had a possible positive association with ASD (IVW OR=1.14, 95% CI: 1.00-1.29, =3.7×10), four gut microbiota with a potential protective effect on ASD: (OR=0.81, 95% CI: 0.69-0.96, =1.4×10), (OR=0.81, 95% CI: 0.69-0.96, =1.5×10), (OR=0.83, 95% CI: 0.70-0.98, =2.8×10), and (OR=0.82, 95% CI: 0.68-0.99, =3.6×10). After FDR multiple-testing correction we further observed that there were two gut microbiota still have significant relationship with ASD: (IVW OR=1.24; 95% CI: 1.09-1.40, =9.2×10) was strongly positively correlated with ASD and (IVW OR=0.78, 95% CI: 0.67-0.89, =6.9×10) was strongly negatively correlated with ASD. The sensitivity analysis excluded the influence of heterogeneity and horizontal pleiotropy. Conclusion:Our findings reveal a causal association between several gut microbiomes and ASD. These results deepen our comprehension of the role of gut microbiota in ASD's pathology, providing the foothold for novel ideas and theoretical frameworks to prevent and treat this patient population in the future.
10.3389/fcimb.2023.1267721
Clarifying the effect of gut microbiota on allergic conjunctivitis risk is instrumental for predictive, preventive, and personalized medicine: a Mendelian randomization analysis.
The EPMA journal
Background:Allergic conjunctivitis is an ocular immune disease which affects the conjunctiva, eyelids, and cornea. Growing evidence implicates the gut microbiota in balancing and modulating immunity response, and in the pathogenesis of allergic disease. As a result, gut microbial imbalance could be a useful indicator for allergic conjunctivitis. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of gut microbial imbalance in the development of allergic conjunctivitis could provide a window of opportunity for primary prediction, targeted prevention, and personalized treatment of the disease. Working hypothesis and methodology:In our study, we hypothesized that individuals with microbial dysbiosis may be more susceptible to allergic conjunctivitis due to an increased inflammatory response. To verify the working hypothesis, our analysis selected genetic variants linked with gut microbiota features ( = 18,340) and allergic conjunctivitis (4513 cases, 649,376 controls) from genome-wide association studies. The inverse-variance weighted (IVW) estimate, Mendelian randomization (MR)-Egger, weighted median estimator, maximum likelihood estimator (MLE), and MR robust adjusted profile score (MR.RAPS) were employed to analyze the impact of gut microbiota on the risk of allergic conjunctivitis and identify allergic conjunctivitis-related gut microbes. Ultimately, these findings may enable the identification of individuals at risk of allergic conjunctivitis through screening of gut microbial imbalances, and allow for new targeted prevention and personalized treatment strategies. Results:Genetic liability to (OR, 0.83; 95% CI, 0.70-0.99; = 4.04×10), (OR, 0.78; 95% CI, 0.64-0.96; = 2.04×10), (OR, 0.69; 95% CI, 0.56-0.86; = 1.09×10), (OR, 0.71; 95% CI, 0.55-0.93; = 1.23×10) genus were associated with a low risk of allergic conjunctivitis with IVW. Besides, we found suggestive associations of a genetic-driven increase in the (OR, 1.41; 95% CI, 1.00-2.00; = 4.63×10) genus with a higher risk of allergic conjunctivitis. Moreover, MLE and MR.RAPS show consistent results with IVW after further validation and strengthened confidence in the true causal associations. No heterogeneity and pleiotropy was detected. Conclusions:Our study suggests that gut microbiota may play a causal role in the development of allergic conjunctivitis and provides new insights into the microbiota-mediated mechanism of the disease. Gut microbiota may serve as a target for future predictive diagnostics, targeted prevention, and individualized therapy in allergic conjunctivitis, facilitating the transition from reactive medical services to PPPM in the management of the disease. Supplementary Information:The online version contains supplementary material available at 10.1007/s13167-023-00321-9.
10.1007/s13167-023-00321-9
Causal relationships between gut microbiota and programmed cell death protein 1/programmed cell death-ligand 1: A bidirectional Mendelian randomization study.
Frontiers in immunology
Background:Multiple clinical studies have indicated that the gut microbiota influences the effects of immune checkpoint blockade (ICB) therapy comprising PD-1/PD-L1 inhibitors, but the causal relationship is unclear. Because of numerous confounders, many microbes related to PD-1/PD-L1 have not been identified. This study aimed to determine the causal relationship between the microbiota and PD-1/PD-L1 and identify possible biomarkers for ICB therapy. Method:We used bidirectional two-sample Mendelian randomization with two different thresholds to explore the potential causal relationship between the microbiota and PD-1/PD-L1 and species-level microbiota GWAS to verify the result. Result:In the primary forward analysis, genus_Holdemanella showed a negative correlation with PD-1 [βIVW = -0.25; 95% CI (-0.43 to -0.07); P = 0.028] and genus_Prevotella9 showed a positive correlation with PD-1 [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.027]; order_Rhodospirillales [βIVW = 0.2; 95% CI (0.1 to 0.4); P = 0.044], family_Rhodospirillaceae [βIVW = 0.2; 95% CI (0 to 0.4); P = 0.032], genus_Ruminococcaceae_UCG005 [βIVW = 0.29; 95% CI (0.08 to 0.5); P = 0.028], genus_Ruminococcus_gnavus_group [βIVW = 0.22; 95% CI (0.05 to 0.4); P = 0.029], and genus_Coprococcus_2 [βIVW = 0.4; 95% CI (0.1 to 0.6); P = 0.018] were positively correlated with PD-L1; and phylum_Firmicutes [βIVW = -0.3; 95% CI (-0.4 to -0.1); P = 0.031], family_ClostridialesvadinBB60group [βIVW = -0.31; 95% CI (-0.5 to -0.11), P = 0.008], family_Ruminococcaceae [βIVW = -0.33; 95% CI (-0.58 to -0.07); P = 0.049], and genus_Ruminococcaceae_UCG014 [βIVW = -0.35; 95% CI (-0.57 to -0.13); P = 0.006] were negatively correlated with PD-L1. The one significant species in further analysis was species_Parabacteroides_unclassified [βIVW = 0.2; 95% CI (0-0.4); P = 0.029]. Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analyses confirmed the robustness of the MR results.
10.3389/fimmu.2023.1136169
Genetic evidence strengthens the bidirectional connection between gut microbiota and periodontitis: insights from a two-sample Mendelian randomization study.
Journal of translational medicine
BACKGROUND:Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis. MATERIALS AND METHODS:A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation. RESULTS:2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10-1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05-1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03-1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01-1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00-1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70-0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated. CONCLUSIONS:The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.
10.1186/s12967-023-04559-9
Mendelian randomization analysis revealed a gut microbiota-mammary axis in breast cancer.
Frontiers in microbiology
Background:Observational epidemiological studies suggested an association between the gut microbiota and breast cancer, but it remains unclear whether the gut microbiota causally influences the risk of breast cancer. We employed two-sample Mendelian randomization (MR) analysis to investigate this association. Methods:We used summary statistics of the gut microbiome from a genome-wide association study (GWAS) of 18,340 individuals in the MiBioGen study. GWAS summary statistics for overall breast cancer risk and hormone receptor subtype-specific analyses were obtained from the UK Biobank and FinnGen databases, totaling 400,000 individuals. The inverse variance-weighted (IVW) MR method was used to examine the causal relationship between the gut microbiome and breast cancer and its subtypes. Sensitivity analyses were conducted using maximum likelihood, MR-Egger, and MR pleiotropic residual sums and outliers methods. Results:The IVW estimates indicated that an increased abundance of Genus_Sellimonas is causally associated with an increased risk of ER+ breast cancer [odds ratio (OR) = 1.09, = 1.72E-04, false discovery rate (FDR) = 0.02], whereas an increased abundance of Genus_Adlercreutzia was protective against ER+ breast cancer (OR = 0.88, = 6.62E-04, FDR = 0.04). For Her2+ breast cancer, an increased abundance of Genus_Ruminococcus2 was associated with a decreased risk (OR = 0.77, = 4.91E-04, FDR = 0.04), whereas an increased abundance of Genus_Erysipelatoclostridium was associated with an increased risk (OR = 1.25, = 6.58E-04, FDR = 0.04). No evidence of heterogeneity or horizontal pleiotropy was found. Conclusion:Our study revealed a gut microbiota-mammary axis, providing important data supporting the potential use of the gut microbiome as a candidate target for breast cancer prevention, diagnosis, and treatment.
10.3389/fmicb.2023.1193725
Exploring the Complex Relationship between Gut Microbiota and Risk of Colorectal Neoplasia Using Bidirectional Mendelian Randomization Analysis.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
BACKGROUND:Human gut microbiome has complex relationships with the host, contributing to metabolism, immunity, and carcinogenesis. METHODS:Summary-level data for gut microbiota and metabolites were obtained from MiBioGen, FINRISK and human metabolome consortia. Summary-level data for colorectal cancer were derived from a genome-wide association study meta-analysis. In forward Mendelian randomization (MR), we employed genetic instrumental variables (IV) for 24 gut microbiota taxa and six bacterial metabolites to examine their causal relationship with colorectal cancer. We also used a lenient threshold for nine apriori gut microbiota taxa as secondary analyses. In reverse MR, we explored association between genetic liability to colorectal neoplasia and abundance of microbiota studied above using 95, 19, and 7 IVs for colorectal cancer, adenoma, and polyps, respectively. RESULTS:Forward MR did not find evidence indicating causal relationship between any of the gut microbiota taxa or six bacterial metabolites tested and colorectal cancer risk. However, reverse MR supported genetic liability to colorectal adenomas was causally related with increased abundance of two taxa: Gammaproteobacteria (β = 0.027, which represents a 0.027 increase in log-transformed relative abundance values of Gammaproteobacteria for per one-unit increase in log OR of adenoma risk; P = 7.06×10-8), Enterobacteriaceae (β = 0.023, P = 1.29×10-5). CONCLUSIONS:We find genetic liability to colorectal neoplasia may be associated with abundance of certain microbiota taxa. It is more likely that subset of colorectal cancer genetic liability variants changes gut biology by influencing both gut microbiota and colorectal cancer risk. IMPACT:This study highlights the need of future complementary studies to explore causal mechanisms linking both host genetic variation with gut microbiome and colorectal cancer susceptibility.
10.1158/1055-9965.EPI-22-0724
Mendelian randomization supports causality between gut microbiota and chronic hepatitis B.
Frontiers in microbiology
Background:Observational studies have provided evidence of a close association between gut microbiota and the progression of chronic hepatitis B (CHB). However, establishing a causal relationship between gut microbiota and CHB remains a subject of investigation. Methods:Genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of CHB came from the Medical Research Council Integrative Epidemiology Unit (IEU) Open GWAS project. Based on the maximum likelihood (ML), Mendelian randomization (MR)-Egger regression, inverse variance weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and weighted-mode and weighted-median methods, we conducted a bidirectional, two-sample, MR analysis to explore the causal relationship between the gut microbiota and CHB. Additionally, we evaluated the genetic associations between individual gut microbes and CHB using the Linkage disequilibrium score regression (LDSC) program. Results:According to the IVW method estimates, genetically predicted class Alphaproteobacteria (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.34-0.96; false discovery rate [FDR] = 0.046), genus group (OR = 0.60; 95% CI, 0.39-0.91; FDR = 0.026), genus (OR = 0.73; 95% CI, 0.56-0.94; FDR = 0.022) exhibited a protective effect against CHB. On the other hand, family Family XIII (OR = 1.79; 95% CI, 1.03-3.12; FDR = 0.061), genus group (OR = 1.34; 95% CI, 1.04-1.74; FDR = 0.043), genus group (OR = 1.59; 95% CI, 1.01-2.51; FDR = 0.056), genus (OR = 1.35; 95% CI, 1.00-1.82; FDR = 0.049), and genus group (OR = 1.69; 95% CI, 1.10-2.61; FDR = 0.076) were associated with an increased risk of CHB. The results from LDSC also indicated a significant genetic correlation between most of the aforementioned gut microbiota and CHB. Our reverse MR analysis demonstrated no causal relationship between genetically predicted CHB and gut microbiota, and we observed no significant horizontal pleiotropy or heterogeneity of instrumental variables (IVs). Conclusion:In this study, we identified three types of gut microbiota with a protective effect on CHB and five types with an adverse impact on CHB. We postulate that this information will facilitate the clinical prevention and treatment of CHB through fecal microbiota transplantation.
10.3389/fmicb.2023.1243811
A Large Genetic Causal Analysis of the Gut Microbiota and Urological Cancers: A Bidirectional Mendelian Randomization Study.
Nutrients
BACKGROUND:Several observational studies and clinical trials have shown that the gut microbiota is associated with urological cancers. However, the causal relationship between gut microbiota and urological cancers remains to be elucidated due to many confounding factors. METHODS:In this study, we used two thresholds to identify gut microbiota GWAS from the MiBioGen consortium and obtained data for five urological cancers from the UK biobank and Finngen consortium, respectively. We then performed a two-sample Mendelian randomization (MR) analysis with Wald ratio or inverse variance weighted as the main method. We also performed comprehensive sensitivity analyses to verify the robustness of the results. In addition, we performed a reverse MR analysis to examine the direction of causality. RESULTS:Our study found that family , genus , genus , genus , genus , genus , genus , and genus were related to bladder cancer; genus , genus , genus , genus , and genus were related to prostate cancer; class , class , family , genus , genus , genus , genus , genus , and genus were related to renal cell cancer; family , family , genus , genus , and genus were related to renal pelvis cancer; family , genus , and genus were related to testicular cancer. Comprehensive sensitivity analyses proved that our results were reliable. CONCLUSIONS:Our study confirms the role of specific gut microbial taxa on urological cancers, explores the mechanism of gut microbiota on urological cancers from a macroscopic level, provides potential targets for the screening and treatment of urological cancers, and is dedicated to providing new ideas for clinical research.
10.3390/nu15184086
Genetically supported causality between gut microbiota, gut metabolites and low back pain: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Previous studies have implicated a vital association between gut microbiota/gut microbial metabolites and low back pain (LBP), but their causal relationship is still unclear. Therefore, we aim to comprehensively investigate their causal relationship and identify the effect of gut microbiota/gut microbial metabolites on risk of LBP using a two-sample Mendelian randomization (MR) study. Methods:Summary data from genome-wide association studies (GWAS) of gut microbiota (18,340 participants), gut microbial metabolites (2,076 participants) and LBP (FinnGen biobank) were separately obtained. The inverse variance-weighted (IVW) method was used as the main MR analysis. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were conducted to evaluate the horizontal pleiotropy and to eliminate outlier single-nucleotide polymorphisms (SNPs). Cochran's -test was applied for heterogeneity detection. Besides, leave-one-out analysis was conducted to determine whether the causal association signals were driven by any single SNP. Finally, a reverse MR was performed to evaluate the possibility of reverse causation. Results:We discovered that 20 gut microbial taxa and 2 gut microbial metabolites were causally related to LBP ( < 0.05). Among them, the lower level of family (OR: 0.771, 95% CI: 0.652-0.913, FDR-corrected = 0.045) and (OR: 0.875, 95% CI: 0.801-0.955, FDR-corrected = 0.045) retained a strong causal relationship with higher risk of LBP after the Benjamini-Hochberg Corrected test. The Cochrane's test revealed no Heterogeneity ( > 0.05). Besides, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy ( > 0.05). Furthermore, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the 17 gut microbial taxa exposure-outcome effect were significantly attenuated and tended to be null. Conclusion:Our findings confirm the the potential causal effect of specific gut microbiota and gut microbial metabolites on LBP, which offers new insights into the gut microbiota-mediated mechanism of LBP and provides the theoretical basis for further explorations of targeted prevention strategies.
10.3389/fmicb.2023.1157451
Genetically proxied gut microbiota, gut metabolites with risk of epilepsy and the subtypes: A bi-directional Mendelian randomization study.
Frontiers in molecular neuroscience
Background:An increasing number of observational studies have revealed an association among the gut microbiota, gut metabolites, and epilepsy. However, this association is easily influenced by confounders such as diet, and the causality of this association remains obscure. Methods:Aiming to explore the causal relationship and ascertain specific gut microbe taxa for epilepsy, we conducted a bi-directional Mendelian randomization (MR) study based on the genome-wide association study (GWAS) data of epilepsy from the International League Against Epilepsy, with the gut microbiota GWAS results from MiBioGen, and summary-level GWAS data of gut microbiota-dependent metabolites trimethylamine N-oxide and its predecessors. Results:Nine phyla, 15 classes, 19 orders, 30 families, and 96 genera were analyzed. A suggestive association of host-genetic-driven increase in family Veillonellaceae with a higher risk of childhood absence epilepsy (odds ratio [OR]: 1.033, confidential interval [CI]: 1.015-1.051, = 0.0003), class Melainabacteria with a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.986, CI = 0.979-0.994, = 0.0002), class Betaproteobacteria (OR = 0.958, CI = 0.937-0.979, = 0.0001), and order Burkholderiales (OR = 0.960, CI = 0.937-0.984, = 0.0010) with a lower risk of juvenile myoclonic epilepsy were identified after multiple-testing correction. Our sensitivity analysis revealed no evidence of pleiotropy, reverse causality, weak instrument bias, or heterogeneity. Conclusion:This is the first MR analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. Four gut microbiota features (two class levels, one order level, and one family level) were identified as potential interventional targets for patients with childhood absence epilepsy, generalized epilepsy with tonic-clonic seizures, and juvenile myoclonic epilepsy. Previous associations in numerous observational studies may had been interfered by confounders. More rigorous studies were needed to ascertain the relationship among the gut microbiota, metabolites, and epilepsy.
10.3389/fnmol.2022.994270
Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study.
Xiang Kun,Wang Peng,Xu Zhiwei,Hu Yu-Qian,He Yi-Sheng,Chen Yue,Feng Ya-Ting,Yin Kang-Jia,Huang Ji-Xiang,Wang Jie,Wu Zheng-Dong,Yang Xiao-Ke,Wang De-Guang,Ye Dong-Qing,Pan Hai-Feng
Frontiers in immunology
The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that and were positively correlated with the risk of SLE and , and were negatively correlated with SLE risk. The results of weighted median method supported that , , and were risk factors for SLE and and served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.
10.3389/fimmu.2021.667097
Investigating causal associations among gut microbiota, gut microbiota-derived metabolites, and gestational diabetes mellitus: a bidirectional Mendelian randomization study.
Aging
BACKGROUND:Previous studies have shown that gut microbiota (GM) and gut microbiota-derived metabolites are associated with gestational diabetes mellitus (GDM). However, the causal associations need to be treated with caution due to confounding factors and reverse causation. METHODS:This study obtained genetic variants from genome-wide association study including GM ( = 18,340), GM-derived metabolites ( = 7,824), and GDM (5,687 cases and 117,89 controls). To examine the causal association, several methods were utilized, including inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS. Additionally, reverse Mendelian Randomization (MR) analysis and multivariable MR were conducted to confirm the causal direction and account for potential confounders, respectively. Furthermore, sensitivity analyses were performed to identify any potential heterogeneity and horizontal pleiotropy. RESULTS:Greater abundance of was detected to increase the risk of GDM. Our study also found suggestive associations among , , , , , , and with GDM. Besides, eight GM-derived metabolites were found to be causally associated with GDM. For the phenylalanine metabolism pathway, phenylacetic acid was found to be related to the risk of GDM. CONCLUSIONS:The study first used the MR approach to explore the causal associations among GM, GM-derived metabolites, and GDM. Our findings may contribute to the prevention and treatment strategies for GDM by targeting GM and metabolites, and offer novel insights into the underlying mechanism of the disease.
10.18632/aging.204973
Dissecting the causal effect between gut microbiota, DHA, and urate metabolism: A large-scale bidirectional Mendelian randomization.
Frontiers in immunology
Objectives:Our aim was to investigate the interactive causal effects between gut microbiota and host urate metabolism and explore the underlying mechanism using genetic methods. Methods:We extracted summary statistics from the abundance of 211 microbiota taxa from the MiBioGen (N =18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N =7738), gout from the Global Biobank Meta-analysis Initiative (N =1,448,128), urate from CKDGen (N =288,649), and replication datasets from the Global Urate Genetics Consortium (N gout =69,374; N urate =110,347). We used linkage disequilibrium score regression and bidirectional Mendelian randomization (MR) to detect genetic causality between microbiota and gout/urate. Mediation MR and colocalization were performed to investigate potential mediators in the association between microbiota and urate metabolism. Results:Two taxa had a common causal effect on both gout and urate, whereas the family was replicable. Six taxa were commonly affected by both gout and urate, whereas the genus was replicable. Genetic correlation supported significant results in MR. Two microbiota metabolic pathways were commonly affected by gout and urate. Mediation analysis indicated that the order and family had protective effects on urate mediated by increasing docosahexaenoic acid. These two bacteria shared a common causal variant rs182549 with both docosahexaenoic acid and urate, which was located within locus. Conclusions:Gut microbiota and host urate metabolism had a bidirectional causal association, implicating the critical role of host-microbiota crosstalk in hyperuricemic patients. Changes in gut microbiota can not only ameliorate host urate metabolism but also become a foreboding indicator of urate metabolic diseases.
10.3389/fimmu.2023.1148591
Two-Sample Mendelian Randomization Analysis Investigates Causal Associations Between Gut Microbial Genera and Inflammatory Bowel Disease, and Specificity Causal Associations in Ulcerative Colitis or Crohn's Disease.
Frontiers in immunology
Background:Intestinal dysbiosis is associated with inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD, are characterized by unique microbial signatures, respectively. However, it is unclear whether UC or CD has a specific causal relationship with gut microbiota. Objective:To investigate the potential causal associations between gut microbial genera and IBD, UC, or CD, two-sample Mendelian randomization (MR) analyses were conducted. Materials and Methods:We obtained genome-wide association study (GWAS) summary statistics of gut microbiota and IBD, UC, or CD from published GWASs. Two-sample MR analyses were performed to identify potential causal gut microbial genera for IBD, UC, and CD using the inverse-variance weighted (IVW) method. Sensitivity analyses were also conducted to validate the robustness of the primary results of the MR analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results:Combining the results from the primary and sensitivity analyses, six bacterial genera were associated with the risk of IBD, UC, or CD in the IVW method. Briefly, group was associated with a lower risk of IBD (=0.011) and UC (=1.00×10), whereas 2 was associated with a higher risk of IBD (=0.022) and UC (=0.007). In addition, we found a positive association between with IBD (=0.001) and CD (=0.002), and UCG014 with IBD (=0.005) and CD (=0.007). We also noticed a negative association between (=0.044) and IBD, and between UCG001 (=0.023) and CD. We did not find causal effects of IBD, UC, or CD on these bacterial genera in the reverse MR analysis. Conclusion:This study expanded gut microbial genera that were causally associated with the risk of IBD, and also revealed specificity-gut microbial genera for UC or CD.
10.3389/fimmu.2022.921546
Gut microbiome and frailty: insight from genetic correlation and mendelian randomization.
Gut microbes
Observational studies have shown that the gut microbiome is associated with frailty. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between the genetically predicted gut microbiome and frailty using linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR). Summary statistics for the gut microbiome were obtained from a genome-wide association study (GWAS) meta-analysis of the MiBioGen consortium ( = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene ( = 175,226). We used LDSC and MR analyses to estimate the genetic correlation and causality between the genetically predicted gut microbiome and frailty. Our findings indicate a suggestive genetic correlation between and frailty. Moreover, we found evidence for suggestive causal effects of twelve genus-level gut microbes on frailty using at least two MR methods. There was no evidence of horizontal pleiotropy or heterogeneity in the MR analysis. This study provides suggestive evidence for a potential genetic correlation and causal association between several genetically predicted gut microbes and frailty. More population-based observational studies and animal experiments are required to clarify this association and the underlying mechanisms.
10.1080/19490976.2023.2282795
Roles of gut microbiota in atrial fibrillation: insights from Mendelian randomization analysis and genetic data from over 430,000 cohort study participants.
Cardiovascular diabetology
BACKGROUND:Gut microbiota imbalances have been suggested as a contributing factor to atrial fibrillation (AF), but the causal relationship is not fully understood. OBJECTIVES:To explore the causal relationships between the gut microbiota and AF using Mendelian randomization (MR) analysis. METHODS:Summary statistics were from genome-wide association studies (GWAS) of 207 gut microbial taxa (5 phyla, 10 classes, 13 orders, 26 families, 48 genera, and 105 species) (the Dutch Microbiome Project) and two large meta-GWASs of AF. The significant results were validated in FinnGen cohort and over 430,000 UK Biobank participants. Mediation MR analyses were conducted for AF risk factors, including type 2 diabetes, coronary artery disease (CAD), body mass index (BMI), blood lipids, blood pressure, and obstructive sleep apnea, to explore the potential mediation effect of these risk factors in between the gut microbiota and AF. RESULTS:Two microbial taxa causally associated with AF: species Eubacterium ramulus (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.04-1.12, P = 0.0001, false discovery rate (FDR) adjusted p-value = 0.023) and genus Holdemania (OR 1.15, 95% CI 1.07-1.25, P = 0.0004, FDR adjusted p-value = 0.042). Genus Holdemania was associated with incident AF risk in the UK Biobank. The proportion of mediation effect of species Eubacterium ramulus via CAD was 8.05% (95% CI 1.73% - 14.95%, P = 0.008), while the proportion of genus Holdemania on AF via BMI was 12.01% (95% CI 5.17% - 19.39%, P = 0.0005). CONCLUSIONS:This study provided genetic evidence to support a potential causal mechanism between gut microbiota and AF and suggested the mediation role of AF risk factors.
10.1186/s12933-023-02045-6
Gut microbiota causally affects cholelithiasis: a two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:The gut microbiota is closely linked to cholesterol metabolism-related diseases such as obesity and cardiovascular diseases. However, whether gut microbiota plays a causal role in cholelithiasis remains unclear. Aims:This study explored the causal relationship between gut microbiota and cholelithiasis. We hypothesize that the gut microbiota influences cholelithiasis development. Methods:A two-sample Mendelian randomization method was combined with STRING analysis to test this hypothesis. Summary data on gut microbiota and cholelithiasis were obtained from the MiBioGen (n=13,266) and FinnGen R8 consortia (n=334,367), respectively. Results:, , and increased the risk of cholelithiasis and expressed more bile salt hydrolases. In contrast, , , and weakly expressed bile salt hydrolases and were implied to have a protective effect against cholelithiasis by Mendelian randomization analysis. Conclusion:Gut microbiota causally influences cholelithiasis and may be related to bile salt hydrolases. This work improves our understanding of cholelithiasis causality to facilitate the development of treatment strategies.
10.3389/fcimb.2023.1253447
Causality Investigation between Gut Microbiota, Derived Metabolites, and Obstructive Sleep Apnea: A Bidirectional Mendelian Randomization Study.
Nutrients
Various studies have highlighted the important associations between obstructive sleep apnea (OSA) and gut microbiota and related metabolites. Nevertheless, the establishment of causal relationships between these associations remains to be determined. Multiple mendelian randomization (MR) analyses were performed to genetically predict the causative impact of 196 gut microbiota and 83 metabolites on OSA. Two-sample MR was used to assess the potential association, and causality was evaluated using inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Multivariable MR (MVMR) was employed to ascertain the causal independence between gut microbiota and the metabolites linked to OSA. Additionally, Cochran's Q test, the MR Egger intercept test and the MR Steiger test were used for the sensitivity analyses. The analysis of the 196 gut microbiota revealed that _ () (P = 0.010) and _ (P = 0.041) were associated with an increased risk of OSA onset. Conversely, _ (P = 0.030), _ (P = 0.025), _ (P = 0.011), and _ (_) (P = 0.001) were negatively related to the risk of OSA. Among the 83 metabolites evaluated, 3-dehydrocarnitine, epiandrosterone sulfate, and leucine were determined to be potential independent risk factors associated with OSA. Moreover, the reverse MR analysis demonstrated a suggestive association between OSA exposure and six microbiota taxa. This study offers compelling evidence regarding the potential beneficial or detrimental causative impact of the gut microbiota and its associated metabolites on OSA risk, thereby providing new insights into the mechanisms of gut microbiome-mediated OSA development.
10.3390/nu15214544
Association between gut microbiota and primary ovarian insufficiency: a bidirectional two-sample Mendelian randomization study.
Frontiers in endocrinology
Background:Recent studies have indicated a potential correlation between intestinal bacteria and primary ovarian insufficiency (POI). However, the causal relationship between the gut microbiota (GM) and POI remains unclear. Methods:A bidirectional two-sample Mendelian randomization (MR) study was conducted to investigate the relationship between the GM and POI. Data on the GM were based on the MiBioGen consortium's summary statistics from the most comprehensive genome-wide association study meta-analysis to date (n=13,266), and POI data were obtained from the R8 release of the FinnGen consortium, containing a total of 424 cases and 181,796 controls. A variety of analytical methods, including inverse variance weighting, maximum likelihood, MR-Egger, weighted median, and constrained maximum likelihood and model averaging and Bayesian information criterion, were utilized to explore the connection between the GM and POI. The Cochran's Q statistics were used to evaluate the heterogeneity of instrumental variables. The MR-Egger and MR-pleiotropy residual sum and outlier (PRESSO) methods were used to identify the horizontal pleiotropy of instrumental variables. The MR Steiger test was used to evaluate the strength of causal relationships. A reverse MR study was performed to investigate the causal relationship between POI and the targeted GMs which were indicated to have a causal relationship with POI in the forward MR evaluation. Results:The inverse variance weighted analysis indicated that Eubacterium (hallii group) (odds ratio [OR]=0.49, 95% confidence interval [CI]: 0.26-0.9, P=0.022) and Eubacterium (ventriosum group) (OR=0.51, 95% CI: 0.27-0.97, P=0.04) had protective effects on POI, and Intestinibacter (OR=1.82, 95% CI: 1.04-3.2, P=0.037) and Terrisporobacter (OR=2.47, 95% CI: 1.14-5.36, P=0.022) had detrimental effects on POI. Results of the reverse MR analysis indicated that POI had no significant influence on the four GMs. No significant heterogeneity or horizontal pleiotropy was observed in the performance of the instrumental variables. Conclusion:This bidirectional two-sample MR study revealed a causal link between Eubacterium (hallii group), Eubacterium (ventriosum group), Intestinibacter, and Terrisporobacter and POI. Additional clinical trials are needed to gain a clearer understanding of the beneficial or detrimental effects of the GMs on POI and their mechanisms of action.
10.3389/fendo.2023.1183219
Gut microbiota and atopic dermatitis: a two-sample Mendelian randomization study.
Frontiers in medicine
Background:Accumulating evidence suggests that alterations in gut microbiota composition and diversity are associated with Atopic dermatitis (AD). But until now, the causal association between them has been unclear. Methods:We employed a two-sample Mendelian Randomization (MR) study to estimate the potential causality of gut microbiota on AD risk. The summary statistics related to the gut microbiota were obtained from a large-scale genome-wide genotype and 16S fecal microbiome dataset from 18,340 individuals (24 cohorts) analyzed by the MiBioGen Consortium, comprising 211 gut microbiota. AD data were also derived from strictly defined AD data collected by FinnGen biobank analysis, which included 218,467 European ancestors (5,321 AD patients and 213,146 controls). The inverse variance weighted method (IVW), weighted median (WME), and MR-Egger were used to determine the changes of AD pathogenic bacterial taxa, followed by sensitivity analysis including horizontal pleiotropy analysis, Cochran's Q test, and the leave-one-out method to assess the reliability of the results. In addition, MR Steiger's test was used to test the suppositional relationship between exposure and outcome. Results:A total of 2,289 SNPs ( < 1 × 10) were included, including 5 taxa and 17 bacterial characteristics (1 phylum, 3 classes, 1 order, 4 families, and 8 genera), after excluding the IVs with linkage disequilibrium (LD). Combining the analysis of the results of the IVW models, there were 6 biological taxa (2 families, and 4 genera) of the intestinal flora positively associated with the risk of AD and 7 biological taxa (1 phylum, 2 classes, 1 order, 1 family, and 2 genera) of the intestinal flora negatively associated. The IVW analysis results showed that Tenericutes, Mollicutes, Clostridia, Bifidobacteriaceae, Bifidobacteriales, , and Christensenellaceae R 7 group were negatively correlated with the risk of AD, while Clostridiaceae 1, Bacteroidaceae, Bacteroides, Anaerotruncus, the unknown genus, and Lachnospiraceae UCG001 showed the opposite trend. And the results of the sensitivity analysis were robust. MR Steiger's test showed a potential causal relationship between the above intestinal flora and AD, but not vice versa. Conclusion:The present MR analysis genetically suggests a causal relationship between changes in the abundance of the gut microbiota and AD risk, thus not only providing support for gut microecological therapy of AD but also laying the groundwork for further exploration of the mechanisms by which the gut microbiota contributes to the pathogenesis of AD.
10.3389/fmed.2023.1174331
Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis.
Frontiers in immunology
Background:Accumulating evidence has suggested that gut microbiota dysbiosis is commonly observed in asthmatics. However, it remains unclear whether dysbiosis is a cause or consequence of asthma. We aimed to examine the genetic causal relationships of gut microbiota with asthma and its three phenotypes, including adult-onset asthma, childhood-onset asthma, and moderate-severe asthma. Methods:To elucidate the causality of gut microbiota with asthma, we applied two sample Mendelian randomization (MR) based on the largest publicly available genome-wide association study (GWAS) summary statistics. Inverse variance weighting meta-analysis (IVW) was used to obtain the main estimates; and Weighted median, MR-Egger, Robust Adjusted Profile Score (MR-RAPS), Maximum likelihood method (ML), and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied in sensitivity analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results:In the absence of heterogeneity and horizontal pleiotropy, the IVW method revealed that genetically predicted and were positively correlated with the risk of asthma, while the association between genetically predicted and asthma was negative. And for the three phenotypes of asthma, genetically predicted reduced the risk of adult-onset asthma, and increased the risk of childhood-onset asthma, and , , and were correlated with the risk of moderate-severe asthma (all <0.05). The reverse MR analysis didn't find evidence supporting the reverse causality from asthma and its three phenotypes to the gut microbiota genus. Conclusion:This study suggested that microbial genera were causally associated with asthma as well as its three phenotypes. The findings deepened our understanding of the role of gut microbiota in the pathology of asthma, which emphasizes the potential of opening up a new vista for the prevention and diagnosis of asthma.
10.3389/fimmu.2023.1148684
Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods:Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results:At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion:Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
10.3389/fcimb.2023.1171517
Gut microbiota and cerebrovascular diseases: a Mendelian randomization study.
Frontiers in microbiology
Background:The causal relationship between gut microbiota and cerebrovascular disease remains unknown, despite several recent studies reporting an association between the two. Methods:To assess this relationship, we conducted a two-sample Mendelian randomization (MR) using summary statistics data from published genome-wide association studies (GWAS). This analysis allowed us to identify bacterial taxa that may affect cerebrovascular disease. Furthermore, we performed reverse MR to further analyze the significant bacterial taxa. Finally, we conducted a two-step MR analysis to examine the mediating role of metabolic factors [systolic blood pressure (SBP), type 2 diabetes (T2D), and body mass index (BMI)] in the association between gut microbiota and cerebrovascular disease. Additionally, a series of sensitivity analyses were carried out to validate the robustness of our findings. Results:Our results showed that a genetically predicted high abundance of family Porphyromonadaceae reduced the risk of intracranial aneurysms (IA). Moreover, using inverse variance weighted (IVW) estimates, we found a nominal causal relationship between seventeen gut microbiota and IA, as well as its subtypes. In the case of stroke and its subtypes, we observed a nominal causal relationship with thirteen, eleven, eleven, nine, and eight bacteria for AS, AIS, CES, LAS, and SVS, respectively. Reverse MR analysis showed no significant causal relationship between intracranial aneurysms and gut microbiota. However, we did find that genetically predicted any stroke (AS) and any ischemic stroke (AIS) reduced the abundance of family Clostridiaceae1 (OR: 0.74, 95% CI: 0.62-0.87, = 3.39 × 10, and OR: 0.75, 95% CI: 0.66-0.87, = 7.06 × 10, respectively). Furthermore, genetic prediction of AIS (OR: 0.87, 95% CI: 0.77-0.99, = 3.05 × 10) was associated with a reduced abundance of the order Clostridiales. Moreover, genus Streptococcus exhibited effects on AS, AIS, and SVS which were mediated by T2D. Conversely, the association between genus group and AIS was mediated by SBP. No significant heterogeneity of instrumental variables or horizontal pleiotropy was observed. Conclusion:This MR analysis indicates that there exists a beneficial or detrimental causal effect of gut microbiota composition on cerebrovascular disease. And SBP and T2D may play mediating role in this process.
10.3389/fmicb.2023.1228815
Causal Relationship between Gut Microbiota and Gout: A Two-Sample Mendelian Randomization Study.
Nutrients
Gout is a form of prevalent and painful inflammatory arthritis characterized by elevated serum urate (SUA) levels. The gut microbiota (GM) is believed to influence the development of gout and SUA levels. Our study aimed to explore the causal relationship between GM composition and gout, as well as SUA levels, utilizing a two-sample Mendelian Randomization (MR) approach. A total of 196 GM taxa from five levels were available for analysis. We identified five taxa associated with SUA levels and 10 taxa associated with gout. In reverse MR analysis, we discovered that gout affected the composition of five GM taxa, while SUA levels influenced the composition of 30 GM taxa. Combining existing research, our study unveiled a potential negative feedback loop between phylum and SUA levels, establishing connections with gout. We also proposed two novel associations connecting GM taxa (genus and genus ), SUA levels, and gout. These findings provide compelling evidence of causal relationships between specific GM taxa with SUA levels and gout, contributing valuable insights for the treatment of gout.
10.3390/nu15194260
Causal effects of specific gut microbiota on musculoskeletal diseases: a bidirectional two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Recent observational studies and clinical trials demonstrated an association between gut microbiota and musculoskeletal (MSK) diseases. Nonetheless, whether the gut microbiota composition has a causal effect on the risk of MSK diseases remains unclear. Methods:Based on large-scale genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between gut microbiota and six MSK diseases, namely osteoporosis (OP), fracture, sarcopenia, low back pain (LBP), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). Instrumental variables for 211 gut microbiota taxa were obtained from the largest available GWAS meta-analysis ( = 18,340) conducted by the MiBioGen consortium. And the summary-level data for six MSK diseases were derived from published GWAS. The inverse-variance weighted (IVW) method was conducted as a primary analysis to estimate the causal effect, and the robustness of the results was tested via sensitivity analyses using multiple methods. The Bonferroni-corrected test was used to determine the strength of the causal relationship between gut microbiota and various MSK diseases. Finally, a reverse MR analysis was applied to evaluate reverse causality. Results:According to the IVW method, we found 57 suggestive causal relationships and 3 significant causal relationships between gut microbiota and MSK diseases. Among them, (β: 0.035, 95% CI: 0.013-0.058, = 0.0002) was associated with increased left handgrip strength, (OR: 1.151, 95% CI: 1.065-1.245, = 0.0003) was correlated with an increased risk of LBP, and (OR: 0.792, 95% CI: 0.698-0.899, = 0.0003) was linked with a decreased risk of RA. Subsequently, sensitivity analyses revealed no heterogeneity, directional pleiotropy, or outliers for the causal effect of specific gut microbiota on MSK diseases ( > 0.05). Reverse MR analysis showed fracture may result in a higher abundance of ( = 0.030) and sarcopenia may lead to a higher abundance of ( = 0.032). Conclusion:Genetic evidence suggested a causal relationship between specific bacteria taxa and six MSK diseases, which highlights the association of the "gut-bone/muscle" axis. Further exploration of the potential microbiota-related mechanisms of bone and muscle metabolism might provide novel insights into the prevention and treatment of MSK diseases.
10.3389/fmicb.2023.1238800
Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study.
Frontiers in immunology
Background:Sepsis stands as a dire medical condition, arising when the body's immune response to infection spirals into overdrive, paving the way for potential organ damage and potential mortality. With intestinal flora's known impact on sepsis but a dearth of comprehensive data, our study embarked on a two-sample Mendelian randomization analysis to probe the causal link between gut microbiota and their metabolites with severe sepsis patients who succumbed within a 28-day span. Methods:Leveraging data from Genome-wide association study (GWAS) and combining it with data from 2,076 European descendants in the Framingham Heart Study, single-nucleotide polymorphisms (SNPs) were employed as Instrumental Variables (IVs) to discern gene loci affiliated with metabolites. GWAS summary statistics for sepsis were extracted from the UK Biobank consortium. Results:In this extensive exploration, 93 distinct genome-wide significant SNPs correlated with gut microbial metabolites and specific bacterial traits were identified for IVs construction. Notably, a substantial link between Coprococcus2 and both the incidence (OR of 0.80, 95% CI: 0.68-0.94, =0.007) and the 28-day mortality rate (OR 0.48, 95% CI: 0.27-0.85, =0.013) of sepsis was observed. The metabolite α-hydroxybutyrate displayed a marked association with sepsis onset (OR=1.08, 95% CI: 1.02-1.15, =0.006) and its 28-day mortality rate (OR=1.17, 95% CI: 1.01-1.36, =0.029). Conclusion:This research unveils the intricate interplay between the gut microbial consortium, especially the genus Coprococcus, and the metabolite α-hydroxybutyrate in the milieu of sepsis. The findings illuminate the pivotal role of intestinal microbiota and their metabolites in sepsis' pathogenesis, offering fresh insights for future research and hinting at novel strategies for sepsis' diagnosis, therapeutic interventions, and prognostic assessments.
10.3389/fimmu.2023.1190230
Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study.
Frontiers in endocrinology
Objective:There is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship. Methods:Instrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW). Results:IVW results confirmed that ( = 0.0249), ( = 0.0237), ( = 0.0245), ( = 0.0083), ( = 0.0163), and ( = 0.0472) were protective factors for NAFLD, and ( = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, ( = 0.0388), ( = 0.0252), and ( = 0.0364), was correlated with a lower risk of ALD, while level was associated with a higher risk of ALD ( = 0.0371). The ( = 0.0069) and ( = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine ( = 0.0076) and phenyllactate ( = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (O = 0.0244) was found to be positively associated with NAFLD. The phenylacetate ( = 0.0353) and ursodeoxycholate ( = 0.0144) had a protective effect on ALD, while the threonate ( = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine ( = 0.0408) and cholate ( = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate ( = 0.0401) displayed its suggestive protective effect against viral hepatitis. Conclusion:In conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.
10.3389/fendo.2023.1159148
Revealing a causal relationship between gut microbiota and lung cancer: a Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:The gut microbiota has been found to be associated with the risk of lung cancer. However, its causal relationship with various types of lung cancer remains unclear. Methods:We conducted a Mendelian randomization (MR) study using the largest genome-wide association analysis of gut microbiota data to date from the MiBioGen consortium, with pooled statistics for various types of lung cancer from the Transdisciplinary Research in Cancer of the Lung, the International Lung Cancer Consortium, and FinnGen Consortium R7 release data. Inverse variance weighted, weighted model, MR-Egger regression, and weighted median were adapted to assess the causal relationship between gut microbiota and various types of lung cancer. Sensitivity analysis was used to test for the presence of pleiotropy and heterogeneity in instrumental variables. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. A reverse MR analysis was performed on these bacteria to determine their potential role in causing lung cancer. Multivariable Mendelian randomization (MVMR) was conducted to assess the direct causal impact of gut microbiota on the risk of various types of lung cancer. Results:Using IVW as the primary analytical method, we identified a total of 40 groups of gut microbiota with potential causal associations with various subtypes of lung cancer, of which 10 were associated with lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell lung cancer, and 11 groups of bacteria associated with small cell lung cancer. After performing FDR correction, we further found that there was still a significant causal relationship between Peptococcaceae and lung adenocarcinoma. Sensitivity analyses demonstrated the robustness of these results, with no heterogeneity or pleiotropy found. Conclusions:Our results confirm a causal relationship between specific gut microbiota and lung cancer, providing new insights into the role of gut microbiota in mediating the development of lung cancer.
10.3389/fcimb.2023.1200299
Gut microbiota and acne: A Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Prior observational studies have identified a relationship between the composition of gut microbiota and the onset of acne. To ascertain the causal relationship underlying this association, we adopted the Mendelian randomization (MR) method, which offers a powerful approach to causal inference. METHODS:Summary statistics on gut microbiota and acne were obtained from the MiBioGen and FinnGen consortium, respectively. The causal relationship was assessed using multiple methods in a two-sample framework, including MR Egger, weighted median, inverse variance weighted (IVW), and weighted mode. Furthermore, the heterogeneity and horizontal pleiotropy analyses were conducted, along with the leave-one-out method. RESULTS:The IVW estimation indicated that Allisonella (odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.18-1.70, p = 0.0002) and Bacteroides (OR = 2.25, 95% CI = 1.48-3.42, p = 0.0001) have adverse effects on acne. By contrast, Ruminococcus torques group (OR = 0.41, 95% CI = 0.25-0.65, p = 0.0002) showed a beneficial effect on acne. In addition, Candidatus soleaferrea (OR = 0.75, 95% CI = 0.60-0.95, p = 0.0149), Eubacterium coprostanoligenes group (OR = 0.67, 95% CI = 0.47-0.95, p = 0.0230), Fusicatenibacter (OR = 0.71, 95% CI = 0.52-0.97, p = 0.02897), and Lactobacillus (OR = 0.72, 95% CI = 0.58-0.90, p = 0.0046) showed suggestive associations with acne. CONCLUSION:The present investigation suggests a causal effect of gut microbiota on acne.
10.1111/srt.13473
Association of gut microbiota with COVID-19 susceptibility and severity: A two-sample Mendelian randomization study.
Journal of medical virology
Evidence supports the observational associations of gut microbiota with the risk of COVID-19; however, it is unclear whether these associations reflect a causal relationship. This study investigated the association of gut microbiota with COVID-19 susceptibility and severity. Data were obtained from a large-scale gut microbiota data set (n = 18 340) and the COVID-19 Host Genetics Initiative (n = 2 942 817). Causal effects were estimated with inverse variance weighted (IVW), MR-Egger, and weighted median, and sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. For COVID-19 susceptibility, IVW estimates suggested that Gammaproteobacteria (odds ratio [OR] = 0.94, 95% confidence interval [CI], 0.89-0.99, p = 0.0295] and Streptococcaceae (OR = 0.95, 95% CI, 0.92-1.00, p = 0.0287) had a reduced risk, while Negativicutes (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Selenomonadales (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Bacteroides (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283), and Bacteroidaceae (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283) were associated with an increased risk (all p < 0.05, nominally significant). For COVID-19 severity, Subdoligranulum (OR = 0.80, 95% CI, 0.69-0.92, p = 0.0018), Cyanobacteria (OR = 0.85, 95% CI, 0.76-0.96, p = 0.0062), Lactobacillales (OR = 0.87, 95% CI, 0.76-0.98, p = 0.0260), Christensenellaceae (OR = 0.87, 95% CI, 0.77-0.99, p = 0.0384), Tyzzerella3 (OR = 0.89, 95% CI, 0.81-0.97, p = 0.0070), and RuminococcaceaeUCG011 (OR = 0.91, 95% CI, 0.83-0.99, p = 0.0247) exhibited negative correlations, while RikenellaceaeRC9 (OR = 1.09, 95% CI, 1.01-1.17, p = 0.0277), LachnospiraceaeUCG008 (OR = 1.12, 95% CI, 1.00-1.26, p = 0.0432), and MollicutesRF9 (OR = 1.14, 95% CI, 1.01-1.29, p = 0.0354) exhibited positive correlations (all p < 0.05, nominally significant). Sensitivity analyses validated the robustness of the above associations. These findings suggest that gut microbiota might influence the susceptibility and severity of COVID-19 in a causal way, thus providing novel insights into the gut microbiota-mediated development mechanism of COVID-19.
10.1002/jmv.28734
Association of gut microbiota and dietary component intake with COVID-19: A mendelian randomization study.
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND:Growing evidence has indicated that alterations in the gut microbiota and nutritional quality of dietary intake were associated with COVID-19. Whether these associations reflect causality is still unknown. METHODS:We performed a two-sample Mendelian randomization analysis using genetic variants as instrumental variables for gut microbiota, dietary component intake, and COVID-19. FINDINGS:We found that the Ruminococcustorques group genus was significantly associated with COVID-19. The Ruminococcaceae UCG013 genus and Ruminococcus1 genus were suggestively associated with COVID-19. The Actinobacteria class, Bifidobacteriales order, Bifidobacteriaceae genus, R. group, and Tyzzerella3 genus were potentially associated with severe COVID-19. COVID-19 was significantly associated with the Lachnospira genus, Oscillospira, and RuminococcaceaeUCG009 genus and potentially associated with the Victivallis genus. Severe COVID-19 was significantly associated with the Turicibacter and Olsenella genus and potentially associated with Ruminococcus1, CandidatusSoleaferrea, and Parasutterella genus. Moreover, processed meat intake was significantly associated with COVID-19. Beef intake was suggestively associated with COVID-19. Salt added to food intake, and fresh fruit intake was suggestively associated with severe COVID-19. CONCLUSIONS:Our findings provide evidence supporting a causal effect of gut microbiota and dietary intake on COVID-19. We also found the causal effect of COVID-19 on the alteration of gut microbiota.
10.1016/j.clnu.2023.06.017
Causal associations between gut microbiota and sepsis: A two-sample Mendelian randomization study.
European journal of clinical investigation
BACKGROUND:Targeting the gut microbiota may become a new therapeutic to prevent and treat sepsis. Nonetheless, the causal relationship between specific intestinal flora and sepsis is still unclear. METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study (n = 18,340). The summary statistics of sepsis were obtained from the UK Biobank (n = 486,484). Inverse-variance weighted, weighted median and MR-Egger were used to examine the causal association between gut microbiota and sepsis. Cochrane's Q test, MR-Egger intercept test, MR-PRESSO Global test and Rucker's Q'-test were used for sensitivity analyses. The leave-one method was used for testing the stability of MR results, and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS:Nine intestinal microflora were found causally associated with sepsis, and 11 intestinal microflora were causally associated with 28-day death in sepsis. Among them, Order Victivallales had a strong causality with lower risk of sepsis (OR = 0.86, 95% CI: 0.78-0.94, p = .00165) and lower 28-day mortality of sepsis (OR = 0.68, 95% CI: 0.53-0.87, p = .00179) after Bonferroni-corrected test. No pleiotropy was detected. CONCLUSIONS:Through the two-sample MR analysis, we identified the specific intestinal flora that had a causal relationship with the risk and prognosis of sepsis at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for sepsis.
10.1111/eci.14064
Association between gut microbiota and gastrointestinal cancer: a two-sample bi-directional Mendelian randomization study.
Frontiers in microbiology
Background:The gut microbiome is closely related to gastrointestinal (GI) cancer, but the causality of gut microbiome with GI cancer has yet to be fully established. We conducted this two-sample Mendelian randomization (MR) study to reveal the potential causal effect of gut microbiota on GI cancer. Materials and methods:Summary-level genetic data of gut microbiome were derived from the MiBioGen consortium and the Dutch Microbiome Project. Summary statistics of six GI cancers were drawn from United Kingdom Biobank. Inverse-variance-weighted (IVW), MR-robust adjusted profile score (MR-RAPS), and weighted-median (WM) methods were used to evaluate the potential causal link between gut microbiota and GI cancer. In addition, we performed sensitivity analyses and reverse MR analyses. Results:We identified potential causal associations between 21 bacterial taxa and GI cancers (values of < 0.05 in all three MR methods). Among them, phylum (OR: 0.17, 95% CI: 0.05-0.59, = 0.005) retained a strong negative association with intrahepatic cholangiocarcinoma after the Bonferroni correction, whereas order (OR: 1.67, 95% CI: 1.23-2.26, = 0.001) retained a strong positive association with pancreatic cancer. Reverse MR analyses indicated that GI cancer was associated with 17 microbial taxa in all three MR methods, among them, a strong inverse association between colorectal cancer and family (OR: 0.91, 95% CI: 0.86-0.96, = 0.001) was identified by Bonferroni correction. Conclusion:Our study implicates the potential causal effects of specific microbial taxa on GI cancer, potentially providing new insights into the prevention and treatment of GI cancer through specific gut bacteria.
10.3389/fmicb.2023.1181328
Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology.
Journal of translational medicine
BACKGROUND:Gut microbiota alterations have been implicated in sepsis and related infectious diseases, but the causal relationship and underlying mechanisms remain unclear. METHODS:We evaluated the association between gut microbiota composition and sepsis using two-sample Mendelian randomization (MR) analysis based on published genome-wide association study (GWAS) summary statistics. Sensitivity analyses were conducted to validate the robustness of the results. Reverse MR analysis and integration of GWAS and expression quantitative trait loci (eQTL) data were performed to identify potential genes and therapeutic targets. RESULTS:Our analysis identified 11 causal bacterial taxa associated with sepsis, with increased abundance of six taxa showing positive causal relationships. Ten taxa had causal effects on the 28-day survival outcome of septic patients, with increased abundance of six taxa showing positive associations. Sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis did not provide evidence of reverse causality. Integration of GWAS and eQTL data revealed 76 genes passing the summary data-based Mendelian randomization (SMR) test. Differential expression of these genes was observed between sepsis patients and healthy individuals. These genes represent potential therapeutic targets for sepsis. Molecular docking analysis predicted potential drug-target interactions, further supporting their therapeutic potential. CONCLUSION:Our study provides insights for the development of personalized treatment strategies for sepsis and offers preliminary candidate targets and drugs for future drug development.
10.1186/s12967-023-04835-8
Causal associations between gut microbiota and adverse pregnancy outcomes: A two-sample Mendelian randomization study.
Frontiers in microbiology
Growing evidence indicates that gut microbiota could be closely associated with a variety of adverse pregnancy outcomes (APOs), but a causal link between gut microbiome and APOs has yet to be established. Therefore, in this study, we comprehensively investigated the relationship between gut microbiota and APOs to identify specific causal bacteria that may be associated with the development and occurrence of APOs by conducting a two-sample Mendelian randomization (MR) analysis. The microbiome genome-wide association study (GWAS) from the MiBioGen consortium was used as exposure data, and the GWAS for six common APOs was used as outcome data. Single-nucleotide polymorphisms (SNPs) that significantly correlated to exposure, data obtained from published GWAS, were selected as instrumental variables (IVs). We used the inverse variance-weighted (IVW) test as the main MR analysis to estimate the causal relationship. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to confirm the presence of horizontal pleiotropy and to exclude outlier SNPs. We performed Cochran's Q test to assess the heterogeneity among SNPs associated with each bacterium. The leave-one-out sensitivity analysis was used to evaluate whether the overall estimates were affected by a single SNP. Our analysis shows a causal association between specific gut microbiota and APOs. Our findings offer novel insights into the gut microbiota-mediated development mechanism of APOs.
10.3389/fmicb.2022.1059281
Causal associations between gut microbiota and urological tumors: a two-sample mendelian randomization study.
BMC cancer
BACKGROUND:Dysbiosis of gut microbiota has been linked to numerous diseases, including cancer. The unique role of gut microbiota in urological tumors is gaining prominence. However, it is still controversial whether the dysbiosis of gut microbiota should be one of the etiological factors of bladder cancer (BCa), prostate cancer (PCa) or kidney cancer (KCa). MATERIALS AND METHODS:The microbiome genome-wide association study (GWAS) from the MiBioGen consortium (18,340 samples of 24 population-based cohorts) was utilized as the exposure data. Additionally, outcomes data (951 BCa cases and 307,092 controls; 1,631 KCa cases and 238,678 controls; 79,148 PCa cases and 61,106 controls) were extracted from the GWAS of the FinnGen and PRACTICAL consortia. To detect the potential causative bacterial traits for BCa, PCa, and KCa, a two-sample Mendelian randomization (MR) analysis was performed, employing the inverse-variance weighted or Wald ratio method. Sensitivity analyses were subsequently conducted to explore the robustness of the primary results. Finally, the reverse MR analysis was undertaken to mitigate the reverse causation. RESULTS:This study suggested that Bifidobacterium (p = 0.030), Actinobacteria (p = 0.037 for phylum, 0.041 for class), and Ruminococcustorques group (p = 0.018), exhibited an association with an increased risk of BCa using either the inverse-variance weighted or Wald ratio method. By utilizing the Wald ratio method, Allisonella (p = 0.004, p = 0.038) was associated with a decreased risk of BCa and PCa, respectively. Furthermore, Ruminococcustorques group (p = 0.028) and Erysipelatoclostridium (p = 0.048) were causally linked to an elevated risk of KCa. CONCLUSIONS:This MR study supports that genetically predicted gut microbiota is causally related to BCa, PCa and KCa. Additionally, distinct bacterial traits are identified in relation to each tumor type.
10.1186/s12885-023-11383-3
The causal relationship between gut microbiota and inflammatory dermatoses: a Mendelian randomization study.
Frontiers in immunology
Background:Observational studies have shown that gut microbiota is closely associated with inflammatory dermatoses such as psoriasis, rosacea, and atopic dermatitis (AD). However, the causal relationship between gut microbiota and inflammatory dermatosis remains unclear. Methods:Based on Maximum Likelihood (ML), MR-Egger regression, Inverse Variance Weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Weighted Mode, and Weighted Median Estimator (WME) methods, we performed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between gut microbiota and inflammatory dermatosis. The genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of inflammatory dermatosis (including psoriasis, AD, rosacea, vitiligo, acne, and eczema) came from the FinnGen consortium and IEU Open GWAS project. Cochran's IVW Q test tested the heterogeneity among instrumental variables (IVs). The horizontal pleiotropy was tested by MR-Egger regression intercept analysis and MR-PRESSO analysis. Results:Eventually, the results indicated that 5, 16, 17, 11, 15, and 12 gut microbiota had significant causal effects on psoriasis, rosacea, AD, vitiligo, acne, and eczema, respectively, including 42 protective and 34 risk causal relationships. Especially, Lactobacilli and Bifidobacteria at the Family and Genus Level, as common probiotics, were identified as protective factors for the corresponding inflammatory dermatoses. The results of reverse MR analysis suggested a bidirectional causal effect between AD and genus Eubacterium brachy group, vitiligo and genus Ruminococcaceae UCG004. The causal relationship between gut microbiota and psoriasis, rosacea, acne, and eczema is unidirectional. There was no significant heterogeneity among these IVs. In conclusion, this bidirectional two-sample MR study identified 76 causal relationships between the gut microbiome and six inflammatory dermatoses, which may be helpful for the clinical prevention and treatment of inflammatory dermatoses.
10.3389/fimmu.2023.1231848
Associations between gut microbiota and Parkinson disease: A bidirectional Mendelian randomization analysis.
European journal of neurology
BACKGROUND AND PURPOSE:Parkinson disease (PD)-associated alterations in the gut microbiome have been observed in clinical and animal studies. However, it remains unclear whether this association reflects a causal effect in humans. METHODS:We performed two-sample bidirectional Mendelian randomization using summary statistics from the international consortium MiBioGen (N = 18,340), the Framingham Heart Study (N = 2076), and the International Parkinson's Disease Genomics Consortium for PD (33,674 cases and 449,056 controls) and PD age at onset (17,996 cases). RESULTS:Twelve microbiota features presented suggestive associations with PD risk or age at onset. Genetically increased Bifidobacterium levels correlated with decreased PD risk (odds ratio = 0.77, 95% confidence interval [CI] = 0.60-0.99, p = 0.040). Conversely, high levels of five short-chain fatty acid (SCFA)-producing bacteria (LachnospiraceaeUCG010, RuminococcaceaeUCG002, Clostridium sensustricto1, Eubacterium hallii group, and Bacillales) correlated with increased PD risk, and three SCFA-producing bacteria (Roseburia, RuminococcaceaeUCG002, and Erysipelatoclostridium) correlated with an earlier age at PD onset. Gut production of serotonin was associated with an earlier age at PD onset (beta = -0.64, 95% CI = -1.15 to -0.13, p = 0.013). In the reverse direction, genetic predisposition to PD was related to altered gut microbiota composition. CONCLUSIONS:These results support a bidirectional relationship between gut microbiome dysbiosis and PD, and highlight the role of elevated endogenous SCFAs and serotonin in PD pathogenesis. Future clinical studies and experimental evidence are needed to explain the observed associations and to suggest new therapeutic approaches, such as dietary probiotic supplementation.
10.1111/ene.15848
The Effects of Specific Gut Microbiota and Metabolites on IgA Nephropathy-Based on Mendelian Randomization and Clinical Validation.
Nutrients
BACKGROUND:Although recent research suggests that alterations in gut microbiota and metabolites play a critical role in the pathophysiology of immunoglobulin A nephropathy (IgAN), the causal relationship between specific intestinal flora and metabolites and the risk of IgAN remains unclear. METHOD:This study employed Mendelian randomization (MR) to investigate the causal association between gut microbiota and IgAN. To explore potential associations between gut microbiota and various outcomes, four MR methods were applied: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. If the results of the four methods are inconclusive, we prefer the IVW as the primary outcome. Additionally, MR-Egger, MR-PRESSO-Global, and Cochrane's Q tests were used to detect heterogeneity and pleiotropy. The stability of MR findings was assessed using the leave-one-out approach, and the strength of the causal relationship between exposure and outcome was tested using Bonferroni correction. Additional clinical samples were utilized to validate the results of Mendelian randomization, and the outcomes were visualized through an ROC curve, confusion matrix, and correlation analysis. RESULT:This study examined a total of 15 metabolites and 211 microorganisms. Among them, eight bacteria and one metabolite were found to be associated with the risk of IgAN ( < 0.05). The Bonferroni-corrected test reveals that only Class. Actinobacteria (OR: 1.20, 95% CI: 1.07-1.36, = 0.0029) have a significant causal relationship with IgAN. According to Cochrane's Q test, there is no substantial heterogeneity across different single-nucleotide polymorphisms ( > 0.05). Furthermore, MR-Egger and MR-PRESSO-Global tests ( > 0.05) showed no evidence of pleiotropy. No reverse causal association was found between the risk of IgAN and microbiota or metabolites ( > 0.05). Clinical specimens demonstrated the effectiveness and accuracy of Actinobacteria in distinguishing IgAN patients from those with other glomerular diseases (AUC = 0.9, 95% CI: 0.78-1.00). Additionally, our correlation analysis revealed a potential association between Actinobacteria abundance and increased albuminuria (r = 0.85) and poorer prognosis in IgAN patients ( = 0.01). CONCLUSION:Through MR analysis, we established a causal link between Actinobacteria and the incidence of IgAN. Moreover, clinical validation using fecal samples indicated that Actinobacteria might be associated with the onset and poorer prognosis of IgAN. This finding could provide valuable biomarkers for early, noninvasive detection of the disease and potential therapeutic targets in IgAN.
10.3390/nu15102407
The causal links between gut microbiota and COVID-19: A Mendelian randomization study.
Journal of medical virology
Several studies have shown a possible correlation between gut microbiota and COVID-19. However, the cause-and-effect relationship between the two has not been investigated. We conducted a two-sample Mendelian randomization study (MR) study using publicly available GWAS data. Inverse variance weighted (IVW) analysis was the main MR analysis technique and was supplemented with other sensitivity analyses. Forty-two bacterial genera were associated with COVID-19 susceptibility, hospitalization, and severity in the IVW method. Among these gut microbiota, five gut microbiota (genus unknowngenus [id.1000005472], family unknownfamily [id.1000005471], genus Tyzzerella3, order MollicutesRF9.id.11579, and phylum Actinobacteria) were significantly associated with COVID-19 hospitalization and severity. Three gut microbiota (class Negativicutes, order Selenomonadales, and class Actinobacteria) were significantly associated with COVID-19 hospitalization and susceptibility, while two microbiota (class Negativicutes and order Selenomonadales) were significantly associated with COVID-19 hospitalization and severity, and susceptibility. Sensitivity analysis did not detect any heterogeneity and horizontal pleiotropy. Our findings demonstrated that several microorganisms were causally linked to COVID-19, and improved our understanding of the relationship between gut microbiota and COVID-19 pathology.
10.1002/jmv.28784
Association between gut microbiota and longevity: a genetic correlation and mendelian randomization study.
BMC microbiology
BACKGROUND:Longevity is one of the most complex phenotypes, and its genetic basis remains unclear. This study aimed to explore the genetic correlation and potential causal association between gut microbiota and longevity. RESULTS:Linkage disequilibrium score (LDSC) regression analysis and a bi-directional two-sample Mendelian Randomization (MR) analysis were performed to analyze gut microbiota and longevity-related traits. LDSC analysis detected four candidate genetic correlations, including Veillonella (genetic correlation = 0.5578, P = 4.67 × 10) and Roseburia (genetic correlation = 0.4491, P = 2.67 × 10) for longevity, Collinsella (genetic correlation = 0.3144, P = 4.07 × 10) for parental lifespan and Sporobacter (genetic correlation = 0.2092, P = 3.53 × 10) for healthspan. Further MR analysis observed suggestive causation between Collinsella and parental longevity (father's age at death) (weighted median: b = 1.79 × 10, P = 3.52 × 10). Reverse MR analysis also detected several causal effects of longevity-related traits on gut microbiota, such as longevity and Sporobacter (IVW: b = 7.02 × 10, P = 4.21 × 10). Statistical insignificance of the heterogeneity test and pleiotropy test supported the validity of the MR study. CONCLUSION:Our study found evidence that gut microbiota is causally associated with longevity, or vice versa, providing novel clues for understanding the roles of gut microbiota in aging development.
10.1186/s12866-022-02703-x
Investigating association between gut microbiota and sarcopenia-related traits: a Mendelian randomization study.
Precision clinical medicine
Background:Observational studies have indicated a potential link between gut microbiota and sarcopenia. However, the underlying mechanisms and a causal relationship have not been established. Thus, the objective of this study is to examine the possible causal association between gut microbiota and sarcopenia-related traits, including low hand-grip strength and appendicular lean mass (ALM), to shed light on the gut-muscle axis. Methods:To investigate the potential impact of gut microbiota on low hand-grip strength and ALM, we utilized a two-sample Mendelian randomization (MR) approach. Summary statistics were obtained from genome-wide association studies of gut microbiota, low hand-grip strength, and ALM. The primary MR analysis employed the random-effects inverse-variance weighted (IVW) method. To assess the robustness, we conducted sensitivity analyses using the MR pleiotropy residual sum and outlier (MR-PRESSO) test to detect and correct for horizontal pleiotropy, as well as the MR-Egger intercept test and leave-one-out analysis. Results:, and were positively associated with the risk of low hand-grip strength (-values < 0.05). were negatively associated with low hand-grip strength (-values < 0.05). Eight bacterial taxa (, and were associated with a higher risk of ALM (-values < 0.05). group was negatively associated with ALM (-values < 0.05). Conclusion:We found several gut microbiota components causally associated with sarcopenia-related traits. Our findings provided insights into novel strategies for the prevention and treatment of sarcopenia through the regulation of the gut microbiota, contributing to a better understanding of the gut-muscle axis.
10.1093/pcmedi/pbad010
Causal associations between human gut microbiota and cholelithiasis: a mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:There was some evidence that gut microbiota was closely related to cholelithiasis, but the causal relationship between them remained unclear. In this study, we try to use Two-sample Mendelian randomization (MR) to clarify the potential causal relationship between gut microbiota and cholelithiasis. Methods:Summary Genome-Wide Association Studies (GWAS) statistical data for gut microbiota was obtained from MiBioGen, and the data of cholelithiasis was obtained from UK Biobank (UKB). Two-sample MR analyses were performed to assess causalities between gut microbiota and cholelithiasis mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were used to determine the robustness of the MR results. Reverse MR analyses were performed to examine the reverse causal association. Results:Our research results, based primarily on the IVW method, support the existence of a causal relationship between nine gut microbial taxa and cholelithiasis. We observed a positive association between G (p=0.032), (p=0.015), (p=0.003), (p=0.010) and cholelithiasis, while (p=0.031), (p=0.010), (p=0.036), (p=0.023), (p=0.022) may be associated with a reduced risk of cholelithiasis. We did not find a reverse causal relationship between cholelithiasis and 9 specific gut microbial taxa. Conclusions:This is the first mendelian randomization study to explore the causalities between specific gut microbiota taxa and cholelithiasis, which may provide new ideas and a theoretical basis for the prevention and treatment of cholelithiasis in the future.
10.3389/fcimb.2023.1169119
Gut microbiome and risk of ischaemic stroke: a comprehensive Mendelian randomization study.
European journal of preventive cardiology
AIMS:Increasing evidence implicates the microbiome as a susceptibility factor for ischaemic stroke (IS). Interpretation of this evidence is difficult, for the composition of the microbiome is influenced by various factors and might affect differently in IS subtypes. We aim to determine if the specific gut microbiome is causally associated with IS subtypes and suggest potential approaches for stroke prevention. METHODS AND RESULTS:We conducted a two-sample Mendelian randomization (MR) analysis to test the causal relationship between gut microbiome and IS subtypes. For exposure data, we extracted genetic variants associated with 194 bacterial traits from MiBioGen consortium (n = 18 340). For outcomes, we selected three IS subtypes including cardioembolic stroke (CES, n = 410 484), small vessel stroke (SVS, n = 198 048), and large artery stroke (LAS, n = 198 048). Additionally, we performed a sequence of sensitivity analyses to validate preliminary MR results. There were four, three, and four bacteria showing an increased risk for LAS, SVS, and CES, respectively, and there were five, six, and five bacteria leading a decreasing risk for LAS, SVS, and CES, respectively. Amongst these, the genus_Intestinimonas showed negative associations with LAS [odds ratio (OR) = 0.77, 95% confidence interval (CI) (0.61-0.98)] and SVS (0.85, 0.73-0.98). The genus_LachnospiraceaeNK4A136group was genetically associated with decreased risk of both SVS (0.81, 0.66-0.99) and CES (0.75, 0.60-0.94). CONCLUSION:The study revealed the causal effect of the abundance of specific bacterial features on the risk of IS subtypes. Notably, genus_Intestinimonas and genus_LachnospiraceaeNK4A136group displayed significant protection against more than one IS subtype, further suggesting potential applications of targeted probiotics in IS prevention.
10.1093/eurjpc/zwad052
Gut microbiota and intervertebral disc degeneration: a bidirectional two-sample Mendelian randomization study.
Journal of orthopaedic surgery and research
BACKGROUND:Although previous studies have suggested a close association between gut microbiota (GM) and intervertebral disc degeneration (IVDD), the causal relationship between them remains unclear. Hence, we thoroughly investigate their causal relationship by means of a two-sample Mendelian randomization (MR) study, aiming to determine the impact of gut microbiota on the risk of developing intervertebral disc degeneration. METHODS:Summary data from genome-wide association studies of GM (the MiBioGen) and IVDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS:We identified nine gut microbial taxa that were causally associated with IVDD (P < 0.05). Following the Benjamini-Hochberg corrected test, the association between the phylum Bacteroidetes and a higher risk of IVDD remained significant (IVW FDR-corrected P = 0.0365). The results of the Cochrane Q test did not indicate heterogeneity (P > 0.05). Additionally, both the MR-Egger intercept test and the MR-PRESSO global test revealed that our results were not influenced by horizontal pleiotropy (P > 0.05). Furthermore, the leave-one-out analysis substantiated the reliability of the causal relationship. In the reverse analysis, no evidence was found to suggest that IVDD has an impact on the gut microbiota. CONCLUSION:Our results validate the potential causal impact of particular GM taxa on IVDD, thus providing fresh insights into the gut microbiota-mediated mechanism of IVDD and laying the groundwork for further research into targeted preventive measures.
10.1186/s13018-023-04081-0
Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis.
BMC gastroenterology
BACKGROUND:Growing evidence has suggested that gut microbiota is closely related to the risk of irritable bowel syndrome (IBS), but whether there is a causal effect remains unknown. We adopted a Mendelian randomization (MR) approach to evaluate the potential causal relationships between gut microbiota and the risk of IBS. METHODS:Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics of IBS were drawn from a GWAS including 53,400 cases and 433,201 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, reverse MR analysis was performed to evaluate the possibility of reverse causation. RESULTS:We identified suggestive associations between three bacterial traits and the risk of IBS (odds ratio (OR): 1.08; 95% confidence interval (CI): 1.02, 1.15; p = 0.011 for phylum Actinobacteria; OR: 0.95; 95% CI: 0.91, 1.00; p = 0.030 for genus Eisenbergiella and OR: 1.10; 95% CI: 1.03, 1.18; p = 0.005 for genus Flavonifractor). The results of sensitivity analyses for these bacterial traits were consistent. We did not find statistically significant associations between IBS and these three bacterial traits in the reverse MR analysis. CONCLUSIONS:Our systematic analyses provide evidence to support a potential causal relationship between several gut microbiota taxa and the risk of IBS. More studies are required to show how the gut microbiota affects the development of IBS.
10.1186/s12876-023-02791-7
Gut microbiota and chronic obstructive pulmonary disease: a Mendelian randomization study.
Frontiers in microbiology
Background:A growing number of studies implies a strong association between gut microbiota and chronic obstructive pulmonary disease (COPD). However, the causal impact between gut microbiota and COPD remains unclear. As a result, we used a two-sample Mendelian randomization (MR) method to investigate the connection between gut microbiota and COPD in this study. Methods:The largest available genome-wide association study (GWAS) of gut microbiota was obtained from the MiBioGen consortium. Summary-level dataset for COPD were obtained from the FinnGen consortium. The main analysis method for determining the causal link between gut microbiota and COPD was inverse variance weighted (IVW). Subsequently, pleiotropy and heterogeneity tests were performed to determine the reliability of the results. Results:IVW method identified 9 bacterial taxa nominally associated with the risk of COPD. Class Actinobacteria ( = 0.020), genus ( = 0.024), genus ( = 0.002) and genus ( = 0.018) were protective against COPD. In addition, order Desulfovibrionales ( = 0.011), family Desulfovibrionaceae ( = 0.039), family Peptococcaceae ( = 0.020), family Victivallaceae ( = 0.012) and genus ( = 0.017) were associated with a higher risk of COPD. No pleiotropy or heterogeneity were found. Conclusion:According to the findings of this MR analysis, a causal relationship exists between certain gut microbiota and COPD. New insights into the mechanisms of COPD mediated by gut microbiota are provided.
10.3389/fmicb.2023.1196751
Causal effects of gut microbiota on the risk of periodontitis: a two-sample Mendelian randomization study.
Frontiers in cellular and infection microbiology
Introduction:The oral cavity and the gut tract are interconnected, and both contain abundant natural microbiota. Gut microbiota may interact with oral flora and participate in the development of periodontitis. However, the specific role of certain gut microbiota taxa for periodontitis has not been investigated. Mendelian Randomization is an ideal method to explore causal relationships avoiding reverse causality and potential confounding factors. Thus, we conducted a two-sample Mendelian Randomization study to comprehensively reveal the potential genetic causal effect of gut microbiota on periodontitis. Methods:SNPs strongly associated with 196 gut microbiota taxa (18,340 individuals) were selected as instrument variables, and periodontitis (17,353 periodontitis cases and 28,210 controls) was used as the outcome. The causal effect was analyzed via random effect inverse variance-weighted, weighted median, and MR-Egger. The sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. Results:Nine gut microbiota taxa ( 7, UCG-008, , , , , S24.7 group, , and ) are predicted to play a causal role in enhancing the risk of periodontitis (< 0.05). Besides, two gut microbiota taxa ( and 6) have potentially inhibitive causal effects on the risk of periodontitis (< 0.05). No significant estimation of heterogeneity or pleiotropy is detected. Conclusion:Our study demonstrates the genetic causal effect of 196 gut microbiota taxa on periodontitis and provides guidance for the clinical intervention of periodontitis.
10.3389/fcimb.2023.1160993
Association between Gut Microbiota and Digestive System Cancers: A Bidirectional Two-Sample Mendelian Randomization Study.
Nutrients
Accumulating evidence indicates that gut microbiota closely correlates with the tumorigenesis of digestive system cancers (DSCs). However, whether the causality between gut microbiota and DSCs exists is unknown. Genome-wide association study (GWAS) summary statistics for gut microbiota and DSCs and the bidirectional two-sample Mendelian randomization (MR) analysis were utilized to assess the causality between gut microbiota and DSCs. Sensitivity analyses were performed to evaluate the robustness of our results. We found that the (OR = 0.464, 95%CI: 0.27 to 0.796, = 0.005) was negatively associated with the risk of gastric cancer. The genetically predicted (OR = 0.607, 95%CI: 0.439 to 0.84, = 0.003) correlated with a lower risk of colorectal cancer, and (OR = 0.271, 95%CI: 0.109 to 0.676, = 0.005) was a protective factor for liver cancer. In the reverse MR, DSCs regulated the relative abundance of specific strains of gut microbiota. We comprehensively screened the association between gut microbiota and DSCs using a bidirectional two-sample MR analysis and identified the causality between several microbial taxa and DSCs. Our discoveries are beneficial for the development of novel microbial markers and microbiota-modifying therapeutics for DSC patients.
10.3390/nu15132937
Mendelian randomization analyses support causal relationships between blood metabolites and the gut microbiome.
Nature genetics
The gut microbiome has been implicated in a variety of physiological states, but controversy over causality remains unresolved. Here, we performed bidirectional Mendelian randomization analyses on 3,432 Chinese individuals with whole-genome, whole-metagenome, anthropometric and blood metabolic trait data. We identified 58 causal relationships between the gut microbiome and blood metabolites, and replicated 43 of them. Increased relative abundances of fecal Oscillibacter and Alistipes were causally linked to decreased triglyceride concentration. Conversely, blood metabolites such as glutamic acid appeared to decrease fecal Oxalobacter, and members of Proteobacteria were influenced by metabolites such as 5-methyltetrahydrofolic acid, alanine, glutamate and selenium. Two-sample Mendelian randomization with data from Biobank Japan partly corroborated results with triglyceride and with uric acid, and also provided causal support for published fecal bacterial markers for cancer and cardiovascular diseases. This study illustrates the value of human genetic information to help prioritize gut microbial features for mechanistic and clinical studies.
10.1038/s41588-021-00968-y
Gut microbiota and type 1 diabetes: a two-sample bidirectional Mendelian randomization study.
Frontiers in cellular and infection microbiology
Objective:The real causal relationship between human gut microbiota and T1D remains unclear and difficult to establish. Herein, we adopted a two-sample bidirectional mendelian randomization (MR) study to evaluate the causality between gut microbiota and T1D. Methods:We leveraged publicly available genome-wide association study (GWAS) summary data to perform MR analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen were used. The summary statistic data for T1D (n = 264,137) were obtained from the latest release from the FinnGen consortium as the outcome of interest. The selection of instrumental variables conformed strictly to a series of preset inclusion and exclusion criteria. MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods were used to assess the causal association. The Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy. Results:At the phylum level, only Bacteroidetes was indicated to have causality on T1D (OR = 1.24, 95% CI = 1.01-1.53, = 0.044) in the IVW analysis. When it comes to their subcategories, Bacteroidia class (OR = 1.28, 95% CI = 1.06-1.53, = 0.009, = 0.085), Bacteroidales order (OR = 1.28, 95% CI = 1.06-1.53, = 0.009, = 0.085), and group genus (OR = 0.64, 95% CI = 0.50-0.81, = 2.84×10, = 0.031) were observed to have a causal relationship with T1D in the IVW analysis. No heterogeneity and pleiotropy were detected. Conclusions:The present study reports that Bacteroidetes phylum, Bacteroidia class, and Bacteroidales order causally increase T1D risk, whereas group genus, which belongs to the Firmicutes phylum, causally decreases T1D risk. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa's role in the pathophysiology of T1D.
10.3389/fcimb.2023.1163898
Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study.
Liver international : official journal of the International Association for the Study of the Liver
BACKGROUND AND AIMS:Observational epidemiology studies suggested a relationship between the gut microbiome and primary liver cancer. However, the causal relationship remains unclear because of confounding factors and reverse causality. We aimed to explore the causal role of the gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS:Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWAS) of the gut microbiome and liver cancer, and sequencing data from a case-control study validated the findings. A 5-cohort GWAS study in Germany (N = 8956) served as exposure, whilst the UK biobank GWAS study (N = 456 348) served as an outcome. The case-control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from December 2018 to October 2020 and included 184 HCC patients, 63 ICC patients and 40 healthy controls. RESULTS:A total of 57 features were available for MR analysis, and protective causal associations were identified for Family_Ruminococcaceae (OR = 0.46 [95% CI, 0.26-0.82]; p = .009) and Genus_Porphyromonadaceae (OR = 0.59 [95% CI, 0.42-0.83]; p = .003) with HCC, and for Family_Porphyromonadaceae (OR = 0.36 [95% CI, 0.14-0.94]; p = .036) and Genus_Bacteroidetes (OR = 0.55 [95% CI, 0.34-0.90]; p = .017) with ICC respectively. The case-control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (p = .00033), Family_Porphyromonadaceae (p = .0055) and Genus_Bacteroidetes (p = .021) than the liver cancer patients. CONCLUSIONS:This study demonstrates that Ruminococcaceae, Porphyromonadaceae and Bacteroidetes are related to a reduced risk of liver cancer (HCC or ICC), suggesting potential significance for the prevention and control of liver cancer.
10.1111/liv.15466
Causal effects of gut microbiota on sepsis: a two-sample Mendelian randomization study.
Frontiers in microbiology
Background:Recent studies had provided evidence that the gut microbiota is associated with sepsis. However, the potential causal relationship remained unclear. Methods:The present study aimed to explore the causal effects between gut microbiota and sepsis by performing Mendelian randomization (MR) analysis utilizing publicly accessible genome-wide association study (GWAS) summary-level data. Gut microbiota GWAS ( = 18,340) were obtained from the MiBioGen study and GWAS-summary-level data for sepsis were gained from the UK Biobank (sepsis, 10,154 cases; 452,764 controls). Two strategies were used to select genetic variants, i.e., single nucleotide polymorphisms (SNPs) below the locus-wide significance level (1 × 10) and the genome-wide statistical significance threshold (5 × 10) were chosen as instrumental variables (IVs). The inverse variance weighted (IVW) was used as the primary method for MR study, supplemented by a series of other methods. Additionally, a set of sensitivity analysis methods, including the MR-Egger intercept test, Mendelian randomized polymorphism residual and outlier (MR-PRESSO) test, Cochran's Q test, and leave-one-out test, were carried out to assess the robustness of our findings. Results:Our study suggested that increased abundance of , and were negatively associated with sepsis risk, while , and were positively correlated with the risk of sepsis. Sensitivity analysis revealed no evidence of heterogeneity and pleiotropy. Conclusion:This study firstly found suggestive evidence of beneficial or detrimental causal associations of gut microbiota on sepsis risk by applying MR approach, which may provide valuable insights into the pathogenesis of microbiota-mediated sepsis and strategies for sepsis prevention and treatment.
10.3389/fmicb.2023.1167416
Mendelian randomization study of causal link from gut microbiota to colorectal cancer.
BMC cancer
Recent studies have shown the relevance of gut microbiota in the occurrence and development of colorectal cancer (CRC), but the causal relationship remains unclear in the human population. The present study aims to assess the causal relationship from the gut microbiota to CRC and to identify specific causal microbe taxa via genome-wide association study (GWAS) summary statistics based two-sample Mendelian randomization (MR) analyses. Microbiome GWAS (MGWAS) in the TwinsUK 1,126 twin pairs was used as discovery exposure sample, and MGWAS in 1,812 northern German participants was used as replication exposure sample. GWAS of CRC in 387,156 participants from the UK Biobank (UKB) was used as the outcome sample. Bacteria were grouped into taxa features at both family and genus levels. In the discovery sample, a total of 30 bacteria features including 15 families and 15 genera were analyzed. Five features, including 2 families (Verrucomicrobiaceae and Enterobacteriaceae) and 3 genera (Akkermansia, Blautia, and Ruminococcus), were nominally significant. In the replication sample, the genus Blautia (discovery beta=-0.01, P = 0.04) was successfully replicated (replication beta=-0.18, P = 0.01) with consistent effect direction. Our findings identified genus Blautia that was causally associated with CRC, thus offering novel insights into the microbiota-mediated CRC development mechanism.
10.1186/s12885-022-10483-w
Gut microbiota and Sjögren's syndrome: a two-sample Mendelian randomization study.
Frontiers in immunology
Background:The link between the gut microbiota (GM) and Sjögren's Syndrome (SS) is well-established and apparent. Whether GM is causally associated with SS is uncertain. Methods:The MiBioGen consortium's biggest available genome-wide association study (GWAS) meta-analysis (n=13,266) was used as the basis for a two-sample Mendelian randomization study (TSMR). The causal relationship between GM and SS was investigated using the inverse variance weighted, MR-Egger, weighted median, weighted model, MR-PRESSO, and simple model methods. In order to measure the heterogeneity of instrumental variables (IVs), Cochran's Q statistics were utilized. Results:The results showed that genus Fusicatenibacter (odds ratio (OR) = 1.418, 95% confidence interval (CI), 1.072-1.874, P = 0.0143) and genus Ruminiclostridium9 (OR = 1.677, 95% CI, 1.050-2.678, P = 0.0306) were positively correlated with the risk of SS and family Porphyromonadaceae (OR = 0.651, 95% CI, 0.427-0.994, P = 0.0466), genus Subdoligranulum (OR = 0.685, 95% CI, 0.497-0.945, P = 0.0211), genus Butyricicoccus (OR = 0.674, 95% CI, 0.470-0.967, P = 0.0319) and genus Lachnospiraceae (OR = 0.750, 95% CI, 0.585-0.961, P = 0.0229) were negatively correlated with SS risk using the inverse variance weighted (IVW) technique. Furthermore, four GM related genes: ARAP3, NMUR1, TEC and SIRPD were significant causally with SS after FDR correction (FDR<0.05). Conclusions:This study provides evidence for either positive or negative causal effects of GM composition and its related genes on SS risk. We want to provide novel approaches for continued GM and SS-related research and therapy by elucidating the genetic relationship between GM and SS.
10.3389/fimmu.2023.1187906
Dissecting Causal Relationships Between Gut Microbiota, Blood Metabolites, and Stroke: A Mendelian Randomization Study.
Journal of stroke
BACKGROUND AND PURPOSE:We investigated the causal relationships between the gut microbiota (GM), stroke, and potential metabolite mediators using Mendelian randomization (MR). METHODS:We leveraged the summary statistics of GM (n=18,340 in the MiBioGen consortium), blood metabolites (n=115,078 in the UK Biobank), and stroke (cases n=60,176 and controls n=1,310,725 in the Global Biobank Meta-Analysis Initiative) from the largest genome-wide association studies to date. We performed bidirectional MR analyses to explore the causal relationships between the GM and stroke, and two mediation analyses, two-step MR and multivariable MR, to discover potential mediating metabolites. RESULTS:Ten taxa were causally associated with stroke, and stroke led to changes in 27 taxa. In the two-step MR, Bifidobacteriales order, Bifidobacteriaceae family, Desulfovibrio genus, apolipoprotein A1 (ApoA1), phospholipids in high-density lipoprotein (HDL_PL), and the ratio of apolipoprotein B to ApoA1 (ApoB/ApoA1) were causally associated with stroke (all P<0.044). The causal associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were validated using the weighted median method in an independent cohort. The three GM taxa were all positively associated with ApoA1 and HDL_PL, whereas Desulfovibrio genus was negatively associated with ApoB/ApoA1 (all P<0.010). Additionally, the causal associations between the three GM taxa and ApoA1 remained significant after correcting for the false discovery rate (all q-values <0.027). Multivariable MR showed that the associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were mediated by ApoA1 and HDL_PL, each accounting for 6.5% (P=0.028) and 4.6% (P=0.033); the association between Desulfovibrio genus and stroke was mediated by ApoA1, HDL_PL, and ApoB/ApoA1, with mediated proportions of 7.6% (P=0.019), 4.2% (P=0.035), and 9.1% (P=0.013), respectively. CONCLUSION:The current MR study provides evidence supporting the causal relationships between several specific GM taxa and stroke and potential mediating metabolites.
10.5853/jos.2023.00381
No Evidence of a Genetic Causal Relationship between Ankylosing Spondylitis and Gut Microbiota: A Two-Sample Mendelian Randomization Study.
Nutrients
Ankylosing spondylitis (AS) is associated with a variety of gut microbiotas. We aim to analyze the causal relationship between the two at the genetic level. Methods: Mendelian randomization (MR) is a type of instrumental variables (IVs) analysis; MR follows the Mendelian genetic rule of "parental alleles are randomly assigned to offspring" and takes genetic variation as IVs to infer the causal association between exposure factors and study outcome in observational studies. Genome-wide association study (GWAS) summary data of AS were from the FinnGen consortium, and the gut microbiota (Bacteroides, Streptococcus, Proteobacteria, Lachnospiraceae) were from the MiBioGen consortium. The TwoSampleMR and MRPRESSO packages of the R were used to perform a two-sample MR study. Random-effects inverse variance weighted (IVW) was the main analysis method, and MR Egger, weighted median, simple mode, and weighted mode were used as supplementary methods. We examined heterogeneity and horizontal pleiotropy, and examined whether the analysis results were influenced by a single SNP. We applied radial variants of the IVW and MR-Egger model for the improved visualization of the causal estimate. We further examined the causal relationship between AS and gut microbiota, and the robustness of the analysis results. Finally, we performed maximum likelihood, penalized weighted median, and IVW (fixed effects) to further identify the potential causal association. The random-effects IVW results showed that Bacteroides ( = 0.965, OR 95% confidence interval [CI] = 0.990 [0.621-1.579]), Streptococcus ( = 0.591, OR 95% CI = 1.120 [0.741-1.692]), Proteobacteria ( = 0.522, OR 95% CI = 1.160 [0.737-1.826]), and Lachnospiraceae ( = 0.717, OR 95% CI = 1.073 [0.732-1.574]) have no genetic causal relationship with AS. There was no heterogeneity, horizontal pleiotropy or outliers, and results were normally distributed. The MR analysis results were not driven by a single SNP. This study showed that Bacteroides, Streptococcus, Proteobacteria and Lachnospiraceae, four common gut microbiotas associated with AS, had no causal relationship with AS at the genetic level. This study makes a positive contribution to the genetics of AS, but the insufficient number of gut microbiota included is a limitation.
10.3390/nu15041057
Causal Effects of Specific Gut Microbiota on Chronic Kidney Diseases and Renal Function-A Two-Sample Mendelian Randomization Study.
Nutrients
BACKGROUND:Targeting the gut microbiota may become a new therapeutic to prevent and delay the progression of chronic kidney disease (CKD). Nonetheless, the causal relationship between specific intestinal flora and CKD is still unclear. MATERIALS AND METHOD:To identify genetically predicted microbiota, we used summary data from genome-wide association studies on gut microbiota in 18340 participants from 24 cohorts. Furthermore, we genetically predicted the causal relationship between 211 gut microbiotas and six phenotypes (outcomes) (CKD, estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (UACR), dialysis, rapid progress to CKD, and rapid decline of eGFR). Four Mendelian randomization (MR) methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode were used to investigate the casual relationship between gut microbiotas and various outcomes. The result of IVW was deemed as the primary result. Then, Cochrane's Q test, MR-Egger, and MR-PRESSO Global test were used to detect heterogeneity and pleiotropy. The leave-one method was used for testing the stability of MR results and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS:Through the MR analysis of 211 microbiotas and six clinical phenotypes, a total of 36 intestinal microflora were found to be associated with various outcomes. Among them, Class Bacteroidia (=-0.005, 95% CI: -0.001 to -0.008, = 0.002) has a strong causality with lower eGFR after the Bonferroni-corrected test, whereas phylum Actinobacteria (OR = 1.0009, 95%CI: 1.0003-1.0015, = 0.0024) has a strong causal relationship with dialysis. The Cochrane's Q test reveals that there is no significant heterogeneity between various single nucleotide polymorphisms. In addition, no significant level of pleiotropy was found according to MR-Egger and MR-PRESSO Global tests. CONCLUSIONS:Through the two-sample MR analysis, we identified the specific intestinal flora that has a causal relationship with the incidence and progression of CKD at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for CKD.
10.3390/nu15020360
Gut Microbiota and Psychiatric Disorders: A Two-Sample Mendelian Randomization Study.
Ni Jing-Jing,Xu Qian,Yan Shan-Shan,Han Bai-Xue,Zhang Hong,Wei Xin-Tong,Feng Gui-Juan,Zhao Min,Pei Yu-Fang,Zhang Lei
Frontiers in microbiology
Evidence supports the observational associations of gut microbiota with a variety of psychiatric disorders, but the causal nature of such associations remains obscure. Aiming to comprehensively investigate their causal relationship and to identify specific causal microbe taxa for psychiatric diseases, we conducted a two-sample Mendelian randomization (MR) analysis of gut microbiome with 15 psychiatric diseases. Specifically, the microbiome genome-wide association study (GWAS) in 18,473 individuals from the MiBioGen study was used as exposure sample, and the GWAS for 15 psychiatric diseases was used as outcome samples. One-hundred ninety bacterial taxa from six levels were available for analysis. At a multiple-testing corrected significance level (phylum < 5.56 × 10, class < 3.33 × 10, order < 2.63 × 10, family < 1.67 × 10, genus < 4.90 × 10, and species < 3.33 × 10), the following eight causal associations from seven bacterial features (one phylum + three classes + one order + one family + one species) were identified: family with autism spectrum disorder ( = 5.31 × 10), class with bipolar disorder ( = 1.53 × 10), class with schizophrenia ( = 1.33 × 10), class and order with Tourette syndrome ( = 2.51 × 10 and 2.51 × 10), phylum and class with extroversion ( = 8.22 × 10 and 1.09 × 10), and species with neuroticism ( = 8.92 × 10). Sensitivity analysis showed no evidence of reverse causality, pleiotropy, and heterogeneity. Our findings offered novel insights into the gut microbiota-mediated development mechanism of psychiatric disorders.
10.3389/fmicb.2021.737197
Gut microbiota, circulating cytokines and dementia: a Mendelian randomization study.
Journal of neuroinflammation
BACKGROUND:Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear. METHODS:Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia. RESULTS:There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors. CONCLUSIONS:Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia.
10.1186/s12974-023-02999-0
Gut microbiota and major depressive disorder: A bidirectional Mendelian randomization.
Journal of affective disorders
BACKGROUND:Observational studies showed an association between gut microbiota and depression, but the causality relationship between them is unclear. We aimed to determine whether there is a bidirectional causal relationship between the composition of gut microbiota and major depressive disorders (MDD) and explore the role of gut microbiota in decreasing the risk of MDD. METHODS:Our two-sample Mendelian randomization (MR) study acquired top SNPs associated with the composition of gut microbiota (n = 18,340) and with MDDs (n = 480,359) from publicly available genome-wide association studies (GWAS). The SNPs estimates were pooled using inverse-variance weighted meta-analysis, with sensitivity analyses-weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS:The Actinobacteria class had protective causal effects on MDD (OR 0.88, 95%CI 0.87 to 0.9). The Bifidobacterium (OR 0.89, 95%CI 0.88 to 0.91) were further found to have similar effects as the Actinobacteria class. The genus Ruminococcus1 had a protective effect on MDD (OR 0.88, 95%CI 0.76 to 0.99) while the Streptococcaceae family and its genus had an anti-protective effect on MDD (OR 1.07, 95%CI 1.01 to 1.13), but these findings were not supported by the MR-Egger analysis. Bidirectional MR showed no effect of MDD on gut microbiota composition. LIMITATIONS:The use of summary-level data, the risk of sample overlap and low statistical power are the major limiting factors. CONCLUSIONS:Our MR analysis showed a protective effect of Actinobacteria, Bifidobacterium, and Ruminococcus and a potentially anti-protective effect of Streptococcaceae on MDD pathogenesis. Further studies are needed to transform the findings into practice.
10.1016/j.jad.2022.08.012
A large-scale causal analysis of gut microbiota and delirium: A Mendelian randomization study.
Journal of affective disorders
BACKGROUND:Several studies have linked gut microbiota to human brain activity. This study used Mendelian randomization (MR) to investigate the causal relationship between gut microbes and delirium. METHODS:MR was used to select SNPs from large-scale GWAS summary data on 211 gut microbiota taxa and delirium. Inverse variance weighting (IVW), weighted median, and MR-Egger methods were used for statistical analyses. Outliers were assessed using the leave-one-out method. To avoid horizontal pleiotropy, we performed the MR-PRESSO and MR-Egger intercept tests. Cochran's Q and I values for IVW and MR-Egger were used to assess heterogeneity. RESULTS:IVW suggested that genetic prediction of the family Desulfovibrionaceae (1.784 (1.267-2.512), P = 0.001), order Desulfovibrionales (1.501 (1.058-2.128), P = 0.023), and genus Candidatus Soleaferrea (1.322 (1.052-1.659), P = 0.016) increased the risk of delirium, but the family Oxalobacteraceae (0.841 (0.722-0.981), P = 0.027), and genera Holdemania (0.766 (0.620-0.946), P = 0.013), Ruminococcus gnavus (0.806 (0.661-0.982), P = 0.033), and Eggerthella (0.815 (0.667-0.997), P = 0.047) reduced the risk of delirium. LIMITATIONS:(1) Limited sample size, (2) inability to assess gut microbiota interactions, and (3) limited to European populations. CONCLUSION:Our results suggest that presence of the microbial family Desulfovibrionaceae, order Desulfovibrionales, and genus Candidatus Soleaferrea increased the risk of delirium, whereas the Oxalobacteraceae family, and the genera Holdemania, Ruminococcus gnavus, and Eggerthella decreased the risk of delirium. However, the potential of gut probiotic interventions in the prevention of perioperative delirium should be emphasized.
10.1016/j.jad.2023.02.078
Investigating Casual Associations Among Gut Microbiota, Metabolites, and Neurodegenerative Diseases: A Mendelian Randomization Study.
Journal of Alzheimer's disease : JAD
BACKGROUND:Recent studies had explored that gut microbiota was associated with neurodegenerative diseases (including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS)) through the gut-brain axis, among which metabolic pathways played an important role. However, the underlying causality remained unclear. OBJECTIVE:Our study aimed to evaluate potential causal relationships between gut microbiota, metabolites, and neurodegenerative diseases through Mendelian randomization (MR) approach. METHODS:We selected genetic variants associated with gut microbiota traits (N = 18,340) and gut microbiota-derived metabolites (N = 7,824) from genome-wide association studies. Summary statistics of neurodegenerative diseases were obtained from IGAP (AD, 17,008 cases; 37,154 controls), IPDGC (PD, 37,688 cases; 141,779 controls), and IALSC (ALS, 20,806 cases; 59,804 controls) respectively. RESULTS:Greater abundance of Ruminococcus (OR, 1.245; 95% CI, 1.103-1.405; p = 0.0004) was found significantly related to higher risk of ALS. Besides, our study found suggestive associations of Actinobacteria, Lactobacillaceae, Faecalibacterium, Ruminiclostridium, and Lachnoclostridium with AD, of Lentisphaerae, Lentisphaeria, Oxalobacteraceae, Victivallales, Bacillales, Eubacteriumhalliigroup, Anaerostipes, and Clostridiumsensustricto1 with PD, and of Lachnospira, Fusicatenibacter, Catenibacterium, and Ruminococcusgnavusgroup with ALS. Our study also revealed suggestive associations between 12 gut microbiome-dependent metabolites and neurodegenerative diseases. Glutamine was related to lower risk of AD. For the serotonin pathway, serotonin was found as a protective factor of PD, while kynurenine as a risk factor for ALS. CONCLUSION:Our study firstly applied a two-sample MR approach to detect causal relationships among gut microbiota, gut metabolites, and neurodegenerative diseases. Our findings may provide new targets for treatments and may offer valuable insights for further studies on the underlying mechanisms.
10.3233/JAD-215411
Gut Microbiota and Respiratory Infections: Insights from Mendelian Randomization.
Microorganisms
The role of the gut microbiota in modulating the risk of respiratory infections has garnered increasing attention. However, conventional clinical trials have faced challenges in establishing the precise relationship between the two. In this study, we conducted a Mendelian randomization analysis with single nucleotide polymorphisms employed as instrumental variables to assess the causal links between the gut microbiota and respiratory infections. Two categories of bacteria, family and genus , were causally associated with the occurrence of upper respiratory tract infections (URTIs). Four categories of gut microbiota existed that were causally associated with lower respiratory tract infections (LRTIs), with order and genus showing a positive association and genus and genus showing a negative association. The metabolites and metabolic pathways only played a role in the development of LRTIs, with the metabolite deoxycholine acting negatively and menaquinol 8 biosynthesis acting positively. The identification of specific bacterial populations, metabolites, and pathways may provide new clues for mechanism research concerning therapeutic interventions for respiratory infections. Future research should focus on elucidating the potential mechanisms regulating the gut microbiota and developing effective strategies to reduce the incidence of respiratory infections. These findings have the potential to significantly improve global respiratory health.
10.3390/microorganisms11082108
The associations between gut microbiota and chronic respiratory diseases: a Mendelian randomization study.
Frontiers in microbiology
Introduction:Growing evidence indicates that variations in the composition of the gut microbiota are linked to the onset and progression of chronic respiratory diseases (CRDs), albeit the causal relationship between the two remains unclear. Methods:We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the relationship between gut microbiota and five main CRDs, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. For MR analysis, the inverse variance weighted (IVW) method was utilized as the primary method. The MR-Egger, weighted median, and MR-PRESSO statistical methods were used as a supplement. To detect heterogeneity and pleiotropy, the Cochrane and Rucker Q test, MR-Egger intercept test, and MR-PRESSO global test were then implemented. The leave-one-out strategy was also applied to assess the consistency of the MR results. Results:Based on substantial genetic data obtained from genome-wide association studies (GWAS) comprising 3,504,473 European participants, our study offers evidence that several gut microbial taxa, including 14 probable microbial taxa (specifically, 5, 3, 2, 3 and 1 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) and 33 possible microbial taxa (specifically, 6, 7, 8, 7 and 5 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) play significant roles in the formation of CRDs. Discussion:This work implies causal relationships between the gut microbiota and CRDs, thereby shedding new light on the gut microbiota-mediated prevention of CRDs.
10.3389/fmicb.2023.1200937
Causal effects of gut microbiota on the risk of chronic kidney disease: a Mendelian randomization study.
Frontiers in cellular and infection microbiology
Background:Previous studies have reported that gut microbiota is associated with an increased risk of chronic kidney disease (CKD) progression. However, whether gut microbiota has a causal effect on the development of CKD has not been revealed. Thus, we aimed to analyze the potential causal effect of gut microbiota on the risk of CKD using mendelian randomization (MR) study. Materials and Methods:Independent single nucleotide polymorphisms closely associated with 196 gut bacterial taxa (N = 18340) were identified as instrumental variables. Two-sample MR was performed to evaluate the causal effect of gut microbiota on CKD (N = 480698), including inverse-variance-weighted (IVW) method, weighted median method, MR-Egger, mode-based estimation and MR-PRESSO. The robustness of the estimation was tested by a series of sensitivity analyses including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis and funnel plot. Statistical powers were also calculated. Results:The genetically predicted higher abundance of order was causally associated with an increased risk of CKD (odds ratio = 1.15, 95% confidence interval: 1.05-1.26; = 0.0026). Besides, we also detected potential causalities between nine other taxa (, , , , , , , and ) and CKD ( < 0.05). No heterogeneity or pleiotropy was detected for significant estimates. Conclusion:We found that and nine other taxa are associated with CKD, thus confirming that gut microbiota plays an important role in the pathogenesis of CKD. Our work also provides new potential indicators and targets for screening and prevention of CKD.
10.3389/fcimb.2023.1142140
Effects of Gut Microbiota and Metabolites on Heart Failure and Its Risk Factors: A Two-Sample Mendelian Randomization Study.
Frontiers in nutrition
Introduction:Previous observational studies have indicated that gut microbiota and metabolites may contribute to heart failure and its risk factors. However, with the limitation of reverse causality and confounder in observational studies, such relationship remains unclear. This study aims to reveal the causal effect of gut microbiota and metabolites on heart failure and its risk factors. Methods:This study collected summary statistics regarding gut microbiota and metabolites, heart failure, diabetes, hypertension, chronic kidney disease, myocardial infarction, atrial fibrillation, hypertrophic cardiomyopathy, dilated cardiomyopathy, coronary heart disease, valvular heart disease, and myocarditis. Two-sample Mendelian randomization analysis was performed using MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median. Results:Results from gene prediction showed that among all gut microbiota, , and were not associated with higher incidence of heart failure. However, genetic prediction suggested that for every 1 unit increase in concentration, the relative risk increased by 38.1% for myocarditis and 13.3% for hypertrophic cardiomyopathy. Besides, for every 1 unit increased in concentration, the relative risk of chronic kidney disease increased by 7.1%. As for intestinal metabolites, genetic prediction results suggested that for every 1 unit increase in betaine, the relative risk of heart failure and myocardial infarction increased by 1.4% and 1.7%, separately. Conclusions:This study suggested new evidence of the relationship between gut microbiota and heart failure and its risk factors, which may shed light on designing microbiome- and microbiome-dependent metabolite interventions on heart failure and its risk factors in clinical trials in the future.
10.3389/fnut.2022.899746
Gut microbiota and risk of five common cancers: A univariable and multivariable Mendelian randomization study.
Cancer medicine
BACKGROUND:Previous studies have linked gut microbiota with cancer etiology, but the associations for specific gut microbiota are causal or owing to bias remain to be elucidated. METHODS:We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effect of gut microbiota on cancer risk. Five common cancers, including breast, endometrial, lung, ovarian, and prostate cancer as well as their subtypes (sample sizes ranging from 27,209 to 228,951) were included as the outcomes. Genetic information for gut microbiota was obtained from a genome-wide association study (GWAS) comprising 18,340 participants. In univariable MR (UVMR) analysis, the inverse variance weighted (IVW) method was conducted as the primary method, with the robust adjusted profile scores, weighted median, and MR Egger used as supplementary methods for causal inference. Sensitivity analyses including the Cochran Q test, Egger intercept test, and leave-one-out analysis were performed to verify the robustness of the MR results. Multivariable MR (MVMR) was performed to evaluate the direct causal effects of gut microbiota on the risk of cancers. RESULTS:UVMR detected a higher abundance of genus Sellimonas predicted a higher risk of estrogen receptor-positive breast cancer (OR = 1.09, 95% CI 1.05-1.14, p = 2.01 × 10 ), and a higher abundance of class Alphaproteobacteria was associated with a lower risk of prostate cancer (OR = 0.84, 95% CI 0.75-0.93, p = 1.11 × 10 ). Sensitivity analysis found little evidence of bias in the current study. MVMR further confirmed that genus Sellimonas exerted a direct effect on breast cancer, while the effect of class Alphaproteobacteria on prostate cancer was driven by the common risk factors of prostate cancer. CONCLUSION:Our study implies the involvement of gut microbiota in cancer development, which provides a novel potential target for cancer screening and prevention, and might have an implication for future functional analysis.
10.1002/cam4.5772
Causal effects of gut microbiota on diabetic retinopathy: A Mendelian randomization study.
Frontiers in immunology
Background:Previous researches have implicated a vital association between gut microbiota (GM) and diabetic retinopathy (DR) based on the association of the "gut-retina" axis. But their causal relationship has not been elucidated. Methods:Instrumental variables of 211 GM taxa were obtained from genome wide association study (GWAS), and Mendelian randomization study was carried out to estimate their effects on DR risk from FinnGen GWAS (14,584 DR cases and 202,082 controls). Inverse variance weighted (IVW) is the main method to analyze causality, and MR results are verified by several sensitive analyses. Results:As for 211 GM taxa, IVW results confirmed that family- ( = 1.36×10) and family- ( = 3.13×10) were protective factors for DR. Genus- ( = 4.83×10), genus- ( = 3.44×10) and genus- ( = 4.82×10) were correlated with the risk of DR. At the phylum, class and order levels, we found no GM taxa that were causally related to DR (>0.05). Heterogeneity (>0.05) and pleiotropy (>0.05) analysis confirmed the robustness of MR results. Conclusion:We confirmed that there was a potential causal relationship between some GM taxa and DR, which highlights the association of the "gut-retina" axis and offered new insights into the GM-mediated mechanism of DR. Further explorations of their association are required and will lead to find new biomarkers for targeted prevention strategies of DR.
10.3389/fimmu.2022.930318
Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.
Journal of translational medicine
Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
10.1186/s12967-022-03799-5
Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study.
BMC medicine
BACKGROUND:Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with cancer. However, the causal association between gut microbiota and cancer remains to be determined. METHODS:We first identified two sets of gut microbiota based on phylum, class, order, family, and genus level information, and cancer data were obtained from the IEU Open GWAS project. We then performed two-sample Mendelian randomisation (MR) to determine whether the gut microbiota is causally associated with eight cancer types. Furthermore, we performed a bi-directional MR analysis to examine the direction of the causal relations. RESULTS:We identified 11 causal relationships between genetic liability in the gut microbiome and cancer, including those involving the genus Bifidobacterium. We found 17 strong associations between genetic liability in the gut microbiome and cancer. Moreover, we found 24 associations between genetic liability in the gut microbiome and cancer using multiple datasets. CONCLUSIONS:Our MR analysis revealed that the gut microbiota was causally associated with cancers and may be useful in providing new insights for further mechanistic and clinical studies of microbiota-mediated cancer.
10.1186/s12916-023-02761-6
Cross-talks between gut microbiota and tobacco smoking: a two-sample Mendelian randomization study.
BMC medicine
BACKGROUND:Considerable evidence has been reported that tobacco use could cause alterations in gut microbiota composition. The microbiota-gut-brain axis also in turn hinted at a possible contribution of the gut microbiota to smoking. However, population-level studies with a higher evidence level for causality are lacking. METHODS:This study utilized the summary-level data of respective genome-wide association study (GWAS) for 211 gut microbial taxa and five smoking phenotypes to reveal the causal association between the gut microbiota and tobacco smoking. Two-sample bidirectional Mendelian randomization (MR) design was deployed and comprehensively sensitive analyses were followed to validate the robustness of results. We further performed multivariable MR to evaluate the effect of neurotransmitter-associated metabolites on observed associations. RESULTS:Our univariable MR results confirmed the effects of smoking on three taxa (Intestinimonas, Catenibacterium, and Ruminococcaceae, observed from previous studies) with boosted evidence level and identified another 13 taxa which may be causally affected by tobacco smoking. As for the other direction, we revealed that smoking behaviors could be potential consequence of specific taxa abundance. Combining with existing observational evidence, we provided novel insights regarding a positive feedback loop of smoking through Actinobacteria and indicated a potential mechanism for the link between parental smoking and early smoking initiation of their children driven by Bifidobacterium. The multivariable MR results suggested that neurotransmitter-associated metabolites (tryptophan and tyrosine, also supported by previous studies) probably played a role in the action pathway from the gut microbiota to smoking, especially for Actinobacteria and Peptococcus. CONCLUSIONS:In summary, the current study suggested the role of the specific gut microbes on the risk for cigarette smoking (likely involving alterations in metabolites) and in turn smoking on specific gut microbes. Our findings highlighted the hazards of tobacco use for gut flora dysbiosis and shed light on the potential role of specific gut microbiota for smoking behaviors.
10.1186/s12916-023-02863-1
Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn's disease: a multi-omics Mendelian randomization study.
BMC medicine
BACKGROUND:Oxidative stress (OS) is a key pathophysiological mechanism in Crohn's disease (CD). OS-related genes can be affected by environmental factors, intestinal inflammation, gut microbiota, and epigenetic changes. However, the role of OS as a potential CD etiological factor or triggering factor is unknown, as differentially expressed OS genes in CD can be either a cause or a subsequent change of intestinal inflammation. Herein, we used a multi-omics summary data-based Mendelian randomization (SMR) approach to identify putative causal effects and underlying mechanisms of OS genes in CD. METHODS:OS-related genes were extracted from the GeneCards database. Intestinal transcriptome datasets were collected from the Gene Expression Omnibus (GEO) database and meta-analyzed to identify differentially expressed genes (DEGs) related to OS in CD. Integration analyses of the largest CD genome-wide association study (GWAS) summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) from the blood were performed using SMR methods to prioritize putative blood OS genes and their regulatory elements associated with CD risk. Up-to-date intestinal eQTLs and fecal microbial QTLs (mbQTLs) were integrated to uncover potential interactions between host OS gene expression and gut microbiota through SMR and colocalization analysis. Two additional Mendelian randomization (MR) methods were used as sensitivity analyses. Putative results were validated in an independent multi-omics cohort from the First Affiliated Hospital of Sun Yat-sen University (FAH-SYS). RESULTS:A meta-analysis from six datasets identified 438 OS-related DEGs enriched in intestinal enterocytes in CD from 817 OS-related genes. Five genes from blood tissue were prioritized as candidate CD-causal genes using three-step SMR methods: BAD, SHC1, STAT3, MUC1, and GPX3. Furthermore, SMR analysis also identified five putative intestinal genes, three of which were involved in gene-microbiota interactions through colocalization analysis: MUC1, CD40, and PRKAB1. Validation results showed that 88.79% of DEGs were replicated in the FAH-SYS cohort. Associations between pairs of MUC1-Bacillus aciditolerans and PRKAB1-Escherichia coli in the FAH-SYS cohort were consistent with eQTL-mbQTL colocalization. CONCLUSIONS:This multi-omics integration study highlighted that OS genes causal to CD are regulated by DNA methylation and host-microbiota interactions. This provides evidence for future targeted functional research aimed at developing suitable therapeutic interventions and disease prevention.
10.1186/s12916-023-02878-8
Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study.
Frontiers in immunology
Background:Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship. Objective:To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis. Materials and Methods:We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results:Combining the results from the discovery and replication stages, we identified one causal bacterial genus, . A higher relative abundance of the genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; = 4.19 × 10] and CeD (OR: 1.401; 95% CI, 1.139-1.722; = 2.03 × 10), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the genus. Conclusion:This study implied a causal relationship between the genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.
10.3389/fimmu.2021.746998
Association between gut microbiota and preeclampsia-eclampsia: a two-sample Mendelian randomization study.
BMC medicine
BACKGROUND:Several recent observational studies have reported that gut microbiota composition is associated with preeclampsia. However, the causal effect of gut microbiota on preeclampsia-eclampsia is unknown. METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n=13,266) conducted by the MiBioGen consortium. The summary statistics of preeclampsia-eclampsia were obtained from the FinnGen consortium R7 release data (5731 cases and 160,670 controls). Inverse variance weighted, maximum likelihood, MR-Egger, weighted median, weighted model, MR-PRESSO, and cML-MA were used to examine the causal association between gut microbiota and preeclampsia-eclampsia. Reverse Mendelian randomization analysis was performed on the bacteria that were found to be causally associated with preeclampsia-eclampsia in forward Mendelian randomization analysis. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. RESULTS:Inverse variance weighted estimates suggested that Bifidobacterium had a protective effect on preeclampsia-eclampsia (odds ratio = 0.76, 95% confidence interval: 0.64-0.89, P = 8.03 × 10). In addition, Collinsella (odds ratio = 0.77, 95% confidence interval: 0.60-0.98, P = 0.03), Enterorhabdus (odds ratio = 0.76, 95% confidence interval: 0.62-0.93, P = 8.76 × 10), Eubacterium (ventriosum group) (odds ratio = 0.76, 95% confidence interval: 0.63-0.91, P = 2.43 × 10), Lachnospiraceae (NK4A136 group) (odds ratio = 0.77, 95% confidence interval: 0.65-0.92, P = 3.77 × 10), and Tyzzerella 3 (odds ratio = 0.85, 95% confidence interval: 0.74-0.97, P = 0.01) presented a suggestive association with preeclampsia-eclampsia. According to the results of reverse MR analysis, no significant causal effect of preeclampsia-eclampsia was found on gut microbiota. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. CONCLUSIONS:This two-sample Mendelian randomization study found that Bifidobacterium was causally associated with preeclampsia-eclampsia. Further randomized controlled trials are needed to clarify the protective effect of probiotics on preeclampsia-eclampsia and their specific protective mechanisms.
10.1186/s12916-022-02657-x