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Commentary: Causal effects of specific gut microbiota on bone mineral density: a two-sample Mendelian randomization study. Frontiers in endocrinology 10.3389/fendo.2024.1346562
Mendelian randomization study supports effect of gut microflora on fractures. Medicine To investigate the possible causal relationship between intestinal microflora and fractures using Mendelian randomization (MR). A 2-sample MR study of gut microbiota and fractures was conducted using a weighted inverse variance analysis with tests for heterogeneity, horizontal pleiotropy, and sensitivity. A causal association between fracture risk and specific bacterial taxa was identified at various taxonomic levels: 2 (Bacteroidia, P = .0304; Deltaproteobacteria P = .0304) at the class level, 3 (Bacteroidales, P = .0428; Desulfovibrionales, P = .0428; Enterobacteriales, P = .0208) at the order level, 2 (FamilyXI, P = .0304; Enterobacteriaceae P = .0332) at the family level, and 1 (Alistipes, P = .0405) at the genus level. This study revealed a causal relationship between gut microflora and fracture risk, demonstrating that the effect of different flora taxa flora abundance on fracture risk differs. It provides a reference for further studies. 10.1097/MD.0000000000037017
Genome-wide association study in 8,956 German individuals identifies influence of ABO histo-blood groups on gut microbiome. Nature genetics The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory, neurologic and neoplastic diseases. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management. 10.1038/s41588-020-00747-1
Assessing the causal relationships of gut microbial genera with hyperuricemia and gout using two-sample Mendelian randomization. Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:The causal relationship between gut microbiota and gout and hyperuricemia (HUA) has not been clarified. The objective of this research was to evaluate the potential causal effects of gut microbiota on HUA and gout using a two-sample Mendelian randomization (MR) approach. METHODS AND RESULTS:Genetic instruments were selected using summary statistics from genome-wide association studies (GWASs) comprising a substantial number of individuals, including 18,473 participants for gut microbiome, 288,649 for serum urate (SU), and 763,813 for gout. Two-sample MR analyses were performed to determine the possible causal associations of gut microbial genera with the risk of HUA and gout using the inverse-variance weighted (IVW) method, and robustness of the results was confirmed by several sensitivity analyses. A reverse MR analysis was conducted on the bacterial taxa that were identified in forward MR analysis. Based on the results of MR analyses, Escherichia-Shigella (OR = 1.05; 95% CI, 1.01-1.08; P = 0.009) exhibited a positive association with SU levels, while Lachnospiraceae NC2004 group (OR = 0.95; 95% CI, 0.92-0.98; P = 0.001) and Family XIII AD3011 group (OR = 0.94; 95% CI, 0.90-0.99; P = 0.015) were associated with a reduced HUA risk. Moreover, Coprococcus 3 (OR = 1.17, 95% CI: 1.01-1.34, P = 0.031) was causally associated with a higher gout risk. In reverse MR analysis, no causal relationships were identified between these bacterial genera and HUA or gout. CONCLUSION:This study provides evidence for a causal association between gut microbial genera and HUA or gout, and further investigations of the underlying mechanism are warranted. 10.1016/j.numecd.2024.01.021
Improving precision management of anxiety disorders: a Mendelian randomization study targeting specific gut microbiota and associated metabolites. Frontiers in microbiology Background:There is growing evidence of associations between the gut microbiota and anxiety disorders, where changes in gut microbiotas may affect brain function and behavior via the microbiota-gut-brain axis. However, population-level studies offering a higher level of evidence for causality are lacking. Our aim was to investigate the specific gut microbiota and associated metabolites that are closely related to anxiety disorders to provide mechanistic insights and novel management perspectives for anxiety disorders. Method:This study used summary-level data from publicly available Genome-Wide Association Studies (GWAS) for 119 bacterial genera and the phenotype "All anxiety disorders" to reveal the causal effects of gut microbiota on anxiety disorders and identify specific bacterial genera associated with anxiety disorders. A two-sample, bidirectional Mendelian randomization (MR) design was deployed, followed by comprehensive sensitivity analyses to validate the robustness of results. We further conducted multivariable MR (MVMR) analysis to investigate the potential impact of neurotransmitter-associated metabolites, bacteria-associated dietary patterns, drug use or alcohol consumption, and lifestyle factors such as smoking and physical activity on the observed associations. Results:Bidirectional MR analysis identified three bacterial genera causally related to anxiety disorders: the genus and genus were protective, while the genus was associated with an increased risk of anxiety disorders. Further MVMR suggested that a metabolite-dependent mechanism, primarily driven by tryptophan, tyrosine, phenylalanine, glycine and cortisol, which is consistent with previous research findings, probably played a significant role in mediating the effects of these bacterial genera to anxiety disorders. Furthermore, modifying dietary pattern such as salt, sugar and processed meat intake, and adjusting smoking state and physical activity levels, appears to be the effective approaches for targeting specific gut microbiota to manage anxiety disorders. Conclusion:Our findings offer potential avenues for developing precise and effective management approaches for anxiety disorders by targeting specific gut microbiota and associated metabolites. 10.3389/fmicb.2024.1380912
The Role of the Gut-Joint Axis in the Care of Psoriatic Arthritis: A Two-Sample Bidirectional Mendelian Randomization Study. Dermatology and therapy INTRODUCTION:Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. METHODS:A two-sample bi-directional Mendelian randomization analysis 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 psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. RESULTS:Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. CONCLUSION:This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis. 10.1007/s13555-024-01121-3
Blood lipids mediate the effects of gut microbiome on endometriosis: a mendelian randomization study. Lipids in health and disease BACKGROUND:There is evidence for an association between the gut microbiome and endometriosis. However, their causal relationship and the mediating role of lipid metabolism remain unclear. METHODS:Using genome-wide association study (GWAS) data, we conducted a bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiome and endometriosis. The inverse variance weighted (IVW) method was used as the primary model, with other MR models used for comparison. Sensitivity analysis based on different statistical assumptions was used to evaluate whether the results were robust. A two-step MR analysis was further conducted to explore the mediating effects of lipids, by integrating univariable MR and the multivariate MR method based on the Bayesian model averaging method (MR-BMA). RESULTS:We identified four possible intestinal bacteria genera associated with the risk of endometriosis through the IVW method, including Eubacterium ruminantium group (odds ratio [OR] = 0.881, 95% CI: 0.795-0.976, P = 0.015), Anaerotruncus (OR = 1.252, 95% CI: 1.028-1.525, P = 0.025), Olsenella (OR = 1.110, 95% CI: 1.007-1.223, P = 0.036), and Oscillospira (OR = 1.215, 95% CI: 1.014-1.456, P = 0.035). The further two-step MR analysis identified that the effect of Olsenella on endometriosis was mediated by triglycerides (proportion mediated: 3.3%; 95% CI = 1.5-5.1%). CONCLUSION:This MR study found evidence for specific gut microbiomes associated with the risk of endometriosis, which might partially be mediated by triglycerides. 10.1186/s12944-024-02096-y
Causality of the gut microbiome and atherosclerosis-related lipids: a bidirectional Mendelian Randomization study. BMC cardiovascular disorders AIMS:Recent studies have indicated an association between intestinal flora and lipids. However, observational studies cannot indicate causality. In this study, we aimed to investigate the potentially causal relationships between the intestinal flora and blood lipids. METHODS:We performed a bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between intestinal flora and blood lipids. Summary statistics of genome-wide association studies (GWASs) for the 211 intestinal flora and blood lipid traits (n = 5) were obtained from public datasets. Five recognized MR methods were applied to assess the causal relationship with lipids, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. RESULTS:The results indicated a potential causal association between 19 intestinal flora and dyslipidemia in humans. Genus Ruminococcaceae, Christensenellaceae, Parasutterella, Terrisporobacter, Parabacteroides, Class Erysipelotrichia, Family Erysipelotrichaceae, and order Erysipelotrichales were associated with higher dyslipidemia, whereas genus Oscillospira, Peptococcus, Ruminococcaceae UCG010, Ruminococcaceae UCG011, Dorea, and Family Desulfovibrionaceae were associated with lower dyslipidemia. After using the Bonferroni method for multiple testing correction, Only Desulfovibrionaceae [Estimate = -0.0418, 95% confidence interval [CI]: 0.9362-0.9826, P = 0.0007] exhibited stable and significant negative associations with ApoB levels. The inverse MR analysis did not find a significant causal effect of lipids on the intestinal flora. Additionally, no significant heterogeneity or horizontal pleiotropy for IVs was observed in the analysis. CONCLUSION:The study suggested a causal relationship between intestinal flora and dyslipidemia. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address the problems in the clinic. 10.1186/s12872-024-03804-3
Causal relationship between gut microbiome and sex hormone-binding globulin: A bidirectional two-sample Mendelian randomization study. American journal of reproductive immunology (New York, N.Y. : 1989) PROBLEM:Currently, there is a variety of evidence linking the gut microbiota to changes in sex hormones. In contrast, the causal relationship between SHBG, a carrier of sex hormones, and the gut microbiota is unclear. METHOD OF STUDY:Bidirectional two-sample Mendelian randomization (MR) analysis was used to detect the causal effect between SHBG and the gut microbiome. Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and SHBG were obtained from public datasets. Inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger and simple mode methods were used to operate the MR analysis. F-statistics and sensitivity analyses performed to evaluate bias and reliability. RESULTS:When we set gut microbiome as exposure and SHBG as outcome, we identified nine causal relationships. In males, Coprobacter (PIVW = 2.01 × 10 ), Ruminococcus2 (PIVW = 3.40 × 10 ), Barnesiella (PIVW = 2.79 × 10 ), Actinobacteria (PIVW = 3.25 × 10 ) and Eubacterium fissicatena groups (PIVW = 3.64 × 10 ) were associated with lower SHBG levels; Alphaproteobacteria (PIVW = 1.61 × 10 ) is associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 9.75 × 10 ) and Defluviitaleaceae UCG011 (PIVW = 3.67 × 10 ) were associated with higher SHBG levels; Victivallaceae (PIVW = 2.23 × 10 ) was associated with lower SHBG levels. According to the results of reverse MR analysis, three significant causal effect of SHBG was found on gut microbiota. In males, Dorea (PIVW = 4.17 × 10 ) and Clostridiales (PIVW = 4.36 × 10 ) were associated with higher SHBG levels. In females, Lachnoclostridium (PIVW = 7.44 × 10 ) was associated with higherr SHBG levels. No signifcant heterogeneity of instrumental variables or horizontal pleiotropy was found in bidirectional two-sample MR analysis. CONCLUSIONS:This study may provide new insights into the causal relationship between the gut microbiome and sex hormone-binding protein levels, as well as new treatment and prevention strategies for diseases such as abnormal changes in sex hormones. 10.1111/aji.13824
The Causality between Gut Microbiota and Hypertension and Hypertension-related Complications: A Bidirectional Two-Sample Mendelian Randomization Analysis. Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese BACKGROUND:Recent studies have highlighted a connection between gut microbiota and hypertension, yet the precise nature of this relationship remains unclear. OBJECTIVE:This research aims to analyze the causal link between gut microbiota and hypertension, along with associated complications, utilizing two-sample bidirectional Mendelian randomization (MR). MATERIALS AND METHODS:Summary data from genome-wide association studies (GWAS) meta-analyses, including gut microbiota GWAS data from 24 cohorts, and the latest GWAS data for hypertension-related conditions were acquired. Employing various MR methods, including Inverse-variance weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode, we investigated the association between gut microbiota and hypertension-related conditions. Sensitivity analyses were conducted for result stability, and reverse MR analysis assessed the potential for reverse causality. RESULTS:The Mendelian randomization analysis involving 199 microbial taxa and four phenotypes identified 46 microbial taxa with potential causal links to hypertension and its complications. Following Bonferroni correction, genus.Victivallis showed a robust causal relationship with hypertension (OR = 1.08, 95% CI = 1.04-1.12, P = 9.82e-5). This suggests an 8% increased risk of hypertension with each unit rise in genus.Victivallis abundance. CONCLUSION:In conclusion, this study establishes a causal connection between gut microbiota and hypertension, along with common associated complications. The findings unveil potential targets and evidence for future hypertension and complication treatment through gut microbiota interventions, offering a novel avenue for therapeutic exploration. 10.1016/j.hjc.2024.02.002
The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study. Hormones (Athens, Greece) PURPOSE:Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. METHODS:We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. RESULTS:The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: β = 0.063, P = 0.034), the genus Butyrivibrio (IVW: β = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: β=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: β=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: β=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: β = 0.235, P = 0.03) and the order Clostridiales (IVW: β = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: β = 0.953, P = 0.022) and the order Lactobacillales (IVW: β=-0.806, P = 0.042) were suggestive of an association with PAI-1. CONCLUSION:This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases. 10.1007/s42000-024-00553-y
Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A 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:Mechanistic data indicate the benefit of short-chain fatty acids (SCFA) produced by gut microbial fermentation of fiber on colorectal cancer, but direct epidemiologic evidence is limited. A recent study identified SNPs for two SCFA traits (fecal propionate and butyrate-producing microbiome pathway PWY-5022) in Europeans and showed metabolic benefits. METHODS:We conducted a two-sample Mendelian randomization analysis of the genetic instruments for the two SCFA traits (three SNPs for fecal propionate and nine for PWY-5022) in relation to colorectal cancer risk in three large European genetic consortia of 58,131 colorectal cancer cases and 67,347 controls. We estimated the risk of overall colorectal cancer and conducted subgroup analyses by sex, age, and anatomic subsites of colorectal cancer. RESULTS:We did not observe strong evidence for an association of the genetic predictors for fecal propionate levels and the abundance of PWY-5022 with the risk of overall colorectal cancer, colorectal cancer by sex, or early-onset colorectal cancer (diagnosed at <50 years), with no evidence of heterogeneity or pleiotropy. When assessed by tumor subsites, we found weak evidence for an association between PWY-5022 and risk of rectal cancer (OR per 1-SD, 0.95; 95% confidence intervals, 0.91-0.99; P = 0.03) but it did not surpass multiple testing of subgroup analysis. CONCLUSIONS:Genetic instruments for fecal propionate levels and the abundance of PWY-5022 were not associated with colorectal cancer risk. IMPACT:Fecal propionate and PWY-5022 may not have a substantial influence on colorectal cancer risk. Future research is warranted to comprehensively investigate the effects of SCFA-producing bacteria and SCFAs on colorectal cancer risk. 10.1158/1055-9965.EPI-22-0861
Sex specific effect of gut microbiota on the risk of psychiatric disorders: A Mendelian randomisation study and PRS analysis using UK Biobank cohort. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry OBJECTIVE:The relationships between gut microbiota and brain-related diseases/traits remains not fully understood. METHOD:A two-stage study was performed to investigate the relationships between gut microbiota and brain-related diseases/traits, and evaluate the potential sex specific effects of gut microbiota. In discovery stage, we systematically scanned the relationships between 515 brain-related diseases/traits and gut microbiota through two-sample Mendelian randomisation analysis. Using ∼500,000 individuals derived from the UK Biobank, polygenetic risk scoring (PRS) analysis was performed to validate the associations detected in discovery stage. To evaluate the potential sex-specific effect of gut microbiota on brain-related disorders, PRS analysis was conducted in female and male, respectively. RESULTS:After systematically scanning diseases or traits, 41 of the 515 brain-related diseases/traits were identified to be associated with gut microbiota, such as Neuroticism score ( = 0.0018), worrier/anxious feelings ( = 0.0013), Suffer from 'nerves' ( = 0.0062) and Nervous feelings ( = 0.0158). 5 of 41 brain-related diseases or traits were successfully validated in UK Biobank, such as Neuroticism score ( = 0.0024,  = 0.0063,  = 0.1142), Nervous feelings ( = 0.0043,  = 0.0115, 0.1670) and Worrier/anxious feelings ( = 0.0166,  = 0.0196, 0.2930). CONCLUSION:Our results suggest that gut microbiota contributed more to brain-related diseases or traits in females than in males.Key pointsA two-stage study was performed to investigate the relationships between gut microbiota and brain-related diseases/traits.Using the individuals derived from the UK Biobank, polygenetic risk scoring analysis was performed to validate the associations detected in the discovery stage.Our results suggest that gut microbiota contributed more to brain-related diseases or traits in females than in males. 10.1080/15622975.2021.1878428
Influence of genetically predicted autoimmune diseases on NAFLD. Frontiers in immunology Introduction:Non-alcoholic fatty liver disease (NAFLD), the emerging cause of end-stage liver disease, is the most common liver disease. Determining the independent risk factors of NAFLD and patients who need more monitoring is important. Methods:Two-Sample Mendelian randomization (MR) was performed in the analysis to investigate the causal association of different autoimmune diseases with NAFLD using summary level data. Genome-wide association study (GWAS) of 5 autoimmune diseases including celiac disease (CeD), Crohn's disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D) were selected for Instrument variables (IVs). NAFLD was included as outcome. Result:After adjusting for confounding factors, genetic predisposition of CeD (OR= 0.973, [0.949,0.997], IVW p-value=0.026), MS (OR= 1.048, [1.012,1.085], IVW p-value= 0.008), RA (OR= 1.036, [1.006,1.066], IVW p-value=0.019), T1D (OR= 1.039, [1.002,1.079], IVW p-value= 0.041) is causally associated with NAFLD. No causal effect was found between CD and NAFLD. Conclusion:CeD itself may be a protective factor for NAFLD, the results of previous observational studies have been influenced by confounding factors, and the morbidity of NAFLD may be higher in patients with MS, RA, and T1D than in common populations, and monitoring the prevalence of NAFLD in these populations is considerable. 10.3389/fimmu.2023.1229570
Causal associations between human gut microbiota and hemorrhoidal disease: A two-sample Mendelian randomization study. Medicine Hemorrhoidal disease (HEM) is a common condition affecting a significant proportion of the population. However, the causal relationship between the gut microbiota and hemorrhoids remains unclear. In this study, we employed a Mendelian randomization (MR) approach to investigate the potential associations between them. In this study, the exposure factor was determined by selecting summary statistics data from a large-scale gut microbiome whole-genome association study conducted by the MiBioGen Consortium, which involved a sample size of 18,340 individuals. The disease outcome data consisted of 218,920 cases of HEM and 725,213 controls of European ancestry obtained from the European Bioinformatics Institute dataset. Two-sample MR analyses were performed to assess the causalities between gut microbiota and hemorrhoids using various methods, including inverse-variance weighting, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), simple mode, and weighted median. Reverse MR analyses were performed to examine reverse causal association. Our findings suggest phylum Cyanobacteria (OR = 0.947, 95% CI: 0.915-0.980, P = 2.10 × 10 - 3), genus Phascolarctobacterium (OR = 0.960, 95% CI: 0.924-0.997, P = .034) and family FamilyXI (OR = 0.974, 95% CI: 0.952-0.997, P = .027) have potentially protective causal effects on the risk of HEM, while genus Ruminococcaceae_UCG_002 (OR = 1.036, 95% CI: 1.001-1.071, P = .042), family Peptostreptococcaceae (OR = 1.042, 95% CI: 1.004-1.082, P = .029), genus Oscillospira (OR = 1.048, 95% CI: 1.005-1.091, P = .026), family Alcaligenaceae (OR = 1.048, 95% CI: 1.005-1.091, P = .036) and order Burkholderiales (OR = 1.074, 95% CI: 1.020-1.130, P = 6.50 × 10-3) have opposite effect. However, there was a reverse causal relationship between HEM and genus Oscillospira (OR = 1.140, 95% CI: 1.002-1.295, P = .046) This is the first MR study to explore the causalities between specific gut microbiota taxa and hemorrhoidal disease, which may offer valuable insights for future clinical interventions for hemorrhoidal disease. 10.1097/MD.0000000000037599
Causal relationship between the gut microbiome and basal cell carcinoma, melanoma skin cancer, ease of skin tanning: evidence from three two-sample mendelian randomisation studies. Frontiers in immunology Objectives:The present study used publicly available genome-wide association study (GWAS) summary data to perform three two-sample Mendelian randomization (MR) studies, aiming to examine the causal links between gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Methods:SNPs associated with exposures to basal cell carcinoma, melanoma skin cancer and ease of skin tanning from the genome-wide association study data of UK Biobank and MRC-IEU (MRC Integrative Epidemiology Unit), and the meta-analysis data from Biobank and MRC-IEU were used as instrumental variables (IVs). The casual estimates were assessed with a two-sample Mendelian randomisation test using the inverse-variance-weighted (IVW) method, Wald ratio, MR-Egger method, maximum likelihood, weighted median, simple mode, and weighted mode. Results:After the application of MR analysis, diffirent effects of multiple groups of gut microbiota was observed for BCC, melanoma skin cancer and ease of skin tanning. The relationships between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning were supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Conclusion:Our study initially identified potential causal roles between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning, and highlighted the role of gut microbiome in the progression of basal cell carcinoma, melanoma skin cancer, ease of skin tanning. 10.3389/fimmu.2024.1279680
Potential Cause-and-Effect Relationship between Gut Microbiota and Childhood Neuroblastoma: A Mendelian Randomization Analysis. Indian journal of pediatrics OBJECTIVES:To analyze the potential causal-effect of gut microbiota (GM) on neuroblastoma (NB) risk using a Mendelian randomization (MR) study. METHODS:A two-sample MR study was conducted using summary statistics of the GM from the largest available meta-analysis of genome-wide association studies conducted by the MiBioGen consortium. Pooled statistics for childhood NB were obtained from the IEU Consortium release data (1627 cases and 3254 controls). Inverse variance-weighted, weighted median, MR-Egger, and weighted mod were used to examine the causal relationship between GM and childhood NB. Single-nucleotide polymorphism (SNP) genes of positive GM were extracted using the PLINK program, and correlations between key SNP genes and tumor-regulated genes were analyzed. Functional enrichment analysis and transcription factor prediction were performed. RESULTS:Inverse variance weighted (IVW) results indicated that Erysipelotrichia exerted a protective effect against childhood NB (odds ratio = 0.371, 95% Confidence interval: 0.173 - 0.795, P = 0.011) and that Oscillospira exerted a risk effect against childhood NB (odds ratio = 2.378, 95% Confidence interval: 1.121 - 5.043, P = 0.024), indicating the association of GM with childhood NB. Further screening analysis using the IVW test revealed a reliable causal relationship between Erysipelotrichia and NB. Two SNP genes (MUC4 and PELI2) of Erysipelotrichia were extracted and analyzed. Both key genes were significantly associated with tumor-regulated genes, enriched in several pathways associated with tumor progression, and correlated with several upstream transcription factors. CONCLUSIONS:It was observed that Erysipelotrichia is causally associated with NB using a two-sample MR study. Furthermore, the discovery of two SNP genes, MUC4 and PELI2, provides potential targets for the diagnosis and treatment of NB. 10.1007/s12098-024-05065-6
Large-scale correlation analysis of deep venous thrombosis and gut microbiota. Frontiers in cardiovascular medicine Objective:Although previous studies have shown that gut microbiota may be involved in the occurrence of deep venous thrombosis (DVT), the specific link between the two remains unclear. The present study aimed to explore this question from a genetic perspective. Materials and methods:Genome-wide association study (GWAS) summary data of DVT were obtained from the UK Biobank ( = 9,059). GWAS summary data of the gut microbiota were obtained from the Flemish Gut Flora Project ( = 2,223) and two German cohorts (FoCus, = 950; PopGen, = 717). All the participants were of European ancestry. Linkage disequilibrium score (LDSC) regression has great potential for analyzing the heritability of disease or character traits. LDSC regression was used to analyze the genetic correlation between DVT and the gut microbiota based on the GWAS summary data obtained from previous studies. Mendelian randomization (MR) was used to analyze the genetic causal relationship between DVT and the gut microbiota. We used the random effects inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode to perform MR analysis. We performed a sensitivity analysis of the MR analysis results by examining heterogeneity and horizontal pleiotropy. Results:Linkage disequilibrium score analysis showed that Streptococcaceae (correlation coefficient = -0.542, SE = 0.237, = 0.022), Dialister (correlation coefficient = -0.623, SE = 0.316, = 0.049), Streptococcus (correlation coefficient = -0.576, SE = 0.264, = 0.029), and Lactobacillales (correlation coefficient = -0.484, SE = 0.237, = 0.042) had suggestive genetic correlation with DVT. In addition, the MR analysis showed that Streptococcaceae had a positive genetic causal relationship with DVT ( = 0.027, OR = 1.005). There was no heterogeneity or horizontal pleiotropy in the MR analysis ( > 0.05). Conclusion:In this study, four gut microbes (Streptococcaceae, Dialister Streptococcus, Lactobacillales) had suggestive genetic correlations with DVT, and Streptococcaceae had a positive causal relationship with DVT. Our findings provide a new research direction for the further study of and prevention of DVT. 10.3389/fcvm.2022.1025918
Causal associations of genetically predicted gut microbiota and blood metabolites with inflammatory states and risk of infections: a Mendelian randomization analysis. Frontiers in microbiology Background:Inflammation serves as a key pathologic mediator in the progression of infections and various diseases, involving significant alterations in the gut microbiome and metabolism. This study aims to probe into the potential causal relationships between gut microbial taxa and human blood metabolites with various serum inflammatory markers (CRP, SAA1, IL-6, TNF-α, WBC, and GlycA) and the risks of seven common infections (gastrointestinal infections, dysentery, pneumonia, bacterial pneumonia, bronchopneumonia and lung abscess, pneumococcal pneumonia, and urinary tract infections). Methods:Two-sample Mendelian randomization (MR) analysis was performed using inverse variance weighted (IVW), maximum likelihood, MR-Egger, weighted median, and MR-PRESSO. Results:After adding other MR models and sensitivity analyses, genus was simultaneously associated adversely with CRP (Beta = -0.040) and SAA1 (Beta = -0.280), and family was negatively associated with both CRP (Beta = -0.034) and pneumonia risk (Beta = -0.391). After correction by , only glutaroyl carnitine remained significantly associated with elevated CRP levels (Beta = 0.112). Additionally, threonine (Beta = 0.200) and 1-heptadecanoylglycerophosphocholine (Beta = -0.246) were found to be significantly associated with WBC levels. Three metabolites showed similar causal effects on different inflammatory markers or infectious phenotypes, stearidonate (18:4n3) was negatively related to SAA1 and urinary tract infections, and 5-oxoproline contributed to elevated IL-6 and SAA1 levels. In addition, 7-methylguanine showed a positive correlation with dysentery and bacterial pneumonia. Conclusion:This study provides novel evidence confirming the causal effects of the gut microbiome and the plasma metabolite profile on inflammation and the risk of infection. These potential molecular alterations may aid in the development of new targets for the intervention and management of disorders associated with inflammation and infections. 10.3389/fmicb.2024.1342653
Genetic causal relationship between gut microbiota and cutaneous melanoma: a two-sample Mendelian randomization study. Melanoma research Currently, numerous studies suggest a potential association between the gut microbiota and the progression of melanoma. Hence, our objective was to examine the genetic impact of the gut microbiota on melanoma through the utilization of the Mendelian randomization (MR) approach. This research employed Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae as exposure variables and cutaneous melanoma (CM) as the outcome in a two-sample MR analysis. In this MR research, the primary analytical approach was the random-effects inverse-variance weighting (IVW) model. Complementary methods included weighted median, MR Egger, and basic and weighted models. We assessed both heterogeneity and horizontal pleiotropy in our study, scrutinizing whether the analysis results were affected by any individual SNP. The random-effects IVW outcomes indicated that Streptococcus, Bacteroides, Lachnospiraceae and Proteobacteria had no causal relationship with CM, with odds ratios of 1.001 [95% confidence interval (CI) = 0.998-1.004, P  = 0.444], 0.999 (95% CI = 0.996-1.002, P  = 0.692), 1.001 (95% CI = 0.998-1.003, P  = 0.306), and 0.999 (95% CI = 0.997-1.002, P  = 0.998), respectively. No analyses exhibited heterogeneity, horizontal pleiotropy, or deviations. Our research determined that Bacteroides, Streptococcus, Proteobacteria, and Lachnospiraceae do not induce CM at the genetic level. However, we cannot dismiss the possibility that these four gut microbiotas might influence CM through other mechanisms. 10.1097/CMR.0000000000000960
Association between gut microbiota and peptic ulcer disease, particularly gastric ulcer and duodenal ulcer: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Recent an observational study has suggested a potential connection between gut microbiota (GM) and peptic ulcer diseases (PUDs), particularly gastric ulcer (GU) and duodenal ulcer (DU). However, the causal connection remains unsure. Methods:A two-sample Mendelian randomization (MR) is carried out to explore the connection between the GM and DU or GU. Data on the GM comes from the MiBioGend database, and GU or DU data are based on the FinnGen database. One group of single nucleotide polymorphisms (SNPs) ( < 5 × 10) are served as instrumental variables (IVs). To obtain a more comprehensive conclusion, the other SNPs ( < 1 × 10) are selected as IVs. Inverse variance weighting (IVW) is used to determine the causal relationship. Results:At the level of < 1 × 10, the IVW analysis suggests that Clostridiaceae1, Butyriccoccus, and Peptcoccus have harmful effects on GU, while LachnospiraceaeUCG004 and MollicutesRF9 have beneficial effects on GU. Then, in the case of DU, the IVW analysis suggested that Lentisphaeria, Negativicutes, Clostridiaceae1, ClostridiumseMnsustricto1, ErysipelotrichaceaeUCG003, LachnospiraceaeNC2004group, Selenomonadale, Victivallales, and Lentisphaerae have harmful effects, while Catenibacterium, Escherichia.Shigella, LachnospiraceaeUCG008, and Sutterella have beneficial effects. When < 5 × 10, IVW analysis suggests that GM has no significant influence on GU or DU. Conclusion:This two-sample MR indicates a causal relationship between GM and GU or DU. 10.3389/fmicb.2023.1277300
Genetic evidence strengthens the bidirectional connection between gut microbiota and infection: insights from a two-sample Mendelian randomization study. Frontiers in microbiology Background:In recent investigations, substantial strides have been made in the precise modulation of the gut microbiota to prevent and treat a myriad of diseases. Simultaneously, the pressing issue of widespread antibiotic resistance and multidrug resistance resulting from infections demands urgent attention. Several studies suggest that the antagonistic influence of the gut microbiota could serve as a novel avenue for impeding the colonization of pathogenic microorganisms or treating infections. However, conventional research methodologies encounter inherent challenges in identifying antagonistic microbial agents against , necessitating a comprehensive and in-depth analysis of the causal relationship between infections and the gut microbiota. Materials and methods:Utilizing the aggregated summary statistics from Genome-Wide Association Studies (GWAS), we conducted Mendelian Randomization (MR) analyses encompassing 18,340 participants to explore the interplay between the gut microbiota and infections. This investigation also involved 83 cases of infection patients and 336,396 control subjects. In the positive strand of our findings, we initially performed a preliminary analysis using the Inverse Variance Weighting (IVW) method. Subsequently, we undertook sensitivity analyses to assess the robustness of the results, addressing confounding factors' influence. This involved employing the Leave-One-Out method and scrutinizing funnel plots to ensure the reliability of the MR analysis outcomes. Conclusively, a reverse MR analysis was carried out, employing the Wald ratio method due to the exposure of individual Single Nucleotide Polymorphisms (SNPs). This was undertaken to explore the plausible associations between infections and genetically predicted compositions of the gut microbiota. Results:In this study, we employed 2,818 SNPs associated with 211 species of gut microbiota as instrumental variables (IVs). Through IVW analysis, our positive MR findings revealed a significant negative correlation between the occurrence of infections and the phylum Tenericutes (OR: 0.18, 95% CI: 0.04-0.74, = 0.02), class Mollicutes (OR: 0.18, 95% CI: 0.04-0.74, p = 0.02), genus (OR: 0.16, 95% CI: 0.04-0.63, = 0.01), genus (OR: 0.39, 95% CI: 0.16-0.93, = 0.03), and genus (OR: 0.44, 95% CI: 0.23-0.87, = 0.02). Conversely, a positive correlation was observed between the occurrence of infections and genus (OR: 10.16, 95% CI: 1.87-55.13, = 0.01) and genus (OR: 12.24, 95% CI: 1.71-87.34, = 0.01). In sensitivity analyses, utilizing MR-Egger regression analysis and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) detection, all outcomes demonstrated robust stability. Simultaneously, in the reverse MR analysis, infections resulted in an upregulation of four bacterial genera and a downregulation of three bacterial genera. Conclusion:In summation, the MR analysis outcomes corroborate the presence of bidirectional causal relationships between the gut microbiota and infections. This study not only unveils novel perspectives for the prevention and treatment of infections but also furnishes fresh insights into the mechanistic underpinnings of how the gut microbiota contributes to the pathogenesis of infections. Consequently, the established dual causal association holds promise for advancing our understanding and addressing the complexities inherent in the interplay between the gut microbiota and infections, thereby paving the way for innovative therapeutic interventions and preventive strategies in the realm of -related diseases. 10.3389/fmicb.2024.1361927
Preliminary study of the effect of gut microbiota on the development of prostatitis. BMC medical genomics BACKGROUND:Dysbacteriosis of intestinal tract may cause systemic inflammation, making distant anatomical locations more susceptible to illness. Recent research has demonstrated that the microbiome can affect both prostatitis and the inflammation of the prostate that is linked to prostate cancer. It is still unclear, though, whether this relationship indicates causation. We conducted a Mendelian randomization investigation on two samples to fully uncover gut microbiota's potential genetic causal role in prostatitis. METHOD:Prostatitis (1859 prostatitis cases and 72,799 controls) was utilized as the outcome, while SNPs highly linked with 196 microbial taxa (18 340 people) were chosen as instrumental factors. Random effects, inverse variance weighting, weighted medians, and MR-Egger were used to analyze causal effects. The Cochran's Q test, funnel plot, leave-one-out analysis, and MR-Egger intercept test were all used in the sensitivity analysis. RESULTS:A causal effect in lowering the incidence of prostatitis is anticipated for five gut microorganisms (Methanobacteria, Methanobacteriaceae, Erysipelatoclostridium, Parasutterella, and Slackia; P < 0.05). Four gut bacteria, including Faecalibacterium, LachnospiraceaeUCG004, Sutterella, and Gastranaerophilales, are predicted to play a causal role in increasing the risk of prostatitis (P < 0.05). There were no discernible estimates of pleiotropy or heterogeneity. CONCLUSION:Our investigation established the genetic links between nine gut microorganisms and prostatitis, which may offer fresh perspectives and a theoretical framework for the future prevention and management of prostatitis. 10.1186/s12920-024-01812-y
Causal effects of gut microbiome on HIV infection: a two-sample mendelian randomization analysis. BMC infectious diseases BACKGROUND:The causal association between gut microbiome and HIV infection remains to be elucidated. We conducted a two-sample mendelian randomization analysis to estimate the causality between gut microbiome and HIV infection. METHODS:Publicly released genome-wide association studies summary data were collected to perform the mendelian analysis. The GWAS summary data of gut microbiome was retrieved from the MiBioGen consortium, which contains 18 340 samples from 24 cohorts. GWAS summary data of HIV infection was collected from the R5 release of FinnGen consortium, including 357 HIV infected cases and 218 435 controls. The SNPs were selected as instrumental variables according to our selection rules. And SNPs with a F-statistics less than ten were regarded as weak instrumental variables and excluded. Mendelian randomization analysis was conducted by five methods, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode. The Cochran's Q test and MR-Egger intercept test were performed to identify heterogeneity and pleiotropy. Leave-one-out analysis were used to test the sensitivity of the results. RESULTS:Fifteen gut microbiota taxa showed causal effects on HIV infection according to the MR methods. Four taxa were observed to increase the risk of HIV infection, including Ruminococcaceae (OR: 2.468[1.043, 5.842], P: 0.039), Ruminococcaceae UCG005 (OR: 2.051[1.048, 4.011], P: 0.036), Subdoligranulum (OR: 3.957[1.762, 8.887], P < 0.001) and Victivallis (OR: 1.605[1.012, 2.547], P=0.044). Erysipelotrichaceae was protective factor of HIV infection (OR: 0.278[0.106, 0.731], P < 0.001) and Methanobrevibacter was also found to be associated with reduced risk of HIV infection (OR: 0.509[0.265, 0.980], P=0.043). Horizontal pleiotropy was found for Fusicatenibacter (P<0.05) according to the MR-Egger regression intercept analysis. No heterogeneity was detected. CONCLUSION:Our results demonstrate significant causal effects of gut microbiome on HIV infection. These findings facilitate future studies to develop better strategies for HIV prophylaxis through gut microbiome regulation. Further explorations are also warranted to dissect the mechanism of how gut microbiome affects HIV susceptibility. 10.1186/s12879-024-09176-5
A causal relationship between gut microbiota and subcortical brain structures contributes to the microbiota-gut-brain axis: a Mendelian randomization study. Cerebral cortex (New York, N.Y. : 1991) A correlation between gut microbiota and brain structure, referring to as a component of the gut-brain axis, has been observed in observational studies. However, the causality of this relationship and its specific bacterial taxa remains uncertain. To reveal the causal effects of gut microbiota on subcortical brain volume, we applied Mendelian randomization (MR) studies in this study. Genome-wide association study data were obtained from the MiBioGen Consortium (n = 18,340) and the Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium (n = 13,170). The primary estimate was obtained utilizing the inverse-variance weighted, while heterogeneity and pleiotropy were assessed using the Cochrane Q statistic, MR Pleiotropy RESidual Sum and Outlier, and MR-Egger intercept. Our findings provide strong evidence that a higher abundance of the genus Parasutterella is causally correlated with a decrease in intracranial volume (β = -30,921.33, 95% CI -46,671.78 to -15,170.88, P = 1.19 × 10-4), and the genus FamilyXIIIUCG001 is associated with a decrease in thalamus volume (β = -141.96, 95% CI: -214.81 to -69.12, P = 1.0× 10-4). This MR study offers novel perspectives on the intricate interplay between the gut microbiota and subcortical brain volume, thereby lending some support to the existence of the microbiota-gut-brain axis. 10.1093/cercor/bhae056
Human gut microbiome impacts skeletal muscle mass via gut microbial synthesis of the short-chain fatty acid butyrate among healthy menopausal women. Journal of cachexia, sarcopenia and muscle BACKGROUND:Increasing evidence suggests that human gut microbiome plays an important role in variation of skeletal muscle mass (SMM). However, specific causal mechanistic relationship of human gut microbiome with SMM remains largely unresolved. Understanding the causal mechanistic relationship may provide a basis for novel interventions for loss of SMM. This study investigated whether human gut microbiome has a causal effect on SMM among Chinese community-dwelling healthy menopausal women. METHODS:Estimated SMM was derived from whole-body dual-energy X-ray absorptiometry. We performed integrated analyses on whole-genome sequencing, shotgun metagenomic sequencing, and serum short-chain fatty acids (SCFAs), as well as available host SMM measurements among community-dwelling healthy menopausal women (N = 482). We combined the results with summary statistics from genome-wide association analyses for human gut microbiome (N = 952) and SMM traits (N = 28 330). As a prerequisite for causality, we used a computational protocol that was proposed to measure correlations among gut metagenome, metabolome, and the host trait to investigate the relationship between human gut microbiome and SMM. Causal inference methods were applied to assess the potential causal effects of gut microbial features on SMM, through one-sample and two-sample Mendelian randomization (MR) analyses, respectively. RESULTS:In metagenomic association analyses, the increased capacity for gut microbial synthesis of the SCFA butyrate was significantly associated with serum butyrate levels [Spearman correlation coefficient (SCC) = 0.13, P = 0.02] and skeletal muscle index (SCC = 0.084, P = 0.002). Of interest was the finding that two main butyrate-producing bacterial species were both positively associated with the increased capacity for gut microbial synthesis of butyrate [Faecalibacterium prausnitzii (SCC = 0.25, P = 6.6 × 10 ) and Butyricimonas virosa (SCC = 0.15, P = 0.001)] and for skeletal muscle index [F. prausnitzii (SCC = 0.16, P = 6.2 × 10 ) and B. virosa (SCC = 0.17, P = 2.4 × 10 )]. One-sample MR results showed a causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.04, 95% confidence interval 0.029 to 0.051, P = 0.003). Two-sample MR results further confirmed the causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.06, 95% confidence interval 0 to 0.13, P = 0.06). CONCLUSIONS:Our results may help the future development of novel intervention approaches for preventing or alleviating loss of SMM. 10.1002/jcsm.12788
Causal association between gut microbiota and hyperemesis gravidarum: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Observational studies have reported an association between the gut microbiota (GM) and hyperemesis gravidarum (HG). However, the causal relationship is unclear. In this study, Mendelian randomization (MR) was used to infer causal relationships between GM and HG. Methods:Inverse-variance weighted MR was performed using summary statistics for genetic variants from genome-wide association studies (GWAS). Sensitivity analyses were performed to validate the MR results and assess the robustness of the causal inference. Reverse MR analysis was performed for bacterial taxa that were causally linked to the HG risk in the forward MR analysis to evaluate reverse causality. Results:MR analysis revealed that the genera , , , , and and phylum are positively associated with the risk of HG. Additionally, the genus was related to a decreased risk of HG. Sensitivity studies validated the strength and reliability of the link between the composition of the GM and HG. No evidence for reverse causality from HG to identified bacterial taxa was found. Conclusion:Our MR analysis provided novel insight into the association between GM and HG. In particular, our results indicated that targeting the GM could serve as an effective therapeutic strategy for HG. 10.3389/fmicb.2024.1307729
Exploring the causal relationship between gut microbiota and multiple myeloma risk based on Mendelian randomization and biological annotation. Frontiers in microbiology Introduction:The microbial genome-wide association studies (mbGWAS) have highlighted significant host-microbiome interactions based on microbiome heritability. However, establishing causal relationships between particular microbiota and multiple myeloma (MM) remains challenging due to limited sample sizes. Methods:Gut microbiota data from a GWAS with 18,340 participants and MM summary statistics from 456,348 individuals. The inverse variance-weighted (IVW) method was used as the main bidirectional Mendelian randomization (MR) analysis. To assess the robustness of our results, we further performed supplementary analyses, including MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger, Weighted median, Simple mode, and Weighted mode. Moreover, a backward MR analysis was conducted to investigate the potential for reverse causation. Finally, gene and gene-set-based analyses were then conducted to explore the common biological factors connecting gut microbiota and MM. Results:We discovered that 10 gut microbial taxa were causally related to MM risk. Among them, family , family S24-7, family , genus , genus , and genus were positively correlated with MM. Conversely, class , family , genus , and order were negatively correlated with MM. The heterogeneity test revealed no Heterogeneity. MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. Importantly, leave-one-out analysis confirmed the robustness of MR results. In the backward MR analysis, no statistically significant associations were discovered between MM and 10 gut microbiota taxa. Lastly, we identified novel host-microbiome shared genes (AUTS2, CDK2, ERBB3, IKZF4, PMEL, SUOX, and RAB5B) that are associated with immunoregulation and prognosis in MM through biological annotation. Discussion:Overall, this study provides evidence supporting a potential causal relationship between gut microbiota and MM risk, while also revealing novel host-microbiome shared genes relevant to MM immunoregulation and clinical prognosis. 10.3389/fmicb.2024.1310444
Causal effects of gut microbiota in the development of lung cancer and its histological subtypes: A Mendelian randomization study. Thoracic cancer BACKGROUND:Numerous studies have characterized the gut microbiome (GM) in lung cancer (LC). Yet, the causality between GM and LC and its subtypes remain uncharacterized. METHODS:Two-sample Mendelian randomization (MR) was designed to investigate the causal relationship between the GM and LC and its subtypes, using publicly available summary data of genome-wide association studies. The researchers ran two groups of MR analyses, including the genome-wide statistical significance threshold (5 × 10 ) and the locus-wide significance level (1 × 10 ). RESULTS:Using MR analysis, we ascertained 42 groups of GM that are intimately linked to LC and its subtypes at the locus-wide significance level. Of the 42 groups, 12 were in LC, nine in non-small cell lung cancer (NSCLC), six in small cell lung cancer (SCLC), two in lung adenocarcinomas, and 13 in lung squamous carcinomas. After false discovery rate correction, we still found a remarkable causal interaction between the Eubacterium ruminantium group and SCLC. Moreover, five groups of GM closely linked to LC and its subtypes were recognised at the genome-wide statistical significance threshold. This finding included one group each in LC, NSCLC and SCLC, two groups in lung adenocarcinoma and none in lung squamous carcinoma. None of the foregoing findings were heterogeneous or horizontal pleiotropy. Reverse MR revealed that genetic susceptibility to LC and its subtypes caused significant changes in three groups of GM. CONCLUSION:Our findings substantiate the causality between GM and LC and its subtypes. This study offers fresh insights into the function of GM in mediating the progression of LC. 10.1111/1759-7714.15220
Causal association of gut microbiome on the risk of rheumatoid arthritis: a Mendelian randomisation study. Annals of the rheumatic diseases 10.1136/annrheumdis-2019-216747
The causality between gut microbiome and chronic regional pain: a Mendelian randomization analysis. Frontiers in microbiology Background:Numerous investigations have underscored the causal effect between chronic pain (CP) and gut microbiota, jointly contributing to the onset and development of widespread CP. Nonetheless, there was still uncertainty about the causal effect between gut microbiota and chronic regional pain (CRP). Methods:Genome-wide association study (GWAS) summary data of gut microbial taxa (MiBioGen Consortium: 211 microbiotas and the Dutch Microbiome Project: 207 microbiotas) and eight types of CRP were used to reveal the causal effect between persistent pain in a specific region of the body and gut microbiota. A two-sample bidirectional Mendelian randomization (MR) design was used. In order to ensure the accuracy of the results, multiple sensitivity analyses were employed. Results:This study uncovered significant causal associations between six gut microbial taxa and three types of CRP (forward: for general pain; , and for back pain. Reverse: knee pain for and ) by forward and reverse MR analysis. These findings had been verified by a rigorous Bonferroni correction. Furthermore, this research identified 19 microbial taxa that exhibited potential correlations with four types of CRP. There are no significant or potential gut microbiotas that were associated with other types of CRP, including fascial pain, stomach or abdominal pain, and hip pain. Conclusion:This two-sample bidirectional MR analysis unveiled the causality between gut microbial taxa and eight CRP conditions. The findings reveal the interplay between CRP and 6 gut microbiotas while also delineating 19 potential specific microbial taxa corresponding to diverse locations of persistent pain. 10.3389/fmicb.2024.1329521
Multiple reports on the causal relationship between various chronic pain and gut microbiota: a two-sample Mendelian randomization study. Frontiers in neuroscience Background:Previous evidence suggests a link between gut microbiota and chronic pain, but the causal relationship is not yet fully understood. Methods:We categorized gut microbiota based on phylum, class, order, family, and genus levels and gathered pain-related information from the UKB and FinnGen GWAS project. Then, we conducted MR analysis to explore the potential causal relationship between gut microbiota and chronic pain at 12 specific locations. Results:We have discovered a direct connection between genetic susceptibility in the gut microbiota (gut metabolites) and pain experienced at 12 specific locations. Notably, Serotonin (5-HT) and Glycine were found to be associated with a higher risk of pain in the extremities. On the other hand, certain microbial families and orders were found to have a protective effect against migraines. Specifically, the family Bifidobacteriaceae (IVW, FDR  = 0.013) was associated with a lower risk of migraines. Furthermore, the genus Oxalobacter (IVW, FDR  = 0.044) was found to be linked to an increased risk of low back pain. Importantly, these associations remained significant even after applying the Benjamini-Hochberg correction test. Our analysis did not find any heterogeneity in the data ( > 0.05), as confirmed by the Cochrane's -test. Additionally, both the MR-Egger and MR-PRESSO tests indicated no significant evidence of horizontal pleiotropy ( > 0.05). Conclusion:Our MR analysis demonstrated a causal relationship between the gut microbiota and pain, highlighting its potential significance in advancing our understanding of the underlying mechanisms and clinical implications of microbiota-mediated pain. 10.3389/fnins.2024.1369996
Exploring causality in the association between gut microbiota and irritable bowel syndrome risk: a large Mendelian randomization study. Aging BACKGROUND:In the past, some observational studies have highlighted the correlation between gut microbiota and irritable bowel syndrome (IBS). However, it is still unknown if the composition of gut microbiota shows a causal effect on the risk of IBS. AIM:To conduct Mendelian randomization (MR) analysis of the samples to study the probable causal relationship between the gut microbiota, their taxonomic groups, and the risk of IBS. MATERIALS AND METHODS:In this study, the summarized data regarding 211 gut microbiota and their IBS genome-wide association studies (GWAS) were collected from public databases. The causal estimates were determined using five MR techniques, where Inverse Variance Weighted (IVW) regression was employed as the major MR technique. Herein, MR-PRESSO and MR-Egger intercept tests were conducted to prevent horizontal pleiotropy. Cochran's test was used to evaluate heterogeneity using the IVW and MR-Egger techniques. RESULTS:IVW results showed that gut microbes, belonging to Class ( = 0.04; OR = 1.45), Family XIII ( = 0.03; OR = 1.34), Family ( = 0.003; OR =1.24), and UCG004 ( = 0.049; OR = 1.19) increased the risk of IBS, while ( = 0.03; OR = 0.83, 95% CI: 0.69-0.98) and ( = 0.02; OR = 0.86, 95% CI: 0.76-0.98) decreased the risk of IBS. CONCLUSIONS:This study presented novel insights that highlighted the causal relationship between gut microbiota and IBS, and offered new treatment strategies for preventing or treating IBS. 10.18632/aging.205771
Causal influence of gut microbiota on small cell lung cancer: a Mendelian randomization study. The clinical respiratory journal BACKGROUND:Previous studies have hinted at a significant link between lung cancer and the gut microbiome, yet their causal relationship remains to be elucidated. METHODS:GWAS data for small cell lung cancer (SCLC) was extracted from the FinnGen consortium, comprising 179 cases and 218 613 controls. Genetic variation data for 211 gut microbiota were obtained as instrumental variables from MiBioGen. Mendelian randomization (MR) was employed to determine the causal relationship between the two, with inverse variance weighting (IVW) being the primary method for causal analysis. The MR results were validated through several sensitivity analyses. RESULTS:The study identified a protective effect against SCLC for the genus Eubacterium ruminantium group (OR = 0.413, 95% CI: 0.223-0.767, p = 0.00513), genus Barnesiella (OR = 0.208, 95% CI: 0.0640-0.678, p = 0.00919), family Lachnospiraceae (OR = 0.319, 95% CI: 0.107-0.948, p = 0.03979), and genus Butyricimonas (OR = 0.376, 95% CI: 0.144-0.984, p = 0.04634). Conversely, genus Intestinibacter (OR = 3.214, 95% CI: 1.303-7.926, p = 0.01125), genus Eubacterium oxidoreducens group (OR = 3.391, 95% CI: 1.215-9.467, p = 0.01973), genus Bilophila (OR = 3.547, 95% CI: 1.106-11.371, p = 0.03315), and order Bacillales (OR = 1.860, 95% CI: 1.034-3.347, p = 0.03842) were found to potentially promote the onset of SCLC. CONCLUSION:We identified potential causal relationships between certain gut microbiota and SCLC, offering new insights into microbiome-mediated mechanisms of SCLC pathogenesis, resistance, mutations, and more. 10.1111/crj.13764
Unraveling the mystery: a Mendelian randomized exploration of gut microbiota and different types of obesity. Frontiers in cellular and infection microbiology Background:Numerous studies have demonstrated the influence of gut microbiota on the development of obesity. In this study, we utilized Mendelian randomization (MR) analysis to investigate the gut microbiota characteristics among different types of obese patients, aiming to elucidate the underlying mechanisms and provide novel insights for obesity treatment. Methods:Two-sample multivariable Mendelian randomization (MR) analysis was employed to assess causal relationships between gut microbiota and various obesity subtypes. Gut microbiota data were obtained from the international consortium MiBioGen, and data on obese individuals were sourced from the Finnish National Biobank FinnGen. Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables. Various analytical methods, including inverse variance weighted (IVW), MR-Egger regression, weighted median, MR-RAPS, and Lasso regression, were applied. Sensitivity analyses for quality control included MR-Egger intercept tests, Cochran's Q tests, and leave-one-out analyses and others. Results:Mendelian randomization studies revealed distinct gut microbiota profiles among European populations with different obesity subtypes. Following multivariable MR analysis, we found that [: 0.842, : 0.766-0.926, Adjusted value: 0.028] independently reduced the risk of obesity induced by excessive calorie intake, while [: 4.252, : 2.177-8.307, Adjusted value: 0.002] independently increased the risk of medication-induced obesity. For localized adiposity, [: 0.213, : 0.115-0.395, Adjusted value: <0.001] acted as a protective factor. In the case of extreme obesity with alveolar hypoventilation, [: 0.724, : 0.609-0.860, Adjusted value: 0.035] reduced the risk of its occurrence. Additionally, six gut microbiota may have potential roles in the onset of different types of obesity. Specifically, the torques group may increase the risk of its occurrence. and may serve as protective factors in the onset of Drug-induced obesity. , , and , on the other hand, could potentially increase the risk of Drug-induced obesity. No evidence of heterogeneity or horizontal pleiotropy among SNPs was found in the above studies (all values for Q test and MR-Egger intercept > 0.05). Conclusion:Gut microbiota abundance is causally related to obesity, with distinct gut microbiota profiles observed among different obesity subtypes. Four bacterial species, including , , and independently influence the development of various types of obesity. Probiotic and prebiotic supplementation may represent a novel approach in future obesity management. 10.3389/fcimb.2024.1352109
Genetic insights into gut microbiota and risk of prostatitis: a Mendelian randomization study. Frontiers in microbiology Background:The dysbiosis of gut microbiota (GM) is considered a contributing factor to prostatitis, yet the causality remains incompletely understood. Methods:The genome-wide association study (GWAS) data for GM and prostatitis were sourced from MiBioGen and FinnGen R10, respectively. In the two-sample Mendelian randomization (MR) analysis, inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, weighted mode, and maximum likelihood (ML) methods were utilized to investigate the causal relationship between GM and prostatitis. A series of sensitivity analysis were conducted to confirm the robustness of the main results obtained from the MR analysis. Results:According to the IVW results, genus (OR: 1.37, 95% CI: 1.09-1.71, = 0.006) and genus (OR: 1.21, 95% CI: 1.02-1.43, = 0.028) were associated with an increased risk of prostatitis. The phylum Verrucomicrobia (OR: 0.76, 95% CI: 0.58-0.98, = 0.033) and genus (OR: 0.84, 95% CI: 0.70-1.00, = 0.045) exhibited a negative association with prostatitis, indicating a potential protective effect. Sensitivity analysis showed that these results were not affected by heterogeneity and horizontal pleiotropy. Furthermore, the majority of statistical methods yielded results consistent with those of the IVW analysis. Conclusions:In this study, we identified two GM taxon that might be protective against prostatitis and two GM taxon that could increase the risk of developing prostatitis. These findings could potentially provide a valuable theoretical basis for the future development of preventive and therapeutic strategies for prostatitis. 10.3389/fmicb.2024.1389715
A commentary on 'causal effects of gut microbiota on renal tumor: a Mendelian randomization study' ( Int J Surg 2024 Jan 15; Online ahead of print.). International journal of surgery (London, England) 10.1097/JS9.0000000000001249
Causal Relationships Between Gut Microbiota, Inflammatory Cells/Proteins, and Subarachnoid Hemorrhage: A Multi-omics Bidirectional Mendelian Randomization Study and Meta-analysis. Molecular neurobiology Subarachnoid hemorrhage (SAH) is a neurological emergency that can lead to fatal outcomes. It occurs when bleeding happens in the subarachnoid space, a small gap between the arachnoid and pia mater. This condition results from the rupture of diseased or damaged blood vessels at the brain's base or surface. This study combined various omics approaches with Mendelian randomization analysis, including MR-IVW, MR Egger, MR weight median, and MR weight mode, to generate preliminary results. It also employed reverse Mendelian randomization, treating SAH as the exposure. Finally, a meta-analysis was conducted to summarize these findings. The study found positive correlations between SAH and both GBPA-Pyridoxal 5 phosphate biosynthesis I (OR=1.48, 95% CI, 1.04-2.12) and GBPA-glucose biosynthesis I (OR=0.68, 95% CI, 0.52-0.90). Increased levels of urokinase-type plasma activator were also associated with SAH (OR=1.17, 95% CI, 1.04-1.32). Associations were observed with SAH for CD80 on CD62L+ plasmacytoid dendritic cells, CD80 on plasmacytoid dendritic cells, CD123 on CD62L+ plasmacytoid dendritic cells, and SSC-A on plasmacytoid dendritic cells. This study, through Mendelian randomization and meta-analysis, established links between SAH and four inflammatory cells, one inflammatory protein, and two gut microbiota-related pathways. These findings suggest potential treatment targets for SAH, highlighting the importance of modulating gut microbiota and utilizing anti-inflammatory drugs in its management. 10.1007/s12035-024-04101-y
Association between gut microbiota and onset of type 2 diabetes mellitus: a two-sample Mendelian randomization study. Frontiers in cellular and infection microbiology Aim:Mendelian randomization (MR) analysis has been used in the exploration of the role of gut microbiota (GM) in type 2 diabetes mellitus (T2DM); however, it was limited to the genus level. This study herein aims to investigate the relationship of GM, especially at the species level, with T2DM in order to provide some evidence for further exploration of more specific GM taxa and pathway abundance in T2DM. Methods:This two-sample MR study was based on the summary statistics of GM from the available genome-wide association study (GWAS) meta-analysis conducted by the MiBioGen consortium as well as the Dutch Microbiome Project (DMP), whereas the summary statistics of T2DM were obtained from the FinnGen consortium released data. Inverse variance weighted (IVW), MR-Egger, strength test (), and weighted median methods were used to examine the causal association between GM and the onset of T2DM. Cochran's statistics was employed to quantify the heterogeneity of instrumental variables. Bonferroni's correction was conducted to correct the bias of multiple testing. We also performed reverse causality analysis. Results:The corrected IVW estimates suggested the increased relative abundance of family (OR = 1.0704) and genus (OR = 1.0874), respectively, were associated with higher odds of T2DM, while that of species (OR = 0.9460) had a negative relationship with T2DM. The relationships of class , family , species , and species with T2DM were also significant according to the IVW results (all < 0.05). Conclusions:GM had a potential causal association with T2DM, especially species , , and . Further studies are still needed to clarify certain results that are contradictory with previous findings. 10.3389/fcimb.2024.1327032
Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort. Metabolites The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, = 0.033), body mass index (BMI) (β = 0.025, = 1.3 × 10), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, = 5.8 × 10), triglyceride (0.087, = 1.3 × 10), systolic (β = 0.012, = 2.5 × 10) and diastolic blood pressure (β = 0.011, = 3.4 × 10). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, = 4.4 × 10), and BMI (β = 0.097, = 5.1 × 10). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, = 3.8 × 10) and triglycerides (β = -0.12, = 5.9 × 10). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors. 10.3390/metabo14030174
The cause and effect of gut microbiota in development of inflammatory disorders of the breast. European journal of medical research BACKGROUND:Inflammatory disorders of the breast (IDB) damages the interests of women and children and hinders the progress of global health seriously. Several studies had offered clues between gut microbiota (GM) and inflammatory disorders of the breast (IDB). The gut-mammary gland axis also implied a possible contribution of the GM to IDB. However, the causality between them is still elusive. METHODS:The data of two-sample Mendelian randomization (MR) study related to the composition of GM (n = 18,340) and IDB (n = 177,446) were accessed from openly available genome-wide association studies (GWAS) database. As the major analytical method, inverse variance weighted (IVW) was introduced and several sensitive analytical methods were conducted to verify results. RESULTS:Inverse variance weighted revealed Eubacterium rectale group (OR = 1.87, 95% CI: 1.02-3.43, p = 4.20E-02), Olsenella (OR = 1.29, 95% CI: 1.02-1.64, p = 3.30E-02), Ruminiclostridium-6 (OR = 1.53, 95% CI: 1.08-2.14, p = 1.60E-02) had an anti-protective effect on IDB. Peptococcus (OR = 0.75, 95% CI: 0.60-0.94, p = 1.30E-02) had a protective effect on IDB. The results were credible through a series of test. CONCLUSIONS:We revealed causality between IDB and GM taxa, exactly including Ruminiclostridium-6, Eubacterium rectale group, Olsenella and Peptococcus. These genera may become novel biomarkers and supply new viewpoint for probiotic treatment. However, these findings warrant further test owing to the insufficient evidences. 10.1186/s40001-023-01281-6
The Association between the Gut Microbiota and Erectile Dysfunction. The world journal of men's health PURPOSE:Explore the causal relationship between the gut microbiota and erectile dysfunction (ED) at phylum, class, order, family, and genus levels, and identify specific pathogenic bacteria that may be associated with the onset and progression of ED. MATERIALS AND METHODS:The genetic variation data of 196 human gut microbiota incorporated in our study came from the human gut microbiome Genome Wide Association Studies (GWAS) dataset released by the MiBioGen Consortium. The GWAS statistics for ED were extracted from one study by Bovijn et al., which included 223,805 participants of European ancestry, of whom 6,175 were diagnosed with ED. Subsequently, Mendelian randomization (MR) analysis was carried out to explore whether a causal relationship exists between the gut microbiota and ED. Additionally, bidirectional MR analysis was performed to examine the directionality of the causal relationship. RESULTS:Through MR analysis, we found that family Lachnospiraceae (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 1.05-1.52, p=0.01) and its subclass genus LachnospiraceaeNC2004 group (OR: 1.17, 95% CI: 1.01-1.37, p=0.04) are associated with a higher risk of ED. In addition, genus Oscillibacter (OR: 1.17, 95% CI: 1.02-1.35, p=0.03), genus Senegalimassilia (OR: 1.32, 95% CI: 1.06-1.64, p=0.01) and genus Tyzzerella3 (OR: 1.14, 95% CI: 1.02-1.27, p=0.02) also increase the risk of ED. In contrast, the inverse variance weighted estimate of genus RuminococcaceaeUCG013 (OR: 0.77, 95% CI: 0.61-0.96, p=0.02) suggests that it has a protective effect against the occurrence of ED. CONCLUSIONS:This study preliminarily identified 6 bacterial taxa that may have a causal relationship with ED, including family Lachnospiraceae, genus Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella 3 and Ruminococcaceae UCG013. These identified important bacterial taxa may serve as candidates for microbiome intervention in future ED clinical trials. 10.5534/wjmh.230181
Identifying and ranking causal microbial biomarkers for colorectal cancer at different cancer subsites and stages: a Mendelian randomization study. Frontiers in oncology Introduction:The gut microbiome is directly involved in colorectal carcinogenesis, but much of the epidemiological evidence for the effect of the gut microbiome on colorectal cancer (CRC) risk comes from observational studies, and it is unclear whether identified microbial alterations are the cause or consequence of CRC development. Methods:Univariate Mendelian randomization (MR) analysis and multivariate MR analysis based on Bayesian model averaging were performed to comprehensively explore the microbial risk factors associated with CRC. The Network Module Structure Shift method was used to identify microbial biomarkers associated with CRC. Mediation analysis was used to explore the dietary habits-microbiota-CRC pathway. Results:The results of the four methods showed that 9 bacteria had a robust causal relationship with the development of CRC. Among them, reduced the risk of CRC; and were beneficial bacteria of malignant tumors of colon (CC); Erysipelotrichaceae was a protective factor for malignant tumors of rectal (CR); was a risk factor for benign tumors. Finally, the mediation analysis revealed 10 pathways by which dietary regulation bacteria affected the risk of CRC, including alcohol consumption increased the risk of CC by reducing the abundance of (mediated proportion: 43.044%), and the mediated proportion of other pathways was 7.026%-34.22%. Discussion:These findings will contribute to the understanding of the different carcinogenic mechanisms of intestinal flora in the colon and rectum and the risk of tumor transformation, thereby aiding CRC prevention, early screening, and the development of future strategies to reduce CRC risk. 10.3389/fonc.2023.1224705
Genetic predisposition of the gastrointestinal microbiome and primary biliary cholangitis: a bi-directional, two-sample Mendelian randomization analysis. Frontiers in endocrinology Background:The gut-liver axis indicates a close relationship between the gastrointestinal microbiome (GM) and primary biliary cholangitis (PBC). However, the causality of this relationship remains unknown. This study investigates the causal relationship between the GM and PBC using a bidirectional, two-sample Mendelian randomization (MR) analysis. Methods:Genome-wide association data for GM and PBC were obtained from public databases. The inverse-variance weighted method was the primary method used for MR analysis. Sensitivity analyses were conducted to assess the stability of the MR results. A reverse MR analysis was performed to investigate the possibility of reverse causality. Results:Three bacterial taxa were found to be causally related to PBC. Class Coriobacteriia (odds ratio (OR) = 2.18, 95% confidence interval (CI): 1.295-3.661, P< 0.05) and order Coriobacteriales (OR = 2.18, 95% CI: 1.295-3.661, P<0.05) were associated with a higher risk of PBC. Class Deltaproteobacteria (OR = 0.52, 95% CI: 0.362-0.742, P< 0.05) had a protective effect on PBC. There was no evidence of reverse causality between PBC and the identified bacterial taxa. Conclusion:Previously unrecognized taxa that may be involved in the pathogenesis of PBC were identified in this study, confirming the causality between the GM and PBC. These results provide novel microbial targets for the prevention and treatment of PBC. 10.3389/fendo.2023.1225742
Exploring the Causal Effects of Gut Microbiota on Diabetic Nephropathy: A Two-Sample Mendelian Randomization Study. Combinatorial chemistry & high throughput screening BACKGROUND:In recent years, an increasing number of studies have indicated a bidirectional relationship between gut microbiota and the kidneys (the gut-kidney axis). Currently, the potential causal relationship between gut microbiota and diabetic nephropathy remains unclear. This study explores the causal effects of gut microbiota on diabetic nephropathy through Mendelian randomization. METHODS:We carried out a comprehensive Mendelian Randomization (MR) analysis, drawing on the Genome-wide Association Study (GWAS) data for 196 varieties of gut microbiota and diabetic nephropathy. The primary analytical approach employed was the inverse-variance weighted, supplemented by the MR-Egger, weighted median, simple mode, and weighted mode. We rigorously assessed heterogeneity with Cochran's Q test and examined pleiotropy via MREgger intercept and MR-PRESSO tests. To ensure the reliability of our findings, we conducted funnel plots and leave-one-out analysis. RESULTS:Our study indicates a causal relationship between the increased risk of diabetic nephropathy and specific gut microbiota, including the Bacteroidia (P=0.01892; OR=1.593; 95%CI, 1.080-2.350), Bacteroidales (P=0.01892; OR=1.593; 95%CI, 1.080-2.350), and LachnospiraceaeUCG008 (P=0.01350; OR=1.452; 95%CI, 1.080-1.953). Conversely, potential protective factors include the Proteobacteria (P=0.00397; OR=0.528; 95%CI, 0.342-0.815), Gammaproteobacteria (P=0.00965; OR=0.474; 95%CI, 0.270-0.834), Lentisphaeria (P=0.04417; OR=0.756; 95%CI, 0.576-0.993), Victivallales (P=0.04417; OR=0.756; 95%CI, 0.576-0.993), and Dialister (P=0.00118; OR=0.513; 95%CI, 0.343-0.768). CONCLUSION:This study confirms the causal effects of gut microbiota on diabetic nephropathy. Identifying the risk and protective factors within the gut microbiota for diabetic nephropathy offers fresh insights and novel approaches for preventing and treating this condition. 10.2174/0113862073311197240425073859
Causal Associations Between Gut Microbiota and Cerebrovascular Diseases. World neurosurgery BACKGROUND:Numerous studies suggest that the gut microbiota closely linked to cerebrovascular diseases, such as Intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (aSAH). Nevertheless, the confirmation of a definitive causal connection between gut microbiota, IA, and aSAH is still pending. The aim of our research is to explore the potential bidirectional causality among them. METHODS:This bidirectional Mendelian Randomization (MR) study used single nucleotide polymorphisms linked to gut microbiota, IA, and aSAH from Genome-Wide Association Studies. The Inverse Variance Weighted (IVW) method was used to explore causality. To assess the robustness of the result, sensitivity analyses were further performed, including weighted-median method, MR-Egger regression, Maximum-likelihood method, MR pleiotropy residual sum and outlier test and leave-one-out analysis. RESULTS:In the IVW method, the family Porphyromonadaceae (odds ratio [OR] 0.63; 95% CI 0.47-0.85; P: 0.002) and genus Bilophila (OR 0.66; 95% CI 0.50-0.86; P: 0.002) showed a significant negative association with the risk of IA. Similarly, the genus Bilophila (OR: 0.68; 95% CI: 0.50-0.93; P: 0.017) and genus Ruminococcus1 (OR: 0.48; 95% CI: 0.30-0.78; P: 0.003) were linked to reduced risk of aSAH. The sensitivity analysis yielded similar outcomes in the IVW approach. Through the adoption of reverse MR analysis, a potential correlation between IA and decreased abundance of genus Ruminococcus1 was identified (OR 0.94; 95% CI 0.90-0.99; P 0.024). CONCLUSIONS:This MR analysis investigated the causal associations between gut microbiota, IA, and aSAH risks. The findings expanded current knowledge of the microbiota-gut-brain axis and offered novel perspectives on preventing and managing these conditions. 10.1016/j.wneu.2023.12.150
Diabetes and branched-chain amino acids: What is the link? Bloomgarden Zachary Journal of diabetes Branched-chain amino acids (BCAA) have increasingly been studied as playing a role in diabetes, with the PubMed search string "diabetes" AND "branched chain amino acids" showing particular growth in studies of the topic over the past decade (Fig. ). In the Young Finn's Study, BCAA and, to a lesser extent, the aromatic amino acids phenylalanine and tyrosine were associated with insulin resistance (IR) in men but not in women, whereas the gluconeogenic amino acids alanine, glutamine, or glycine, and several other amino acids (i.e. histidine, arginine, and tryptophan) did not show an association with IR. Obesity may track more strongly than metabolic syndrome and diabetes with elevated BCAA. In a study of 1302 people aged 40-79; higher levels of BCAA tracked with older age, male sex, and metabolic syndrome, as well as with obesity, cardiovascular risk, dyslipidemia, hypertension, and uric acid. Medium- and long-chain acylcarnitines, by-products of mitochondrial catabolism of BCAAs, as well as branched-chain keto acids and the BCAA themselves distinguished obese people having versus not having features of IR, and in a study of 898 patients with essential hypertension, the BCAA and tyrosine and phenylalanine were associated with metabolic syndrome and impaired fasting glucose. In a meta-analysis of three genome-wide association studies, elevations in BCAA and, to a lesser extent, in alanine tracked with IR, whereas higher levels of glutamine and glycine were associated with lesser likelihood of IR. Given these associations with IR, it is not surprising that a number of studies have shown higher BCAA levels in people with and prior to development of type 2 diabetes (T2D), although this has particularly been shown in Caucasian and Asian ethnic groups while not appearing to occur in African Americans. Similarly, higher BCAA levels track with cardiovascular disease. [Figure: see text] The metabolism of BCAA involves two processes: (i) a reversible process catalysed by a branched-chain aminotransferase (BCAT), either cytosolic or mitochondrial, requiring pyridoxal to function as an amino group carrier, by which the BCAA with 2-ketoglutarate produce a branched-chain keto acid plus glutamate; and (ii) the irreversible mitochondrial process catalysed by branched-chain keto acid dehydrogenase (BCKDH) leading to formation of acetyl-coenzyme A (CoA), propionyl-CoA, and 2-methylbutyryl-CoA from leucine, valine, and isoleucine, respectively, which enter the tricarboxylic acid (Krebs) cycle as acetyl-CoA, propionyl-CoA, and 2-methylbutyryl-CoA, respectively, leading to ATP formation. The BCAA stimulate secretion of both insulin and glucagon and, when given orally, of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), with oral administration leading to greater and more prolonged insulin and glucagon secretion. Insulin may particularly reduce BCAA turnover to a greater extent than that of other amino acids, and decreases the appearance and increases the uptake of amino acids. However, older studies of the effect of glucose or insulin on BCAA concentrations and rates of leucine appearance and oxidation showed no reduction in T2D, although the higher baseline levels of BCAA in obesity have long been recognized. Impaired function of BCAT and BCKDH has been posited, either as a primary genetic abnormality or due to effects of elevated fatty acids, proinflammatory cytokines, or insulin levels with consequent accumulation of branched-chain keto acids and metabolites such as diacylglycerol and ceramide, potentially contributing to the development of further insulin resistance, and decreased skeletal muscle BCAT and BCKDH expression has been shown in people with diabetes, supporting this concept. A Mendelian randomization study used measured variation in genes involved in BCAA metabolism to test the hypothesis of a causal effect of modifiable exposure on IR, showing that variants in protein phosphatase, Mg /Mn dependent 1K (PPM1K), a gene encoding the mitochondrial phosphatase activating the BCKDH complex, are associated with T2D, but another such study suggested that genetic variations associated with IR are causally related to higher BCAA levels. Another hypothesis involves the mammalian target of rapamycin complex 1 (mTORC1), which is activated by BCAA, as well as by insulin and glucose via cellular ATP availability. If this is the relevant pathway, BCAA overload may cause insulin resistance by activation of mammalian target of rapamycin (mTOR), as well as by leading to increases in acylcarnitines, with mTOR seen in this scenario as a central signal of cross-talk between the BCAA and insulin. At this point, whether whole-body or tissue-specific BCAA metabolism is increased or decreased in states of insulin-resistant obesity and T2D is uncertain. Insulin action in the hypothalamus induces but overfeeding decreases hepatic BCKDH, leading to the concept that hypothalamic insulin resistance impairs BCAA metabolism in obesity and diabetes, so that plasma BCAAs may be markers of hypothalamic insulin action rather than direct mediators of changes in IR. A way to address this may be to understand the effects of changes in diet and other interventions on BCAA, as well as on IR and T2D. In an animal model, lowering dietary BCAA increased energy expenditure and improved insulin sensitivity. Two large human population studies showed an association of estimated dietary BCAA intake with T2D risk, although another population study showed higher dietary BCAA to be associated with lower T2D risk. Ethnic differences, reflecting underlying differences in genetic variants, may be responsible for such differences. In the study of Asghari et al. in the current issue of the Journal of Diabetes, BCAA intake was associated with the development of subsequent IR. Studies of bariatric surgery suggest lower basal and post-insulin infusion BCAA levels are associated with greater insulin sensitivity, with reductions in BCAA not seen with weight loss per se with gastric band procedures, but occurring after Roux-en-Y gastric bypass, an intervention that may have metabolic benefits over and above those from reduction in body weight. The gut microbiota may be important for the supply of the BCAA to mammalian hosts, either by de novo biosynthesis or by modifying nutrient absorption. A final fascinating preliminary set of observations is that of the effects of empagliflozin on metabolomics; evidence of increased Krebs cycle activation and of higher levels of BCAA metabolites, such as acylcarnitines, suggests that sodium-glucose cotransporter 2 (SGLT2) inhibition may, to some extent, involve BCAA metabolism. Certainly, we do not yet have a full understanding of these complex associations. However, the suggestion of multiple roles of BCAA in the development of IR promises to be important and to lead to the development of novel effective T2D therapies. 10.1111/1753-0407.12645
Causal associations between gut microbiota with intervertebral disk degeneration, low back pain, and sciatica: a Mendelian randomization study. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society PURPOSE:Although studies have suggested that gut microbiota may be associated with intervertebral disk disease, their causal relationship is unclear. This study aimed to investigate the causal relationship between the gut microbiota and its metabolic pathways with the risk of intervertebral disk degeneration (IVDD), low back pain (LBP), and sciatica. METHODS:Genetic variation data for 211 gut microbiota taxa at the phylum to genus level were obtained from the MiBioGen consortium. Genetic variation data for 105 taxa at the species level and 205 metabolic pathways were obtained from the Dutch Microbiome Project. Genetic variation data for disease outcomes were obtained from the FinnGen consortium. The causal relationships between the gut microbiota and its metabolic pathways and the risk of IVDD, LBP, and sciatica were evaluated via Mendelian randomization (MR). The robustness of the results was assessed through sensitivity analysis. RESULTS:Inverse variance weighting identified 46 taxa and 33 metabolic pathways that were causally related to IVDD, LBP, and sciatica. After correction by weighted median and MR-PRESSO, 15 taxa and nine pathways remained stable. After FDR correction, only the effect of the genus_Eubacterium coprostanoligenes group on IVDD remained stable. Sensitivity analyses showed no evidence of horizontal pleiotropy, heterogeneity, or reverse causation. CONCLUSION:Some microbial taxa and their metabolic pathways are causally related to IVDD, LBP, and sciatica and may serve as potential intervention targets. This study provides new insights into the mechanisms of gut microbiota-mediated development of intervertebral disk disease. 10.1007/s00586-024-08131-x
Causal relationship between gut microbiota and diabetic nephropathy: A bidirectional mendelian randomization study. Cellular and molecular biology (Noisy-le-Grand, France) In this study, we summarized the key findings and potential implications of association studies investigating the relationship between gut microbiota composition and risks for Diabetic nephropathy (DN). We used Mendelian randomization (MR) analysis to explore the relationship between gut microbiota and DN using two different publicly available DN databases. The results were also summarized using five mainstream MR analysis methods. We controlled for various possible biases in the results. The results showed that specific bacterial genera were associated with increased or decreased risk of DN. These associations can be attributed to a variety of factors, including metabolites produced by certain bacteria. Most of our findings are consistent with the existing research findings, but there are still some differences with the existing results. In addition, we also pointed out that some microbiota that may be associated with DN but remain unnoticed can bring new research directions. Our work made use of MR, a reliable technique for examining causal correlations using genetic data investigating potential processes, carrying out longitudinal studies, looking into intervention options, and using a multi-omics approach may be future research avenues. Further, our findings also point to a few unexplored possible study paths for DN in the future. These initiatives may improve our reconciliation of the internal relationships between the gut microbiota and DN and pave the way for more precise prevention and treatment methods. However, it is also critical to recognize any potential restrictions, such as those caused by sample size, population variety, and analytical techniques. 10.14715/cmb/2024.70.4.20
Associations between gut microbiota and adverse neurodevelopmental outcomes in preterm infants: a two-sample Mendelian randomization study. Frontiers in neuroscience Gut microbiota are associated with adverse neurodevelopmental outcomes in preterm infants; however, the precise causal relationship remains unclear. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to comprehensively study the relationship between gut microbiota and adverse neurodevelopmental outcomes in preterm infants and identify specific causal bacteria that may be associated with the occurrence and development of adverse neurodevelopmental outcomes in preterm infants. The genome-wide association analysis (GWAS) of the MiBioGen biogroup was used as the exposure data. The GWAS of six common adverse neurodevelopmental outcomes in premature infants from the FinnGen consortium R9 was used as the outcome data. Genetic variations, namely, single nucleotide polymorphisms (SNPs) below the locus-wide significance level (1 × 10) and genome-wide statistical significance threshold (5 × 10) were selected as instrumental variables (IVs). MR studies use inverse variance weighting (IVW) as the main method. To supplement this, we also applied three additional MR methods: MR-Egger, weighted median, and weighted mode. In addition, the Cochrane's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out methods were used for sensitivity analysis. Our study shows a causal relationship between specific gut microbiota and neurodevelopmental outcomes in preterm infants. These findings provide new insights into the mechanism by which gut microbiota may mediate adverse neurodevelopmental outcomes in preterm infants. 10.3389/fnins.2024.1344125
The causality of gut microbiota on onset and progression of sepsis: a bi-directional Mendelian randomization analysis. Frontiers in immunology Background:Several observational studies have proposed a potential link between gut microbiota and the onset and progression of sepsis. Nevertheless, the causality of gut microbiota and sepsis remains debatable and warrants more comprehensive exploration. Methods:We conducted a two-sample Mendelian randomization (MR) analysis to test the causality between gut microbiota and the onset and progression of sepsis. The genome-wide association study (GWAS) summary statistics for 196 bacterial traits were extracted from the MiBioGen consortium, whereas the GWAS summary statistics for sepsis and sepsis-related outcomes came from the UK Biobank. The inverse-variance weighted (IVW) approach was the primary method used to examine the causal association. To complement the IVW method, we utilized four additional MR methods. We performed a series of sensitivity analyses to examine the robustness of the causal estimates. Results:We assessed the causality of 196 bacterial traits on sepsis and sepsis-related outcomes. Genus [odds ratio (OR) 0.81, 95% confidence interval (CI) (0.69-0.94), = 0.007] and genus (OR 0.85, 95% CI 0.74-0.97, = 0.016) had a protective effect on sepsis, whereas genus (OR 1.10, 95% CI 1.01-1.20, = 0.024) increased the risk of sepsis. When it came to sepsis requiring critical care, genus (OR 0.49, 95% CI 0.31-0.76, = 0.002), genus (OR 0.65, 95% CI 0.43-1.00, = 0.049), and genus (OR 0.51, 95% CI 0.34-0.77, = 0.001) emerged as protective factors. Concerning 28-day mortality of sepsis, genus (OR 0.67, 95% CI 0.48-0.94, = 0.020), genus (OR 0.48, 95% CI 0.27-0.86, = 0.013), genus (OR 0.70, 95% CI 0.52-0.95, = 0.023), and genus (OR 0.82, 95% CI 0.68-0.99, = 0.042) presented a protective effect, whereas genus (OR 1.53, 95% CI 1.00-2.35, = 0.049), genus (OR 1.25, 95% CI 1.04-1.50, = 0.019), and genus (OR 1.43, 95% CI 1.02-2.02, = 0.040) presented a harmful effect. Furthermore, genus (OR 0.42, 95% CI 0.19-0.92, = 0.031), genus (OR 0.34, 95% CI 0.14-0.83, = 0.018), and genus (OR 0.43, 95% CI 0.22-0.83, = 0.012) were associated with a lower 28-day mortality of sepsis requiring critical care. Conclusion:This MR analysis unveiled a causality between the 21 bacterial traits and sepsis and sepsis-related outcomes. Our findings may help the development of novel microbiota-based therapeutics to decrease the morbidity and mortality of sepsis. 10.3389/fimmu.2024.1266579
The Roles of 27 Genera of Human Gut Microbiota in Ischemic Heart Disease, Type 2 Diabetes Mellitus, and Their Risk Factors: A Mendelian Randomization Study. Yang Qian,Lin Shi Lin,Kwok Man Ki,Leung Gabriel M,Schooling C Mary American journal of epidemiology Manipulation of the gut microbiota presents a new opportunity to combat chronic diseases. Randomized controlled trials of probiotics suggest some associations with adiposity, lipids, and insulin resistance, but to our knowledge no trials with "hard" outcomes have been conducted. We used separate-sample Mendelian randomization to obtain estimates of the associations of 27 genera of gut microbiota with ischemic heart disease, type 2 diabetes mellitus, adiposity, lipid levels, and insulin resistance, based on summary data from CARDIoGRAAMplusC4D and other consortia. Among the 27 genera, a 1-allele increase in single nucleotide polymorphisms related to greater abundance of Bifidobacterium was associated with lower risk of ischemic heart disease (odds ratio = 0.985, 95% confidence interval (CI): 0.971, 1.000; P = 0.04), a 0.011-standard-deviation lower body mass index (95% CI: -0.017, -0.005), and a 0.026-standard-deviation higher low-density lipoprotein cholesterol level (95% CI: 0.019, 0.033), but the findings were not robust to exclusion of potential pleiotropy. We also identified Acidaminococcus, Aggregatibacter, Anaerostipes, Blautia, Desulfovibrio, Dorea, and Faecalibacterium as being nominally associated with type 2 diabetes mellitus or other risk factors. Results from our study indicate that these 8 genera of gut microbiota should be given priority in future research relating the gut microbiome to ischemic heart disease and its risk factors. 10.1093/aje/kwy096
Causal effect of gut microbiota on the risk of prostatitis: a two-sample Mendelian randomization study. International urology and nephrology BACKGROUND:Recent studies demonstrated that chronic prostatitis (CP) is closely related to the gut microbiota (GM). Nevertheless, the causal relationship between GM and CP has not been fully elucidated. Therefore, the two-sample Mendelian randomization (MR) analysis was employed to investigate this association. METHODS:The summary data of gut microbiota derived from a genome-wide association study (GWAS) involving 18,340 individuals in the MiBioGen study served as the exposure, and the corresponding summary statistics for CP risk, representing the outcome, were obtained from the FinnGen databases (R9). The causal effects between GM and CP were estimated using the inverse-variance weighted (IVW) method supplemented with MR-Egger, weighted median, weighted mode, and simple mode methods. Additionally, the false discovery rate (FDR) correction was performed to adjust results. The detection and quantification of heterogeneity and pleiotropy were accomplished through the MR pleiotropy residual sum and outlier method, Cochran's Q statistics, and MR-Egger regression. RESULTS:The IVW estimates indicated that a total of 11 GM taxa were related to the risk of CP. Seven of them was correlated with an increased risk of CP, while the remained linked with a decreased risk of CP. However, only Methanobacteria (OR 0.86; 95% CI 0.74-0.99), Methanobacteriales (OR 0.86; 95% CI 0.74-0.99), NB1n (OR 1.16; 95% CI 1.16-1.34), Methanobacteriaceae (OR 0.86; 95% CI 0.74-0.99), Odoribactergenus Odoribacter (OR 1.43; 95% CI 1.05-1.94), and Sutterellagenus Sutterella (OR 1.33; 95% CI 1.01-1.76) still maintain significant association with CP after FDR correction. Consistent directional effects for all analyses were observed in the supplementary methods. Subsequently, sensitivity analyses indicated the absence of heterogeneity, directional pleiotropy, or outliers concerning the causal effect of specific gut microbiota on CP (p > 0.05). CONCLUSION:Our study demonstrated a gut microbiota-prostate axis, offering crucial data supporting the promising use of the GM as a candidate target for CP prevention, diagnosis, and treatment. There is a necessity for randomized controlled trials to validate the protective effect of the linked GM against the risk of CP, and to further investigate the underlying mechanisms involved. 10.1007/s11255-024-04020-w
The Gut Microbiome and Osteoarthritis: A Two-Sample Mendelian Randomization Study. Journal of rheumatic diseases Objective:The aim of this study was to examine if the intestinal microbiome is causally correlated with osteoarthritis (OA) incidence. Methods:A two-sample Mendelian randomization (MR) study was conducted using inverse variance weighting (IVW), weighted median, and MR-Egger regression techniques Publicly accessible summary statistics dataset of intestinal microbiomes of European descent from genome-wide association studies (GWASs) (a total with 3,326 individuals) was used as an exposure As an outcome, summary data from the GWAS include 3,498 patients with OA of the knee and hip from the arcOGEN sample and 11,009 controls of European descent. Results:We identified 29 single-nucleotide polymorphisms from GWAS of intestinal microbiomes as instrumental variables The IVW approach found no evidence to suggest a causal relationship between the intestinal microbiota and OA (beta=-0001, standard error [SE]=0004, p=0748) The regression test of MR-Egger showed that the directional pleiotropy was unlikely to be a bias (intercept=0002, SE=0007, p=0697) and the MR-Egger study showed no causal relation between the intestinal microbiota and the OA (beta=-0002, SE=0005, p=0630) The weighted median analysis also did not have indications of a causal relationship between the intestinal microbiota and OA (beta=-0002, SE=0005, p=0630) The MR results calculated using IVW, the median weighted and the MR-Egger regression approaches were consistent. Conclusion:The findings of the MR analysis did not support a causal relationship between intestinal microbiome and OA risk. 10.4078/jrd.2021.28.2.94
Investigating causal relationships between the gut microbiota and inflammatory skin diseases: A Mendelian randomization study. The Australasian journal of dermatology BACKGROUND:Numerous inflammatory skin diseases are associated with the gut microbiota. Studies of the association between gut microbiota and inflammatory skin diseases have yielded conflicting results owing to confounding factors, and the causal relationship between them remains undetermined. METHODS:Two-sample Mendelian randomization (MR) was used to examine the association between gut microbiota and four common inflammatory skin diseases: acne, psoriasis, urticaria and atopic dermatitis. The summary statistics of the gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium along with the summary statistics of the four diseases were obtained from the FinnGen consortium. Causal relationships were assessed using the inverse variance weighted (IVW), weighted median, MR-Egger and maximum likelihood methods, and several sensitivity analyses were performed to ensure the accuracy of the results. Finally, reverse and multivariable MR analyses were performed to verify the robustness of the results. RESULTS:We found causal associations of Bacteroidaceae [odds ratio (OR), 2.25; 95% confidence interval (CI), 1.48-3.42; p = 0.0001], Allisonella (OR, 1.42; 95% CI, 1.18-1.70; p = 0.0002) and Bacteroides (OR, 2.25; 95% CI, 1.48-3.42; p = 0.0001) with acne, the Eubacterium fissicatena group with psoriasis (OR, 1.22; 95% CI, 1.10-1.35; p = 0.0002) and Intestinibacter with urticaria (OR, 1.28; 95% CI, 1.13-1.45; p = 0.0001). These results were corrected for a false discovery rate. Sensitivity analyses were performed to validate the robustness of the associations and reverse MR confirmed that the results were not influenced by the reverse effect. CONCLUSION:Our study revealed that some gut microbiota are risk factors for inflammatory skin diseases, providing new information on potential therapeutic targets. Additionally, a possible association with the gut-skin axis was confirmed. Further research is required to elucidate the mechanisms underlying these relationships. 10.1111/ajd.14231
Causal Relationship between Gut Microbiota and Aneurysm: A Mendelian Randomization Study. Cerebrovascular diseases (Basel, Switzerland) INTRODUCTION:Observational studies have suggested a possible relationship between gut microbiota (GM) and aneurysm development. However, the nature of this association remains unclear due to the inherent limitations of observational research, such as reverse causation and confounding factors. To address this knowledge deficit, this study aimed to investigate and establish a causal link between GM and aneurysm development. METHODS:Summary statistics regarding GM and aneurysms were collected from relevant genome-wide association studies. Two samples were used in mendelian randomization (MR). The principal MR technique utilized was inverse-variance weighting, a technique renowned for producing reliable causal effect estimations. Additional MR methods, including weighted median (WM), MR-Egger, MR-PRESSO, and simple mode methods, were employed to ensure the robustness of the aforementioned association and investigate potential biases. Sensitivity analyses were performed to determine the consistency of the MR findings. RESULTS:Varying associations were observed between specific microbial taxa and the different aneurysms analyzed. A negative correlation was observed between aortic aneurysm (AA) and Lentisphaerae, Lentisphaeria, and Victivallales. Conversely, the genus FamilyXIIIUCG001 exhibited an increased risk association. Regarding abdominal AA, Victivallaceae showed a reduced risk, and Bilophila and Catenibacterium were associated with an increased risk. For thoracic AA, negative and positive correlations were observed with Lentisphaerae and Turicibacter, respectively. Lastly, in the case of cerebral aneurysm (CA), Firmicutes and Haemophilus were associated with a decreased risk, and Lachnoclostridium demonstrated an increased risk of association. CONCLUSION:Our research has established causal relationships between specific GM components and various aneurysms. The obtained knowledge may aid in the development of microbiome-based interventions and the identification of novel biomarkers for targeted prevention strategies. 10.1159/000536177
Causal effect between gut microbiota and gastroesophageal reflux disease: a bidirectional two-sample Mendelian randomization study. European journal of gastroenterology & hepatology Previous observational studies have found that the gut microbiota is closely related to the pathogenesis of gastroesophageal reflux disease (GERD), while their causal relationship is unclear. A two-sample multivariate Mendelian randomization analysis was implemented to estimate the causal effect of gut microbiota on GERD. The gut microbiota aggregated statistics were derived from a meta-analysis of the largest available genome-wide association studies (GWAS) conducted by the MiBioGen alliance ( n  = 13 266). GERD aggregated statistics were derived from published GWAS (129 080 cases and 473 524 controls). A bidirectional two-sample Mendelian randomization study was conducted to explore the causal relationship between gut microbiota and GERD using the inverse variance weighted (IVW), Mendelian randomization Egger, single model, weighted median, and weighted model. To verify the stability of the main results of Mendelian randomization analysis, we performed sensitivity analysis. Based on the results of IVW, we found that Anaerostipes was causally associated with an increased risk of GERD [odds ratio (OR): 1.09, P  = 0.018]. Eight gut microbiota taxa ( Actinobacteria, Bifidobacteriales, Bifidobacteriaceae, Clostridiales vadin BB60 group, Rikenellaceae, Lachnospiraceae UCG004, Methanobrevibacter , and unknown genus id.1000000073 ) are predicted to act causally in suppressing the risk of GERD ( P  < 0.05). In addition, reverse Mendelian randomization analyses revealed that the abundance of 15 gut microbiota taxon was found to be affected by GERD. No significant estimation of heterogeneity or pleiotropy is detected. Our study presents a complicated causal relationship between gut microbiota and GERD that offers guidance on the selection of appropriate probiotics as clinical interventions for GERD. 10.1097/MEG.0000000000002774
Investigating the causal role of the gut microbiota in esophageal cancer and its subtypes: a two-sample Mendelian randomization study. BMC cancer BACKGROUND:Through research on the gut microbiota (GM), increasing evidence has indicated that the GM is associated with esophageal cancer (ESCA). However, the specific cause-and-effect relationship remains unclear. In this study, Mendelian randomization (MR) analysis was applied to investigate the causal relationship between the GM and ESCA, including its subtypes. METHODS:We collected information on 211 GMs and acquired data on ESCA and its subtypes through genome-wide association studies (GWASs). The causal relationship was primarily assessed using the inverse variance weighted (IVW) method. Additionally, we applied the weighted median estimator (WME) method, MR-Egger method, weighted mode, and simple mode to provide further assistance. Subsequent to these analyses, sensitivity analysis was conducted using the MR-Egger intercept test, MR-PRESSO global test, and leave-one-out method. RESULT:Following our assessment using five methods and sensitivity analysis, we identified seven GMs with potential causal relationships with ESCA and its subtypes. At the genus level, Veillonella and Coprobacter were positively correlated with ESCA, whereas Prevotella9, Eubacterium oxidoreducens group, and Turicibacter were negatively correlated with ESCA. In the case of esophageal adenocarcinoma (EAC), Flavonifractor exhibited a positive correlation, while Actinomyces exhibited a negative correlation. CONCLUSION:Our study revealed the potential causal relationship between GM and ESCA and its subtypes, offering novel insights for the advancement of ESCA diagnosis and treatment. 10.1186/s12885-024-12205-w
Causal relationship between gut microflora and dementia: a Mendelian randomization study. Frontiers in microbiology Background:Numerous pertinent investigations have demonstrated a correlation between gut microflora (GM) and the occurrence of dementia. However, a causal connection between GM and dementia and its subtypes has not yet been clarified. Objective:To explore the causal association between GM and dementia, including its subtypes, a two-sample Mendelian randomization (TSMR) analysis was used. Methods:Our data comes from the Genome-Wide Association Study (GWAS). The principal approach employed for the Mendelian randomization study was the inverse-variance weighted method, supplemented by four methods: MR-Egger, weighted median, simple mode, and weighted mode. This was followed by Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out as sensitivity analysis validation. Results:Twenty-one GMs associated with any dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, Parkinson's disease, and dementia under other disease classifications were derived from the analysis, and 21 passed sensitivity tests. Conclusion:We confirmed the causal relationship between GM and dementia and its subtypes, derived specific flora associated with increased or decreased risk of dementia, and provided new ideas for preventive, diagnostic, and therapeutic interventions for dementia mediated by gut microbiota. 10.3389/fmicb.2023.1306048
Uncovering a causal connection between the genus in fecal microbiota and non-alcoholic fatty liver disease: a two-sample Mendelian randomization analysis. Frontiers in microbiology Background:Previous observational studies have indicated that an imbalance in gut microbiota may contribute to non-alcoholic fatty liver disease (NAFLD). However, given the inevitable bias and unmeasured confounders in observational studies, the causal relationship between gut microbiota and NAFLD cannot be deduced. Therefore, we employed a two-sample Mendelian randomization (TSMR) study to assess the causality between gut microbiota and NAFLD. Methods:The gut microbiota-related genome-wide association study (GWAS) data of 18,340 individuals were collected from the International MiBioGen consortium. The GWAS summary data for NAFLD from the Anstee cohort (1,483 cases and 17,781 controls) and the FinnGen consortium (894 cases and 217,898 controls) were utilized in the discovery and verification phases, respectively. The inverse variance weighted (IVW) method was used as the principal method in our Mendelian randomization (MR) study, with sensitivity analyses using the MR-Egger, weighted median, simple mode, and weighted mode methods. The MR-Egger intercept test, Cochran's test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy. Moreover, a fixed-effect meta-analysis was conducted to verify the robustness of the results. Results:The gene prediction results showed that at the genus level, four gut microbiota were causally associated with NAFLD in the GWAS conducted by Anstee et al. The relative abundance of (OR: 0.694, 95%CI: 0.533-0.903,  = 0.006, IVW), (OR: 0.420, 95%CI: 0.245-0.719,  = 0.002, IVW), and (OR: 0.596, 95%CI: 0.363-0.978,  = 0.041, IVW) was negatively associated with NAFLD. The relative abundance of (OR: 1.852, 95%CI: 1.179-2.908,  = 0.007, IVW) was positively correlated with NAFLD. Among them, the genus was validated in FinnGen GWAS (OR: 0.53, 95%CI: 0.304-0.928,  = 0.026, IVW). The genus was also significantly associated with NAFLD risk in the meta-analyses (OR: 0.470, 95%CI: 0.319-0.692,  = 0.0001, IVW). No heterogeneity or pleiotropy was observed. Conclusion:This study provided new evidence of the relationship between the genus and NAFLD, suggesting that augmentation of the relative abundance of the genus through the oral administration of probiotics or fecal microbiota transplantation could be an effective way to reduce the risk of NAFLD. 10.3389/fmicb.2023.1276790
The causal correlation between gut microbiota abundance and pathogenesis of cervical cancer: a bidirectional mendelian randomization study. Frontiers in microbiology Background:Observational studies and animal experiments suggested potential relevance between gut microbiota (GM) and cervical cancer (CC), but the relevance of this association remains to be clarified. Methods:We performed a two-sample bidirectional Mendelian randomization (MR) analysis to explore whether there was a causal correlation between GM and CC, and the direction of causality. Results:In primary outcomes, we found that a higher abundance of and predicted higher risk of CC, and a higher abundance of and predicted lower risk of CC. During verifiable outcomes, we found that a higher abundance of and predicted a higher risk of CC, and a higher abundance of and predicted a lower risk of CC, and vice versa. Conclusion:Our study implied a mutual causality between GM and CC, which provided a novel concept for the occurrence and development of CC, and might promote future functional or clinical analysis. 10.3389/fmicb.2024.1336101
Host genetic factors related to innate immunity, environmental sensing and cellular functions are associated with human skin microbiota. Nature communications Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10 for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing with Staphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction. 10.1038/s41467-022-33906-5
Association between gut microbiota and male infertility: a two-sample Mendelian randomization study. International microbiology : the official journal of the Spanish Society for Microbiology Previous research has confirmed the significant association between gut microbiota (GM) and male infertility (MI), but the causality between them remains unclear. This study aims to investigate the causal relationship between GM and MI using Mendelian randomization (MR) and provide supplementary information for the optimization of future randomized controlled trials (RCTs). Instrumental variables for 211 GM taxa were obtained from genome-wide association studies (GWAS), and inverse variance weighted (IVW) method was used as the main analysis method for two-sample MR analysis to assess the impact of GM on the risk of MI. Four methods were used to test for horizontal pleiotropy and heterogeneity of MR results to ensure the reliability of the MR findings. A total of 50 single-nucleotide polymorphisms (SNPs) closely related to GM were included, and ultimately identified 1 family and 4 general are causally associated with MI. Among them, Anaerotruncus (OR = 1.96, 95% CI 1.31-3.40, P = 0.016) is significantly associated with increased MI risk. Furthermore, we used four MR methods to evaluate the causality, and the results supported these findings. The leave-one-out analysis showed stable results with no instrumental variables exerting strong influence on the results. The causal direction indicated a positive effect, and the effects of heterogeneity and horizontal pleiotropy on the estimation of causal effect were minimized. We confirmed a causal relationship between GM taxa and MI, providing new insights into the mechanisms underlying GM-mediated MI. 10.1007/s10123-024-00512-y
Effect of the gut microbiome, plasma metabolome, peripheral cells, and inflammatory cytokines on obesity: a bidirectional two-sample Mendelian randomization study and mediation analysis. Frontiers in immunology Background:Obesity is a metabolic and chronic inflammatory disease involving genetic and environmental factors. This study aimed to investigate the causal relationship among gut microbiota abundance, plasma metabolomics, peripheral cell (blood and immune cell) counts, inflammatory cytokines, and obesity. Methods:Summary statistics of 191 gut microbiota traits (N = 18,340), 1,400 plasma metabolite traits (N = 8,299), 128 peripheral cell counts (blood cells, N = 408,112; immune cells, N = 3,757), 41 inflammatory cytokine traits (N = 8,293), and 6 obesity traits were obtained from publicly available genome-wide association studies. Two-sample Mendelian randomization (MR) analysis was applied to infer the causal links using inverse variance-weighted, maximum likelihood, MR-Egger, weighted median, weighted mode, and Wald ratio methods. Several sensitivity analyses were also utilized to ensure reliable MR results. Finally, we used mediation analysis to identify the pathway from gut microbiota to obesity mediated by plasma metabolites, peripheral cells, and inflammatory cytokines. Results:MR revealed a causal effect of 44 gut microbiota taxa, 281 plasma metabolites, 27 peripheral cells, and 8 inflammatory cytokines on obesity. Among them, five shared causal gut microbiota taxa belonged to the phylum , order , family , genus UCG008, and species group. Furthermore, we screened 42 shared causal metabolites, 7 shared causal peripheral cells, and 1 shared causal inflammatory cytokine. Based on known causal metabolites, we observed that the metabolic pathways of D-arginine, D-ornithine, linoleic acid, and glycerophospholipid metabolism were closely related to obesity. Finally, mediation analysis revealed 20 mediation relationships, including the causal pathway from gut microbiota to obesity, mediated by 17 metabolites, 2 peripheral cells, and 1 inflammatory cytokine. Sensitivity analysis represented no heterogeneity or pleiotropy in this study. Conclusion:Our findings support a causal relationship among gut microbiota, plasma metabolites, peripheral cells, inflammatory cytokines, and obesity. These biomarkers provide new insights into the mechanisms underlying obesity and contribute to its prevention, diagnosis, and treatment. 10.3389/fimmu.2024.1348347
To analyze the relationship between gut microbiota, metabolites and migraine: a two-sample Mendelian randomization study. Frontiers in microbiology Background:It has been suggested in several observational studies that migraines are associated with the gut microbiota. It remains unclear, however, how the gut microbiota and migraines are causally related. Methods:We performed a bidirectional two-sample mendelian randomization study. Genome-wide association study (GWAS) summary statistics for the gut microbiota were obtained from the MiBioGen consortium ( = 18,340) and the Dutch Microbiota Project ( = 7,738). Pooled GWAS data for plasma metabolites were obtained from four different human metabolomics studies. GWAS summary data for migraine (cases = 48,975; controls = 450,381) were sourced from the International Headache Genetics Consortium. We used inverse-variance weighting as the primary analysis. Multiple sensitivity analyses were performed to ensure the robustness of the estimated results. We also conducted reverse mendelian randomization when a causal relationship between exposure and migraine was found. Results: (OR = 1.12, 95% CI: 1.05-1.20) was a risk factor for migraine. (OR = 0.93, 95% CI: 0.88-0.99), ( group; OR = 0.94, 95% CI: 0.90-0.98), and (OR = 0.97, 95% CI: 0.94-1.00) may have a suggestive association with a lower migraine risk. Functional pathways of methionine synthesis (OR = 0.89, 95% CI: 0.83-0.95) associated with microbiota abundance and plasma hydrocinnamate (OR = 0.85, 95% CI: 0.73-1.00), which are downstream metabolites of and , respectively, may also be associated with lower migraine risk. No causal association between migraine and the gut microbiota or metabolites was found in reverse mendelian randomization analysis. Both significant horizontal pleiotropy and significant heterogeneity were not clearly identified. Conclusion:This Mendelian randomization analysis showed that was associated with an increased risk of migraine, while some bacteria in the gut microbiota may reduce migraine risk. These findings provide a reference for a deeper comprehension of the role of the gut-brain axis in migraine as well as possible targets for treatment interventions. 10.3389/fmicb.2024.1325047
Assessment of bidirectional relationships between 98 genera of the human gut microbiota and amyotrophic lateral sclerosis: a 2-sample Mendelian randomization study. BMC neurology BACKGROUND:Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. OBJECTIVES:To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. RESULTS:Using the inverse variance-weighted method, OTU10032 unclassified Enterobacteriaceae species-level OTU and unclassified Acidaminococcaceae were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01-1.07; P = 0.011 and OR, 1.02; 95% CI, 1.01-1.04; P = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50-2.55; P = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of OTU4607_Sutterella (per 1-unit higher log odds: β, 2.23; 95% CI, 1.27-3.18; P = 0.020) and Lactobacillales_ORDER (per 1-unit higher log odds: β, 0.51; 95% CI, 0.09-0.94; P = 0.019). CONCLUSIONS:Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials. 10.1186/s12883-021-02522-z
An association between chronic widespread pain and the gut microbiome. Rheumatology (Oxford, England) OBJECTIVES:Chronic widespread musculoskeletal pain (CWP) is a characteristic symptom of fibromyalgia, which has been shown to be associated with an altered gut microbiome. Microbiome studies to date have not examined the milder CWP phenotype specifically nor have they explored the role of raised BMI. The aim of this study was to investigate whether the microbiome is abnormal in CWP. METHODS:CWP was assessed using a standardized screening questionnaire in female volunteers from the TwinsUK cohort including 113 CWP cases and 1623 controls. The stool microbiome was characterized using 16S rRNA amplicon sequencing and amplicon sequence variants, and associations with CWP examined using linear mixed-effects models adjusting for BMI, age, diet, family relatedness and technical factors. RESULTS:Alpha diversity was significantly lower in CWP cases than controls (Mann-Whitney test, P-values 2.3e-04 and 1.2e-02, for Shannon and Simpson indices respectively). The species Coprococcus comes was significantly depleted in CWP cases (Padj = 3.04e-03). A genome-wide association study (GWAS) performed for C. comes in TwinsUK followed by meta-analysis with three Dutch cohorts (total n = 3521) resulted in nine suggestive regions, with the most convincing on chromosome 4 near the TRAM1L1 gene (rs76957229, P = 7.4e-8). A Mendelian randomization study based on the results of the GWAS did not support a causal role for C. comes on the development of CWP. CONCLUSIONS:We have demonstrated reduced diversity in the microbiome in CWP, indicating an involvement of the gut microbiota in CWP; prospectively the microbiome may offer therapeutic opportunities for this condition. 10.1093/rheumatology/keaa847
The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for complex human diseases. Microbiome BACKGROUND:Interest in the interplay between host genetics and the gut microbiome in complex human diseases is increasing, with prior evidence mainly being derived from animal models. In addition, the shared and distinct microbiome features among complex human diseases remain largely unclear. RESULTS:This analysis was based on a Chinese population with 1475 participants. We estimated the SNP-based heritability, which suggested that Desulfovibrionaceae and Odoribacter had significant heritability estimates (0.456 and 0.476, respectively). We performed a microbiome genome-wide association study to identify host genetic variants associated with the gut microbiome. We then conducted bidirectional Mendelian randomization analyses to examine the potential causal associations between the gut microbiome and complex human diseases. We found that Saccharibacteria could potentially decrease the concentration of serum creatinine and increase the estimated glomerular filtration rate. On the other hand, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by host genetics, had potential causal effects on the abundance of some specific gut microbiota. For example, atrial fibrillation increased the abundance of Burkholderiales and Alcaligenaceae and decreased the abundance of Lachnobacterium, Bacteroides coprophilus, Barnesiellaceae, an undefined genus in the family Veillonellaceae and Mitsuokella. Further disease-microbiome feature analysis suggested that systemic lupus erythematosus and chronic myeloid leukaemia shared common gut microbiome features. CONCLUSIONS:These results suggest that different complex human diseases share common and distinct gut microbiome features, which may help reshape our understanding of disease aetiology in humans. Video Abstract. 10.1186/s40168-020-00923-9
Causal effects of gut microbiota on the risk of erectile dysfunction: a Mendelian randomization study. International journal of impotence research Erectile dysfunction ranks among the prevalent sexual disorders in men. Several studies have indicated a potential link between gut microbiota and erectile dysfunction. To validate this potential association, we were to screen statistical data from genome-wide association studies of gut microbiota and erectile dysfunction. p values of less than 1 × 10 were set as the threshold for screening instrumental variables that were strongly associated with gut microbiota. At the same time, in order to obtain more convincing findings, we further excluded instrumental variables with possible chain imbalance, instrumental variables with the presence of palindromes, instrumental variables with F-statistics less than 10, and instrumental variables associated with risk factors for erectile dysfunction. Five methods including inverse-variance weighted method, weighted median method, weighted mode, Mendelian randomization egger method and Mendelian randomization pleiotropy residual sum and outlier test were then used to analyse the 2591 instrumental variables obtained from the screening. We identified correlations between six gut microbiota and the risk of erectile dysfunction. The genus Ruminococcaceae UCG-013 exhibited an inverse association with the risk of developing erectile dysfunction (0.79 (0.65-0.97), P = 0.0214). Conversely, the genus Tyzzerella3 (1.13 (1.02-1.26), P = 0.0225), genus Erysipelotrichaceae UCG-003 (1.18 (1.01-1.38), P = 0.0412), genus LachnospiraceaeNC2004group (1.19 (1.03-1.37), P = 0.0191), genus Oscillibacter (1.23 (1.08-1.41), P = 0.0022), and family Lachnospiraceae (1.26 (1.05-1.52), P = 0.0123) demonstrated positive associations with an increased risk of erectile dysfunction. These sensitivity analyses of the gut microbiota were consistent. This study demonstrated a possible causal relationship between gut microbiota and erectile dysfunction risk through Mendelian randomization analysis, providing new potential possibilities for the prevention and treatment of erectile dysfunction. 10.1038/s41443-024-00824-7
Causal relationship between gut microbiota and otitis media: a two-sample Mendelian randomized study. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 10.1007/s00405-023-08102-w
Large-scale causal analysis of gut microbiota and six common complications of diabetes: a mendelian randomization study. Diabetology & metabolic syndrome BACKGROUND:This study aimed to reveal the association between the gut microbiota (GM) and six diabetic complications: diabetic hypoglycemia; ketoacidosis; nephropathy; neuropathy; retinopathy; and Charcot's foot. METHODS:GM data were obtained from the MiBioGen consortium and Dutch Microbiome Project while data on the six diabetic complications were obtained from the FinnGen consortium. Two-sample Mendelian randomization (TSMR) was performed to explore the association between GM and the common diabetic complications. Inverse MR analysis was conducted to examine the effect of diabetic complications on the identified GM. Sensitivity tests were conducted to validate the stability of the results. Finally, multivariate MR (MVMR) was performed to determine whether GM had a direct influence on the diabetic complications. RESULTS:After multiple corrections, the inverse variance weighted (IVW) results predicted 61 suggestive markers between GM and six diabetic complications. In particular, the IVW results revealed that the Bacteroidia class and Bacteroidales order were positively associated with diabetic hypoglycemia while the Verrucomicrobiae class and Verrucomicrobiales order were positively associated with diabetic nephropathy. Based on the replication analysis, these results were identified to be stable. MVMR showed that the results remained stable after accounting for traditional risk factors. CONCLUSION:Extensive causal associations were found between GM and diabetic complications, which may provide new insights into the mechanisms of microbiome-mediated complications of diabetes. 10.1186/s13098-024-01298-9
Association between gut microbiota and spinal stenosis: a two-sample mendelian randomization study. Frontiers in immunology Introduction:Considerable evidence has unveiled a potential correlation between gut microbiota and spinal degenerative diseases. However, only limited studies have reported the direct association between gut microbiota and spinal stenosis. Hence, in this study, we aimed to clarify this relationship using a two-sample mendelian randomization (MR) approach. Materials and Methods:Data for two-sample MR studies was collected and summarized from genome-wide association studies (GWAS) of gut microbiota (MiBioGen, n = 13, 266) and spinal stenosis (FinnGen Biobank, 9, 169 cases and 164, 682 controls). The inverse variance-weighted meta-analysis (IVW), complemented with weighted median, MR-Egger, weighted mode, and simple mode, was used to elucidate the causality between gut microbiota and spinal stenosis. In addition, we employed mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the MR-Egger intercept test to assess horizontal multiplicity. Cochran's Q test to evaluate heterogeneity, and "leave-one-out" sensitivity analysis to determine the reliability of causality. Finally, an inverse MR analysis was performed to assess the reverse causality. Results:The IVW results indicated that two gut microbial taxa, the genus group and the genus , have a potential causal relationship with spinal stenosis. Moreover, eight potential associations between genetic liability of the gut microbiota and spinal stenosis were implied. No significant heterogeneity of instrumental variables or horizontal pleiotropy were detected. In addition, "leave-one-out" sensitivity analysis confirmed the reliability of causality. Finally, the reverse MR analysis revealed that no proof to substantiate the discernible causative relationship between spinal stenosis and gut microbiota. Conclusion:This analysis demonstrated a possible causal relationship between certain particular gut microbiota and the occurrence of spinal stenosis. Further studies focused on the mechanism of gut microbiota-mediated spinal stenosis can lay the groundwork for targeted prevention, monitoring, and treatment of spinal stenosis. 10.3389/fimmu.2024.1360132
Causal role of gut microbiota in intracranial aneurysm: evidence from a Mendelian randomization study. European review for medical and pharmacological sciences OBJECTIVE:An increasing number of studies suggest that the alteration of gut microbiota may affect the pathogenesis of intracranial aneurysm (IA). However, the exact causal relationship between gut microbiota and IA has not been confirmed. MATERIALS AND METHODS:The instrumental variables (IVs) for gut microbiota were obtained from a meta-analysis of a genome-wide association study (GWAS) conducted by the MiBioGen consortium (n = 13,266). The summary of GWAS data for IA was obtained from a large genome-wide meta-analysis involving 23 cohorts. Five Mendelian randomization (MR) methods were used to investigate the causal relationship between gut microbiota and IA (ruptured and unruptured), unruptured intracranial aneurysm only (uIA), and aneurysmal subarachnoid hemorrhage (aSAH) respectively, with inverse variance weighted (IVW) as the main MR method. All MR results were verified through sensitive analyses. RESULTS:Based on the results of the IVW analyses, it was found that five gut microbiota taxa were causally associated with IA (ruptured and unruptured), seven gut microbiota taxa were causally associated with uIA, and six gut microbiota taxa were causally associated with aSAH. Among these taxa, the genus Bilophila was the only one identified to have significant protective effects against IA (ruptured and unruptured), uIA, and aSAH. The sensitivity analysis did not reveal any significant heterogeneity or horizontal pleiotropy among the included IVs. CONCLUSIONS:MR analyses identified several gut microbiota taxa that have a causal relationship with IA. Future research should prioritize understanding the mechanisms underlying this causal relationship, as it is expected to contribute to the development of new methods for predicting and treating IA. 10.26355/eurrev_202403_35609
Genetic analysis of the causal relationship between gut microbiota and intervertebral disc degeneration: a two-sample Mendelian randomized study. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society PURPOSE:Several recent studies have reported a possible association between gut microbiota and intervertebral disc degeneration; however, no studies have shown a causal relationship between gut microbiota and disc degeneration. This study was dedicated to investigate the causal relationship between the gut microbiota and intervertebral disc degeneration and the presence of potentially bacterial traits using two-sample Mendelian randomization. METHODS:A two-sample Mendelian randomization study was performed using the summary statistics of the gut microbiota from the largest available genome-wide association study meta-analysis conducted by the MiBioGen consortium. Summary statistics of intervertebral disc degeneration were obtained from the FinnGen consortium R8 release data. Five basic methods and MR-PRESSO were used to examine causal associations. The results of the study were used to examine the causal association between gut microbiota and intervertebral disc degeneration. Cochran's Q statistics were used to quantify the heterogeneity of instrumental variables. RESULTS:By using Mendelian randomization analysis, 10 bacterial traits potentially associated with intervertebral disc degeneration were identified: genus Eubacterium coprostanoligenes group, genus Lachnoclostridium, unknown genus id.2755, genus Marvinbryantia, genus Ruminococcaceae UCG003, family Rhodospirillaceae, unknown genus id.959, order Rhodospirillales, genus Lachnospiraceae NK4A136 grou, genus Eubacterium brachy group. CONCLUSION:This Mendelian Randomization study found a causal effect between 10 gut microbiota and intervertebral disc degeneration, and we summarize the possible mechanisms of action in the context of existing studies. However, additional research is essential to fully understand the contribution of genetic factors to the dynamics of gut microbiota and its impact on disc degeneration. 10.1007/s00586-023-08059-8
Causal relationship between gut microbiota and prostate cancer contributes to the gut-prostate axis: insights from a Mendelian randomization study. Discover. Oncology BACKGROUND:Changes in gut microbiota abundance have been linked to prostate cancer development. However, the causality of the gut-prostate axis remains unclear. METHODS:The genome-wide association study (GWAS) data for gut microbiota sourced from MiBioGen (n = 14,306), alongside prostate cancer summary data from PRACTICAL (n = 140,254) and FinnGen Consortium (n = 133,164). Inverse-variance-weighted (IVW) was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl), after diligently scrutinizing potential sources of heterogeneity and horizontal pleiotropy via the rigorous utilization of Cochran's Q test, the MR-PRESSO method, and MR-Egger. We used meta-analysis methods in random effects to combine the Mendelian randomization (MR) estimates from the two sources. RESULTS:The pooled analyses of MR results show that genus Eubacterium fissicatena (OR = 1.07, 95% CI 1.01 to 1.13, P = 0.011) and genus Odoribacter (OR = 1.14, 95% CI 1.01 to 1.27, P = 0.025) were positively associated with prostate cancer. However, genus Adlercreutzia (OR = 0.89, 95% CI 0.83 to 0.96, P = 0.002), Roseburia (OR = 0.90, 95% CI 0.83 to 0.99, P = 0.03), Holdemania (OR = 0.92, 95% CI 0.86 to 0.97, P = 0.005), Flavonifractor (OR = 0.85, 95% CI 0.74 to 0.98, P = 0.024) and Allisonella (OR = 0.93, 95% CI 0.89 to 0.98, P = 0.011) seems to be a protective factor for prostate cancer. Sensitivity analysis found no significant heterogeneity, horizontal pleiotropy, or reverse causal links in all causal associations. CONCLUSION:This MR study lends support to a causal relationship between genetically predicted gut microbiota and prostate cancer. Research on the gut-prostate axis, along with further multi-omics analyses, holds significant implications for the prevention and treatment of prostate cancer. 10.1007/s12672-024-00925-1
Associations between Serum Mineral Nutrients, Gut Microbiota, and Risk of Neurological, Psychiatric, and Metabolic Diseases: A Comprehensive Mendelian Randomization Study. Nutrients Recent observational studies have reported associations between serum mineral nutrient levels, gut microbiota composition, and neurological, psychiatric, and metabolic diseases. However, the causal effects of mineral nutrients on gut microbiota and their causal associations with diseases remain unclear and require further investigation. This study aimed to identify the associations between serum mineral nutrients, gut microbiota, and risk of neurological, psychiatric, and metabolic diseases using Mendelian randomization (MR). We conducted an MR study using the large-scale genome-wide association study (GWAS) summary statistics of 5 serum mineral nutrients, 196 gut microbes at the phylum, order, family, and genus levels, and a variety of common neurological, psychiatric, and metabolic diseases. Initially, the independent causal associations of mineral nutrients and gut microbiota with diseases were examined by MR. Subsequently, the causal effect of mineral nutrients on gut microbiota was estimated to investigate whether specific gut microbes mediated the association between mineral nutrients and diseases. Finally, we performed sensitivity analyses to assess the robustness of the study results. After correcting for multiple testing, we identified a total of 33 causal relationships among mineral nutrients, gut microbiota, and diseases. Specifically, we found 4 causal relationships between 3 mineral nutrition traits and 3 disease traits, 15 causal associations between 14 gut microbiota traits and 6 disease traits, and 14 causal associations involving 4 mineral nutrition traits and 15 gut microbiota traits. Meanwhile, 118 suggestive associations were identified. The current study reveals multiple causal associations between serum mineral nutrients, gut microbiota, risk of neurological, psychiatric, and metabolic diseases, and potentially provides valuable insights for subsequent nutritional therapies. 10.3390/nu16020244
Assessing the causal relationship between gut microbiota and diabetic nephropathy: insights from two-sample Mendelian randomization. Frontiers in endocrinology Background:The causal association between gut microbiota (GM) and the development of diabetic nephropathy (DN) remains uncertain. We sought to explore this potential association using two-sample Mendelian randomization (MR) analysis. Methods:Genome-wide association study (GWAS) data for GM were obtained from the MiBioGen consortium. GWAS data for DN and related phenotypes were collected from the FinngenR9 and CKDGen databases. The inverse variance weighted (IVW) model was used as the primary analysis model, supplemented by various sensitivity analyses. Heterogeneity was assessed using Cochran's Q test, while horizontal pleiotropy was evaluated through MR-Egger regression and the MR-PRESSO global test. Reverse MR analysis was conducted to identify any reverse causal effects. Results:Our analysis identified twenty-five bacterial taxa that have a causal association with DN and its related phenotypes (p < 0.05). Among them, only the showed a significant causal association with type 1 DN (p < Bonferroni-adjusted p-value). Our findings remained consistent regardless of the analytical approach used, with all methods indicating the same direction of effect. No evidence of heterogeneity or horizontal pleiotropy was observed. Reverse MR analysis did not reveal any causal associations. Conclusions:This study established a causal association between specific GM and DN. Our findings contribute to current understanding of the role of GM in the development of DN, offering potential insights for the prevention and treatment strategies for this condition. 10.3389/fendo.2024.1329954
Assessing causal relationship from gut microbiota to heel bone mineral density. Ni Jing-Jing,Yang Xiao-Lin,Zhang Hong,Xu Qian,Wei Xin-Tong,Feng Gui-Juan,Zhao Min,Pei Yu-Fang,Zhang Lei Bone Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders + 9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales P = 3.32 × 10P = 7.29 × 10; Lachnospiraceae P = 0.03 P = 7.29 × 10). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism. 10.1016/j.bone.2020.115652
Mendelian randomization analysis reveals an independent causal relationship between four gut microbes and acne vulgaris. Frontiers in microbiology Background:Numerous studies have suggested a correlation between gut microbiota and acne vulgaris; however, no specific causal link has been explored. Materials and methods:To investigate the possible causal relationship between gut microbiota and acne vulgaris, this study employed a large-scale genome-wide association study (GWAS) summary statistic. Initially, a two-sample Mendelian randomization (MR) analysis was utilized to identify the specific gut microflora responsible for acne vulgaris. We used the Inverse Variance Weighted (IVW) method as the main MR analysis method. Additionally, we assessed heterogeneity and horizontal pleiotropy, while also examining the potential influence of individual single-nucleotide polymorphisms (SNPs) on the analysis results. In order to eliminate gut microbiota with reverse causal associations, we conducted reverse MR analysis. Multivariate Mendelian randomization analysis (MVMR) was then employed to verify the independence of the causal associations. Finally, we performed SNP annotation on the instrumental variables of independent gut microbiota and acne vulgaris to determine the genes where these genetic variations are located. We also explored the biological functions of these genes through enrichment analysis. Result:The IVW method of forward MR identified nine gut microbes with a causal relationship with acne vulgaris ( < 0.05). The findings from the sensitivity analysis demonstrate the absence of heterogeneity or horizontal pleiotropy, and leave-one-out analysis indicates that the results are not driven by a single SNP. Additionally, the Reverse MR analysis excluded two reverse-correlated pathogenic gut microbes. And then, MVMR was used to analyze seven gut microbes, and it was found that Cyanobacterium and Family XIII were risk factors for acne vulgaris, while Ruminococcus1 and Ruminiclostridium5 were protective factors for acne vulgaris. After conducting biological annotation, we identified six genes (PLA2G4A, FADS2, TIMP17, ADAMTS9, ZC3H3, and CPSF4L) that may be associated with the pathogenic gut microbiota of acne vulgaris patients. The enrichment analysis results indicate that PLA2G4A/FADS2 is associated with fatty acid metabolism pathways. Conclusion:Our study found independent causal relationships between four gut microbes and acne vulgaris, and revealed a genetic association between acne vulgaris patients and gut microbiota. Consider preventing and treating acne vulgaris by interfering with the relative content of these four gut microbes. 10.3389/fmicb.2024.1326339
Genetic insights into the gut microbiota and risk of facial skin aging: 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:A growing number of experimental studies have shown an association between the gut microbiota (GM) and facial skin aging. However, the causal relationship between GM and facial skin aging remains unclear to date. METHODS:We conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between GM and facial skin aging. MR analysis was mainly performed using the inverse-variance weighting (IVW) method, complemented by the weighted median (MW) method, MR-Egger regression, and weighted mode, and sensitivity analysis was used to test the reliability of MR analysis results. RESULTS:Eleven GM taxa associated with facial skin aging were identified by IVW method analysis, Family Victivallaceae (p = 0.010), Genus Eubacterium coprostanoligenes group (p = 0.038), and Genus Parasutterella (p = 0.011) were negatively associated with facial skin aging, while Phylum Verrucomicrobia (p = 0.034), Family Lactobacillaceae (p = 0.017) and its subgroups Genus Lactobacillus (p = 0.038), Genus Parabacteroides (p = 0.040), Genus Eggerthella (p = 0.049), Genus Family XIII UCG001 (p = 0.036), Genus Phascolarctobacterium (p = 0.027), and Genus Ruminococcaceae UCG005 (p = 0.012) were positively associated with facial skin aging. At Class and Order levels, we did not find a causal relationship between GM and facial skin aging. Results of sensitivity analyses did not show evidence of pleiotropy and heterogeneity. CONCLUSION:Our findings confirm the causal relationship between GM and facial skin aging, providing a new perspective on delaying facial aging. 10.1111/srt.13636
Causal effects of gut microbiota on the risk of urinary tract stones: A bidirectional two-sample mendelian randomization study. Heliyon Background:Recent studies increasingly suggest notable changes in both the quantity and types of gut microbiota among individuals suffering from urinary tract stones. However, the causal relationship between GMB and urinary tract stone formation remains elusive, which we aim to further investigate in this research through Mendelian Randomization (MR) analysis. Materials and methods:Single nucleotide polymorphisms (SNPs) associated with the human GMB were selected from MiBioGen International Consortium GWAS dataset. Data on urinary tract stone-related traits and associated SNPs were sourced from the IEU Open GWAS database. To investigate the causal relationships between gut microbiota and urinary tract stones, Mendelian Randomization (MR) was applied using genetic variants as instrumental variables, utilizing a bidirectional two-sample MR framework. This analysis incorporated various statistical techniques such as inverse variance weighting, weighted median analysis, MR-Egger, and the maximum likelihood method. To ensure the reliability of the findings, a range of sensitivity tests were conducted, including Cochran's Q test, the MR-Egger intercept, leave-one-out cross-validation, and examination of funnel plots. Results:The results revealed the causal relationship between the increase in the abundance of 10 microbial taxa, including Genus-Barnesiella (IVW OR = 0.73, 95%CI 0.73-0.89, P = 2.29 × 10-3) and Genus-Flavonifractor (IVW OR = 0.69, 95%CI 0.53-0.91, P = 8.57 × 10-3), and the decreased risk of urinary tract stone formation. Conversely, the development of urinary tract stones was observed to potentially instigate alterations in the abundance of 13 microbial taxa, among which Genus-Ruminococcus torques group was notably affected (IVW OR = 1.07, 95%CI 0.64-0.98, P = 1.86 × 10-3). In this context, Genus-Clostridium sensustricto1 exhibited a bidirectional causal relationship with urinary tract stones, while the remaining significant microbial taxa demonstrated unidirectional causal effects in the two-sample MR analysis. Sensitivity analyses did not identify significant estimates of heterogeneity or pleiotropy. Conclusion:To summarize, the results of this study suggest a likely causative link between gut microbiota and the incidence of urinary tract stones. This insight opens up potential pathways for discovering biomarkers and therapeutic targets in the management and prevention of urolithiasis. However, further in-depth research is warranted to investigate these associations. 10.1016/j.heliyon.2024.e25704
Cross-talk between the gut microbiota and hypothyroidism: a bidirectional two-sample Mendelian randomization study. Frontiers in nutrition Background:Multiple observational studies suggest a connection between the composition of the gut microbiota and hypothyroidism. However, it has yet to be determined whether the gut microbiota has a causal effect on hypothyroidism. Methods:To investigate the connection between the gut microbiota and hypothyroidism, two-sample Mendelian randomization was performed using data from a genome-wide association study meta-analysis ( = 18,430) conducted by the MiBioGen consortium. Summary statistics for hypothyroidism (26,342 cases and 59,827 controls) were obtained using the data from the FinnGen consortium R8 release data. To investigate the causal link between the gut microbiota and hypothyroidism, various methods, including MR-Egger, weighted median, weighted model, simple model, MR-PRESSO, and inverse variance weighted (IVW), were employed. The bacteria that were causally linked to hypothyroidism in forward Mendelian randomization analysis were subjected to reverse Mendelian randomization analysis. Cochran's statistics were utilized to gauge the heterogeneity of the instrumental variables. Results:The results indicated that Akkermansia had a positive impact on hypothyroidism, with an odds ratio of 0.84 (95% CI 0.74-0.95,  = 0.01) based on the inverse variance-weighted estimates. Additionally, Anaerostipes (OR = 1.17, 95% CI 1.01-1.36,  = 0.04), Butyrivibrio (OR = 0.93, 95% CI 0.88-0.99,  = 0.02), Holdemania (OR = 0.89, 95% CI 0.81-0.99,  = 0.03), Intestinimonas (OR = 1.13, 95% CI 1.02-1.26,  = 0.03), Ruminiclostridium5 (OR = 1.19, 95% CI 1.01-1.41,  = 0.04), and Ruminococcaceae UCG-011 (OR = 0.91, 95% CI 0.84-0.99,  = 0.03) were identified. The gut microbiota was not significantly affected by hypothyroidism, as indicated by the results of the reverse MR analysis. There was no significant variation in the instrumental variables or horizontal pleiotropy. Conclusion:The findings of this study using two-sample Mendelian randomization indicate a causal relationship between Akkermansia and hypothyroidism. Increased Akkermansia inhibits the onset and progression of hypothyroidism. Additional randomized controlled experiments are necessary to elucidate the beneficial impact of probiotics on hypothyroidism and their distinct protective mechanisms. 10.3389/fnut.2024.1286593
Causal effects of PM exposure on neuropsychiatric disorders and the mediation via gut microbiota: A Mendelian randomization study. Ecotoxicology and environmental safety BACKGROUND:Growing evidence has revealed the impacts of exposure to fine particulate matter (PM) and dysbiosis of gut microbiota on neuropsychiatric disorders, but the causal inference remains controversial due to residual confounders in observational studies. METHODS:This study aimed to examine the causal effects of exposure to PM on 4 major neuropsychiatric disorders (number of cases = 18,381 for autism spectrum disorder [ASD], 38,691 for attention deficit hyperactivity disorder [ADHD], 67,390 for schizophrenia, and 21,982 cases for Alzheimer's disease [AD]), and the mediation pathway through gut microbiota. Two-sample Mendelian randomization (MR) analyses were performed, in which genetic instruments were identified from genome-wide association studies (GWASs). The included GWASs were available from (1) MRC Integrative Epidemiology Unit (MRC-IEU) for PM, PM, PM, and NO; (2) the Psychiatric Genomics Consortium (PGC) for ASD, ADHD, and schizophrenia; (3) MRC-IEU for AD; and (4) MiBioGen for gut microbiota. Multivariable MR analyses were conducted to adjust for exposure to NO, PM, and PM. We also examined the mediation effects of gut microbiota in the associations between PM exposure levels and neuropsychiatric disorders, using two-step MR analyses. RESULTS:Each 1 standard deviation (1.06 ug/m) increment in PM concentrations was associated with elevated risk of ASD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.00-2.02), ADHD (1.51, 1.15-1.98), schizophrenia (1.47, 1.15-1.87), and AD (1.57, 1.16-2.12). For all the 4 neurodevelopmental disorders, the results were robust under various sensitivity analyses, while the MR-Egger method yielded non-significant outcomes. The associations remained significant for all the 4 neuropsychiatric disorders after adjusting for PM, while non-significant after adjusting for NO and PM. The effects of PM exposure on ADHD and schizophrenia were partially mediated by Lachnospiraceae and Barnesiella, with the proportions ranging from 8.31% to 15.77%. CONCLUSIONS:This study suggested that exposure to PM would increase the risk of neuropsychiatric disorders, partially by influencing the profile of gut microbiota. Comprehensive regulations on air pollutants are needed to help prevent neuropsychiatric disorders. 10.1016/j.ecoenv.2024.116257
Exploring the causal relationship between periodontitis and gut microbiome: Unveiling the oral-gut and gut-oral axes through bidirectional Mendelian randomization. Journal of clinical periodontology AIM:This Mendelian randomization (MR) study was performed to explore the potential bidirectional causal relationship between the gut microbiome (GM) and periodontitis. MATERIALS AND METHODS:We used genetic instruments from the genome-wide association study of European descent for periodontitis from the GeneLifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 cases and 28,210 controls) and the FinnGen consortium (4434 cases and 259,234 controls) to investigate the causal relationship with GM (the MiBioGen consortium, 18,340 samples), and vice versa. Several MR techniques, which include inverse variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode approaches, were employed to investigate the causal relationship between the exposures and the outcomes. Cochran's Q-test was performed to detect heterogeneity. The MR-Egger regression intercept and MR pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to test potential horizontal pleiotropy. Leave-one-out sensitivity analyses were used to assess the stabilities of single nucleotide polymorphisms (SNPs). Finally, the IVW results from the two databases were analysed using meta-analysis. RESULTS:We confirmed three potential causal relationships between GM taxa and periodontitis at the genus level. Among them, the genera Alistipes and Holdemanella were genetically associated with an increased risk of periodontitis. In reverse, periodontitis may lead to a decreased abundance of the genus Ruminococcaceae UCG014. CONCLUSIONS:The demonstration of a causal link between GM and periodontitis provides compelling evidence, highlighting the interconnectivity and interdependence of the gut-oral and oral-gut axes. 10.1111/jcpe.13906
A two-sample bidirectional Mendelian randomization analysis investigates associations between gut microbiota and type 2 diabetes mellitus. Frontiers in endocrinology Objective:This study sought to elucidate the causal association between gut microbiota (GM) composition and type 2 diabetes mellitus (T2DM) through a comprehensive two-sample bidirectional Mendelian randomization analysis. Method:T2DM data were sourced from the IEU OpenGWAS Project database, complemented by 211 gut microbiota (GM) datasets from the MiBioGen Federation. The primary analytical approach employed was inverse variance weighted (IVW), supplemented by MR-Egger regression and weighted median (WME) methods to investigate their potential interplay. Results were assessed using odds ratios () and 95% confidence intervals (). The robustness and reliability of the findings were confirmed through leave-one-out analysis, heterogeneity testing, and assessment of horizontal pleiotropy. Furthermore, we explored the potential mediating role of metabolites in the pathway linking GM to T2DM. Result:A set of 11 Single Nucleotide Polymorphisms (SNPs) linked to GM were identified as instrumental variables (IVs). The IVW analysis revealed that increased abundance of the , and corresponded to a heightened risk of T2DM. Conversely, higher levels of , and were associated with a reduced risk of T2DM. However, following false discovery rate (FDR) correction, only the abundance of genus Lachnoclostridium retained a significant positive correlation with T2DM risk ( = 1.22, = 0.09), while the other ten GM showed suggestive associations with T2DM. Reverse MR analysis did not reveal any causal relationship between T2DM and the increased risk associated with the identified GM. Additionally, metabolites did not exhibit mediating effects in this context. Conclusion:This study effectively pinpointed specific GM associated with T2DM, potentially paving the way for novel biomarkers in the prevention and treatment of this condition. The findings suggested that probiotics could emerge as a promising avenue for managing T2DM in the future. Furthermore, the analysis indicated that metabolites do not appear to act as mediators in the pathway from GM to T2DM. 10.3389/fendo.2024.1313651
A large-scale causal analysis of gut microbiota and endometriosis associated infertility: A Mendelian randomization study. Medicine Endometriosis is a prevalent condition with notable impacts on fertility. Recent studies have implicated gut microbiota in the development of endometriosis associated infertility (EAI). This study employs Mendelian randomization (MR) to elucidate the causal relationship between specific gut microbes and EAI. Using MR, we selected single nucleotide polymorphisms associated with 211 gut microbiota taxa from large-scale genome-wide association studies summary data. We applied statistical methods including inverse variance weighting, weighted median, and MR-Egger for analysis. Outliers were identified through the leave-one-out method. MR-Egger intercept tests were conducted to address horizontal pleiotropy, while Cochran Q and P values assessed heterogeneity. The false discovery rate method was used for multiple testing correction. Sensitivity analysis and F statistics evaluated the reliability and potential biases of our results. The inverse variance weighting method indicated a significant association of the genus Actinomyces (OR = 1.657, 95% CI: 1.187-2.312, P = .00298) with an increased risk of EAI. Conversely, genera Holdemania (OR = 0.630, 95% CI: 0.444-0.894, P = .00969) and Ruminococcaceae NK4A214 group (OR = 0.689, 95% CI: 0.481-0.999, P = .0439) appeared as protective factors. MR-PRESSO global test and MR-Egger regression indicated no significant horizontal pleiotropy (P > .05). Leave-one-out analysis confirmed the robustness of these findings. Our study provides evidence of a causal relationship between specific gut microbiome taxa and EAI. These findings offer novel insights and may guide the development of new preventive and therapeutic strategies for managing EAI. 10.1097/MD.0000000000037383
Causal impact of gut microbiota and associated metabolites on pulmonary arterial hypertension: a bidirectional Mendelian randomization study. BMC pulmonary medicine BACKGROUND:Patients with pulmonary arterial hypertension (PAH) exhibit a distinct gut microbiota profile; however, the causal association between gut microbiota, associated metabolites, and PAH remains elusive. We aimed to investigate this causal association and to explore whether dietary patterns play a role in its regulation. METHODS:Summary statistics of gut microbiota, associated metabolites, diet, and PAH were obtained from genome-wide association studies. The inverse variance weighted method was primarily used to measure the causal effect, with sensitivity analyses using the weighted median, weighted mode, simple mode, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR-Egger methods. A reverse Mendelian randomisation analysis was also performed. RESULTS:Alistipes (odds ratio [OR] = 2.269, 95% confidence interval [CI] 1.100-4.679, P = 0.027) and Victivallis (OR = 1.558, 95% CI 1.019-2.380, P = 0.040) were associated with an increased risk of PAH, while Coprobacter (OR = 0.585, 95% CI 0.358-0.956, P = 0.032), Erysipelotrichaceae (UCG003) (OR = 0.494, 95% CI 0.245-0.996, P = 0.049), Lachnospiraceae (UCG008) (OR = 0.596, 95% CI 0.367-0.968, P = 0.036), and Ruminococcaceae (UCG005) (OR = 0.472, 95% CI 0.231-0.962, P = 0.039) protected against PAH. No associations were observed between PAH and gut microbiota-derived metabolites (trimethylamine N-oxide [TMAO] and its precursors betaine, carnitine, and choline), short-chain fatty acids (SCFAs), or diet. Although inverse variance-weighted analysis demonstrated that elevated choline levels were correlated with an increased risk of PAH, the results were not consistent with the sensitivity analysis. Therefore, the association was considered insignificant. Reverse Mendelian randomisation analysis demonstrated that PAH had no causal impact on gut microbiota-derived metabolites but could contribute to increased the levels of Butyricicoccus and Holdemania, while decreasing the levels of Clostridium innocuum, Defluviitaleaceae UCG011, Eisenbergiella, and Ruminiclostridium 5. CONCLUSIONS:Gut microbiota were discovered suggestive evidence of the impacts of genetically predicted abundancy of certain microbial genera on PAH. Results of our study point that the production of SCFAs or TMAO does not mediate this association, which remains to be explained mechanistically. 10.1186/s12890-024-03008-7
Causal factors underlying diabetes risk informed by Mendelian randomisation analysis: evidence, opportunities and challenges. Diabetologia Diabetes and its complications cause a heavy disease burden globally. Identifying exposures, risk factors and molecular processes causally associated with the development of diabetes can provide important evidence bases for disease prevention and spur novel therapeutic strategies. Mendelian randomisation (MR), an epidemiological approach that uses genetic instruments to infer causal associations between an exposure and an outcome, can be leveraged to complement evidence from observational and clinical studies. This narrative review aims to summarise the evidence on potential causal risk factors for diabetes by integrating published MR studies on type 1 and 2 diabetes, and to reflect on future perspectives of MR studies on diabetes. Despite the genetic influence on type 1 diabetes, few MR studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. In type 2 diabetes, MR analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. These studies have also identified biomarkers, some of them derived from the gut microbiota, and molecular processes leading to increased disease risk. These studies provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. Because genetic association studies have mostly been restricted to participants of European descent, multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development. 10.1007/s00125-023-05879-7
Commentary: Causal associations of gut microbiota and metabolites on sepsis: a two-sample Mendelian randomization study. Frontiers in immunology 10.3389/fimmu.2024.1339176
Gut microbiome correlates with plasma lipids in amyotrophic lateral sclerosis. Brain : a journal of neurology Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants. Network analysis found several prominent amplicon sequence variants strongly linked to a group of metabolites, primarily lipids. Similarly, identifying the features that contributed most to case versus control separation pinpointed several bacteria correlated to metabolites, predominantly lipids. Mendelian randomization indicated possible causality from specific lipids related to fatty acid and acylcarnitine metabolism. Overall, the results suggest ALS cases and controls differ in their gut microbiome, which correlates with plasma metabolites, particularly lipids, through specific genera. These findings have the potential to identify robust disease biomarkers and shed mechanistic insight into ALS. 10.1093/brain/awad306
Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Previous researches have suggested a significant connection between the gut microbiota/immune cells and morphine tolerance (MT), but there is still uncertainty regarding their causal relationship. Hence, our objective is to inverstigate this causal association and reveal the impact of gut microbiota/immune cells on the risk of developing MT using a two-sample Mendelian randomization (MR) study. Methods:We conducted a comprehensive analysis using genome-wide association study (GWAS) summary statistics for gut microbiota, immune cells, and MT. The main approach employed was the inverse variance-weighted (IVW) method in MR. To assess horizontal pleiotropy and remove outlier single-nucleotide polymorphisms (SNPs), we utilized the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) technique as well as MR-Egger regression. Heterogeneity detection was performed using Cochran's -test. Additionally, leave-one-out analysis was carried out to determine if any single SNP drove the causal association signals. Finally, we conducted a reverse MR to evaluate the potential of reverse causation. Results:We discovered that 6 gut microbial taxa and 16 immune cells were causally related to MT ( < 0.05). Among them, 2 bacterial features and 9 immunophenotypes retained a strong causal relationship with lower risk of MT: genus. (OR: 0.962, 95% CI: 0.940-0.987, = 0.030), genus. (OR: 0.960, 95% CI: 0.946-0.976, = 0.003), BAFF-R on B cell (OR: 0.972, 95% CI: 0.947-0.998, = 0.013). Furthermore, 4 bacterial features and 7 immunophenotypes were identified to be significantly associated with MT risk: genus. (OR: 1.044, 95% CI: 1.017-1.069, = 0.029), genus. (OR: 1.054, 95% CI: 1.020-1.090, = 0.037), B cell % CD3-lymphocyte (OR: 1.976, 95% CI: 1.027-1.129, = 0.026). The Cochrane's test revealed no heterogeneity ( > 0.05). Furthermore, the MR-Egger and MR-PRESSO analyses reveal no instances of horizontal pleiotropy ( > 0.05). Besides, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the gut microbial taxa and immune cells exposure-outcome effect were attenuated. Conclusion:Our research confirm the potential link between gut microbiota and immune cells with MT, shedding light on the mechanism by which gut microbiota and immune cells may contribute to MT. These findings lay the groundwork for future investigations into targeted prevention strategies. 10.3389/fmicb.2024.1343763
Exploring the link between gut microbiota and alopecia areata: a two-sample Mendelian randomization analysis. International journal of dermatology BACKGROUND:While observational studies have suggested a link between gut microbiota diversity and alopecia areata (AA), the causal relationship remains unclear. METHODS:We leveraged data from the MiBioGen and FinnGen consortiums' Genome-wide association studies (GWAS) encompassing gut microbiota (n = 13,266) and AA (n = 211,428) datasets. A comprehensive Mendelian randomization (MR) and reverse MR approach were employed, utilizing five statistical methods to evaluate causality. Sensitivity analyses were also conducted to corroborate the MR results. RESULTS:Inverse variance weighted (IVW) analysis indicated a protective effect against AA from Butyricimonas (OR = 0.37, 95% CI: 0.18-0.77, P = 0.01), Enterorhabdus (OR = 0.40, 95% CI: 0.16-0.95, P = 0.04), Eubacterium (xylanophilum group) (OR = 0.36, 95% CI: 0.15-0.84, P = 0.02), and Phascolarctobacterium (OR = 0.37, 95% CI: 0.15-0.91, P = 0.03), while Ruminococcaceae UCG003 posed as a risk factor (OR = 2.79, 95% CI: 1.27-6.14, P = 0.01). Reverse MR showed no significant causal link between AA and gut microbiota, with no significant heterogeneity or horizontal pleiotropy. CONCLUSIONS:Our analysis suggests probable causality between certain gut microbiota and AA, shedding light on its pathogenesis and potential intervention strategies. 10.1111/ijd.17032
Association of gut microbiome and oral cavity cancer: A two sample mendelian randomization and case-control study. Journal of stomatology, oral and maxillofacial surgery INTRODUCTION:Considering the interconnectedness of the oral cavity and gut tract and the presence of abundant natural microbiota in both. We utilized Mendelian Randomization (MR) in a two-sample study to unveil the genetic causal impact of gut microbiota on the development of oral cavity cancer. MATERIALS & METHODS:The instrumental variables employed in this study consisted of single nucleotide polymorphisms (SNPs) that demonstrated a robust association with 211 distinct gut microbiota taxa, encompassing a sample size of 18,340 individuals. Our investigation sought to explore the potential causal relationship between these genetic variants and the incidence of oral cavity cancer. To accomplish this, we adopted a random effect inverse variance-weighted approach to analyze the causal effect. Additionally, sensitivity analyses were performed utilizing Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests, to assess the robustness and validity of our findings. RESULTS:Five gut microbiota taxa (the family Prevotellaceae, the genus Alloprevotella, the genus Erysipelatoclostridium, the genus Parabacteroides, the genus Ruminococcus gauvreauii group) are predicted to play a causal role in promoting the initiation of the risk of oral cavity cancer. While the genus Christensenellaceae R 7 group, the genus Intestinimonas, the genus Ruminococcaceae, and the order Bacillales causally reduce the risk of oral cavity cancer. Furthermore, no significant evidence suggesting heterogeneity or pleiotropy was observed. DISCUSSION:The novel genetic causal effects of 211 gut microbiota taxa on oral cavity cancer are elucidated in this investigation, thus offering valuable insights for clinical interventions targeting oral cavity cancer. 10.1016/j.jormas.2023.101736
Assessment of Causal Direction Between Gut Microbiota and Inflammatory Bowel Disease: A Mendelian Randomization Analysis. Zhang Zi-Jia,Qu Hong-Lei,Zhao Na,Wang Jing,Wang Xiu-Yan,Hai Rong,Li Bin Frontiers in genetics Background:Recent studies have shown that the gut microbiota is closely related to the pathogenesis of Inflammatory Bowel Disease (IBD), but the causal nature is largely unknown. The purpose of this study was to assess the causal relationship between intestinal bacteria and IBD and to identify specific pathogenic bacterial taxa via the Mendelian randomization (MR) analysis. Materials and Methods:MR analysis was performed on genome-wide association study (GWAS) summary statistics of gut microbiota and IBD. Specifically, the TwinsUK microbiota GWAS ( = 1,126 twin pairs) was used as exposure. The UK inflammatory bowel disease (UKIBD) and the Understanding Social Program (USP) study GWAS ( = 48,328) was used as discovery outcome, and the British IBD study ( = 35,289) was used as replication outcome. SNPs associated with bacteria abundance at the suggestive significance level (α = 1.0 × 10) were used as instrumental variables. Bacteria were grouped into families and genera. Results:In the discovery sample, a total of 30 features were available for analysis, including 15 families and 15 genera. Three features were nominally significant, including one family (, 2 IVs, beta = -0.04, = 0.05) and two genera (, 2 IVs, beta = 0.04, = 0.05; , 2 IVs, beta = -0.07, = 0.04). All of them were successfully replicated in the replication sample ( and = 0.02, = 0.01) with consistent effect direction. Conclusion:We identified specific pathogenic bacteria features that were causally associated with the risk of IBD, thus offering new insights into the prevention and diagnosis of IBD. 10.3389/fgene.2021.631061
Longitudinal change of gut microbiota in hypertensive disorders in pregnancy: a nested case-control and Mendelian randomization study. Scientific reports Mounting evidence has shown that gut microbiota (GM) is related to hypertensive disorders in pregnancy (HDP), however, most studies only focused on one time point in pregnancy. In this study, we conducted a nested case-control study utilizing a follow-up cohort, resulting in the collection of 47 HDP patients and 30 healthy controls. The GM profiles were explored using 16S rRNA sequencing at three time points during pregnancy. The diversity analysis of GM showed no significant difference between HDP patients and controls, however, we found 21 differential GM during pregnancy. Trend analysis showed that there are statistical differences in the relative abundance of Thermomonas, Xanthomonas, and Phenylobacteriumat during pregnancy in the gestational hypertension group, and of Xanthomonas, Polycyclovorans, and Phenylobacterium in the control group. The correlation study found that six genera of GM are related to blood pressure. Furthermore, the MR analysis identified the causal relationship between Methanobrevibacter and pre-eclampsia (PE). This study first explored the longitudinal change of GM in HDP patients during pregnancy, found the differential GM, and detected the causal association. Our findings may promote the prevention and treatment of HDP from the perspective of GM and provide valuable insights into the pathogenesis of HDP. 10.1038/s41598-023-43780-w
The causal association of specific gut microbiota on the risk of membranous nephropathy: a Mendelian randomization study. International urology and nephrology PURPOSE:Gut microbiota transplantation has been reported to improve the renal function of membranous nephropathy (MN). However, whether there is a causal effect of gut microbiota on MN remained unclear. METHODS:We performed two-sample Mendelian randomization (MR) analysis. The inverse variance weighted (IVW) method was used as the main approach to evaluate the causal relationship between gut microbiota and MN. Additional methods including MR-Egger regression, weighted median, and MR-weighted mode were also conducted. Cochrane's Q test, MR-Egger regression, and MR-PRESSO were employed to detect heterogeneity and pleiotropy, respectively. RESULTS:A total of 196 gut microbiota were examined. After IVW and sensitivity analysis, eight gut bacteria taxa were observed causal effects on the risk of MN. Specifically, Genus. Oscillibacter was a protective factor (OR: 0.57; 95% CI 0.328-0.979; P = 0.042), while Class. Melainabacteria (OR: 1.51; 95% CI 1.004-2.277; P = 0.048), Genus. Butyricicoccus (OR: 2.16; 95% CI 1.005-4.621; P = 0.048), Genus. Catenibacterium (OR: 1.49; 95% CI 1.043-2.134; P = 0.028), Genus.Ruminiclostridium5 (OR: 1.74; 95% CI 1.053-2.862; P = 0.030), Genus. Ruminococcaceae UCG-003 (OR: 1.73; 95% CI 1.110-2.692; P = 0.015), Order. Bacillales (OR: 1.52; 95% CI 1.135-2.025; P = 0.0048) and Order. Gastranaerophilales (OR: 1.45; 95% CI 1.010-2.085; P = 0.044) were risk factors. Heterogeneity was not significant for most single-nucleotide polymorphisms, and no statistical difference in pleiotropy. CONCLUSIONS:This study first indicated the causal association between specific gut microbiota and MN, which would be of great significance to guide clinical prevention and treatment in MN. 10.1007/s11255-023-03926-1
Potential effects of specific gut microbiota on periodontal disease: a two-sample bidirectional Mendelian randomization study. Frontiers in microbiology Introduction:Periodontal disease (PD) presents a substantial global health challenge, encompassing conditions from reversible gingivitis to irreversible periodontitis, often culminating in tooth loss. The gut-oral axis has recently emerged as a focal point, with potential gut microbiota dysbiosis exacerbating PD. Methods:In this study, we employed a double-sample bidirectional Mendelian randomized (MR) approach to investigate the causal relationship between specific gut microbiota and periodontal disease (PD) and bleeding gum (BG) development, while exploring the interplay between periodontal health and the gut microenvironment. We performed genome-wide association studies (GWAS) with two cohorts, totalling 346,731 (PD and control) and 461,113 (BG and control) participants, along with data from 14,306 participants' intestinal flora GWAS, encompassing 148 traits (31 families and 117 genera). Three MR methods were used to assess causality, with the in-verse-variance-weighted (IVW) measure as the primary outcome. Cochrane's test, MR-Egger, and MR-PRESSO global tests were used to detect heterogeneity and pleiotropy. The leave-one-out method was used to test the stability of the MR results. An F-statistic greater than 10 was accepted for instrument exposure association. Results and conclusion:Specifically, and were associated with reduced gum bleeding risk, whereas , , and were linked to reduced PD risk. Conversely, was associated with an elevated risk of PD. No significant heterogeneity or pleiotropy was detected. In conclusion, our MR analysis pinpointed specific gut flora with causal connections to PD, offering potential avenues for oral health interventions. 10.3389/fmicb.2024.1322947
Causal relationship between gut microbiota and gastric cancer: A two‑sample Mendelian randomization analysis. Molecular and clinical oncology The gut microbiota is associated with GC; however, the causal association between the gut microbiota and GC remains to be determined. The aim of the present study was to investigate the causal association between gut microbiota and gastric cancer (GC) from the perspective of Mendelian randomization (MR). The present study performed MR analysis using summary statistics from a genome-wide association study of the gut microbiome and GC. Inverse-variance weighted, MR-Egger and weighted median methods were used to investigate the causal relationship between gut microbiota and GC. Heterogeneity tests were performed using Cochrane's Q statistic. Horizontal polytropy was detected using Mendelian Randomization Pleiotropy RESidual Sum and Outlier were eliminated. Estimates from MR indicated that nine gut microorganism remained stable with regard to acceptance of heterogeneity and sensitivity methods. Among them, the genera 7, and UCG014 were associated with an increased risk of GC; by contrast, the family , the genera , FCS020, UCG004 and UCG009, and the order Enterobacteriales decreased the risk of GC development. The present study demonstrated the potential importance of modulating the abundance of gut microbiota for the prevention and treatment of GC. 10.3892/mco.2024.2736
Assessment of the causal relationship between gut microbiota and cardiovascular diseases: a bidirectional Mendelian randomization analysis. BioData mining BACKGROUND:Previous studies have shown an association between gut microbiota and cardiovascular diseases (CVDs). However, the underlying causal relationship remains unclear. This study aims to elucidate the causal relationship between gut microbiota and CVDs and to explore the pathogenic role of gut microbiota in CVDs. METHODS:In this two-sample Mendelian randomization study, we used genetic instruments from publicly available genome-wide association studies, including single-nucleotide polymorphisms (SNPs) associated with gut microbiota (n = 14,306) and CVDs (n = 2,207,591). We employed multiple statistical analysis methods, including inverse variance weighting, MR Egger, weighted median, MR pleiotropic residuals and outliers, and the leave-one-out method, to estimate the causal relationship between gut microbiota and CVDs. Additionally, we conducted multiple analyses to assess horizontal pleiotropy and heterogeneity. RESULTS:GWAS summary data were available from a pooled sample of 2,221,897 adult and adolescent participants. Our findings indicated that specific gut microbiota had either protective or detrimental effects on CVDs. Notably, Howardella (OR = 0.955, 95% CI: 0.913-0.999, P = .05), Intestinibacter (OR = 0.908, 95% CI:0.831-0.993, P = .03), Lachnospiraceae (NK4A136 group) (OR = 0.904, 95% CI:0.841-0.973, P = .007), Turicibacter (OR = 0.904, 95% CI: 0.838-0.976, P = .01), Holdemania (OR, 0.898; 95% CI: 0.810-0.995, P = .04) and Odoribacter (OR, 0.835; 95% CI: 0.710-0.993, P = .04) exhibited a protective causal effect on atrial fibrillation, while other microbiota had adverse causal effects. Similar effects were observed with respect to coronary artery disease, myocardial infarction, ischemic stroke, and hypertension. Furthermore, reversed Mendelian randomization analyses revealed that atrial fibrillation and ischemic stroke had causal effects on certain gut microbiotas. CONCLUSION:Our study underscored the importance of gut microbiota in the context of CVDs and lent support to the hypothesis that increasing the abundance of probiotics or decreasing the abundance of harmful bacterial populations may offer protection against specific CVDs. Nevertheless, further research is essential to translate these findings into clinical practice. 10.1186/s13040-024-00356-2
Genetically predicted causality between gut microbiota, blood metabolites, and intracerebral hemorrhage: a bidirectional Mendelian randomization study. Frontiers in microbiology Background:Recent research linked changes in the gut microbiota and serum metabolite concentrations to intracerebral hemorrhage (ICH). However, the potential causal relationship remained unclear. Therefore, the current study aims to estimate the effects of genetically predicted causality between gut microbiota, serum metabolites, and ICH. Methods:Summary data from genome-wide association studies (GWAS) of gut microbiota, serum metabolites, and ICH were obtained separately. Gut microbiota GWAS ( = 18,340) were acquired from the MiBioGen study, serum metabolites GWAS ( = 7,824) from the TwinsUK and KORA studies, and GWAS summary-level data for ICH from the FinnGen R9 (ICH, 3,749 cases; 339,914 controls). A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects between gut microbiota, serum metabolites, and ICH. The random-effects inverse variance-weighted (IVW) MR analyses were performed as the primary results, together with a series of sensitivity analyses to assess the robustness of the results. Besides, a reverse MR was conducted to evaluate the possibility of reverse causation. To validate the relevant findings, we further selected data from the UK Biobank for analysis. Results:MR analysis results revealed a nominal association ( < 0.05) between 17 gut microbial taxa, 31 serum metabolites, and ICH. Among gut microbiota, the higher level of genus (odds ratio (OR): 1.327, 95% confidence interval (CI):1.154-1.526; Bonferroni-corrected  = 7.28 × 10) retained a strong causal relationship with a higher risk of ICH after the Bonferroni corrected test. Concurrently, the genus Senegalimassilia (OR: 0.843, 95% CI: 0.778-0.915; Bonferroni-corrected  = 4.10 × 10) was associated with lower ICH risk. Moreover, after Bonferroni correction, only two serum metabolites remained out of the initial 31 serum metabolites. One of the serum metabolites, Isovalerate (OR: 7.130, 95% CI: 2.648-19.199; Bonferroni-corrected  = 1.01 × 10) showed a very strong causal relationship with a higher risk of ICH, whereas the other metabolite was unidentified and excluded from further analysis. Various sensitivity analyses yielded similar results, with no heterogeneity or directional pleiotropy observed. Conclusion:This two-sample MR study revealed the significant influence of gut microbiota and serum metabolites on the risk of ICH. The specific bacterial taxa and metabolites engaged in ICH development were identified. Further research is required in the future to delve deeper into the mechanisms behind these findings. 10.3389/fmicb.2024.1257405
Causal effect of gut microbiota and diabetic nephropathy: a Mendelian randomization study. Diabetology & metabolic syndrome BACKGROUND:The interaction of dysbiosis of gut microbiota (GM) with diabetic nephropathy (DN) drew our attention and a better understanding of GM on DN might provide potential therapeutic approaches. However, the exact causal effect of GM on DN remains unknown. METHODS:We applied two-sample Mendelian Randomization (MR) analysis, including inverse variance weighted (IVW), MR-Egger methods, etc., to screen the significant bacterial taxa based on the GWAS data. Sensitivity analysis was conducted to assess the robustness of MR results. To identify the most critical factor on DN, Mendelian randomization-Bayesian model averaging (MR-BMA) method was utilized. Then, whether the reverse causality existed was verified by reverse MR analysis. Finally, transcriptome MR analysis was performed to investigate the possible mechanism of GM on DN. RESULTS:At locus-wide significance levels, the results of IVW suggested that order Bacteroidales (odds ratio (OR) = 1.412, 95% confidence interval (CI): 1.025-1.945, P = 0.035), genus Akkermansia (OR = 1.449, 95% CI: 1.120-1.875, P = 0.005), genus Coprococcus 1 (OR = 1.328, 95% CI: 1.066-1.793, P = 0.015), genus Marvinbryantia (OR = 1.353, 95% CI: 1.037-1.777, P = 0.030) and genus Parasutterella (OR = 1.276, 95% CI: 1.022-1.593, P = 0.032) were risk factors for DN. Reversely, genus Eubacterium ventriosum (OR = 0.756, 95% CI: 0.594-0.963, P = 0.023), genus Ruminococcus gauvreauii (OR = 0.663, 95% CI: 0.506-0.870, P = 0.003) and genus Erysipelotrichaceae (UCG003) (OR = 0.801, 95% CI: 0.644-0.997, P = 0.047) were negatively associated with the risk of DN. Among these taxa, genus Ruminococcus gauvreauii played a crucial role in DN. No significant heterogeneity or pleiotropy in the MR result was found. Mapped genes (FDR < 0.05) related to GM had causal effects on DN, while FCGR2B and VNN2 might be potential therapeutic targets. CONCLUSIONS:This work provided new evidence for the causal effect of GM on DN occurrence and potential biomarkers for DN. The significant bacterial taxa in our study provided new insights for the 'gut-kidney' axis, as well as unconventional prevention and treatment strategies for DN. 10.1186/s13098-024-01327-7
Gut microbiota associated with appetite suppression in high-temperature and high-humidity environments. EBioMedicine BACKGROUND:Food is crucial for maintaining vital human and animal activities. Disorders in appetite control can lead to various metabolic disturbances. Alterations in the gut microbial composition can affect appetite and energy metabolism. While alterations in the gut microbiota have been observed in high-temperature and high-humidity (HTH) environments, the relationship between the gut microbiota during HTH and appetite remains unclear. METHODS:We utilised an artificial climate box to mimic HTH environments, and established a faecal bacteria transplantation (FMT) mouse model. Mendelian randomisation (MR) analysis was used to further confirm the causal relationship between gut microbiota and appetite or appetite-related hormones. FINDINGS:We found that, in the eighth week of exposure to HTH environments, mice showed a decrease in food intake and body weight, and there were significant changes in the intestinal microbiota compared to the control group. After FMT, we observed similar changes in food intake, body weight, and gut bacteria. Appetite-related hormones, including ghrelin, glucagon-like peptide-1, and insulin, were reduced in DH (mice exposed to HTH conditions) and DHF (FMT from mice exposed to HTH environments for 8 weeks), while the level of peptide YY initially increased and then decreased in DH and increased after FMT. Moreover, MR analysis further confirmed that these changes in the intestinal microbiota could affect appetite or appetite-related hormones. INTERPRETATION:Together, our data suggest that the gut microbiota is closely associated with appetite suppression in HTH. These findings provide novel insights into the effects of HTH on appetite. FUNDING:This work was supported by the National Natural Science Foundation of China and Guangzhou University of Chinese Medicine. 10.1016/j.ebiom.2023.104918
Causal effects of gut microbiota on autism spectrum disorder: A two-sample mendelian randomization study. Medicine There is increasing evidence that alterations in gut microbiota (GM) composition are associated with autism spectrum disorder (ASD), but no reliable causal relationship has been established. Therefore, a 2-sample Mendelian randomization (MR) study was conducted to reveal a potential causal relationship between GM and ASD. Instrumental variables for 211 GM taxa were obtained from genome-wide association studies (GWAS) and Mendelian randomization studies to estimate their impact on ASD risk in the iPSYCH-PGC GWAS dataset (18,382 ASD cases and 27,969 controls). Inverse variance weighted (IVW) is the primary method for causality analysis, and several sensitivity analyses validate MR results. Among 211 GM taxa, IVW results confirmed that Tenericutes (P value = .0369), Mollicutes (P value = .0369), Negativicutes (P value = .0374), Bifidobacteriales (P value = .0389), Selenomonadales (P value = .0374), Bifidobacteriaceae (P value = .0389), Family XIII (P value = .0149), Prevotella7 (P value = .0215), Ruminococcaceae NK4A214 group (P value = .0205) were potential protective factors for ASD. Eisenbergiella (P value = .0159) was a possible risk factor for ASD. No evidence of heterogeneous, pleiotropic, or outlier single-nucleotide polymorphism was detected. Additionally, further sensitivity analysis verified the robustness of the above results. We confirm a potential causal relationship between certain gut microbes and ASD, providing new insights into how gut microbes mediate ASD. The association between them needs to be further explored and will provide new ideas for the prevention and treatment of ASD. 10.1097/MD.0000000000037284
Causal relationship of genetically predicted gut microbiota with thyroid cancer: a bidirectional two-sample mendelian randomization study. Frontiers in endocrinology Background:Previous investigations have demonstrated a correlation between the composition of gut microbiota and the development of thyroid cancer (TC). Nonetheless, there was no consensus on the causal effect of gut microbiota composition on TC risk. Therefore, the present study aimed to perform a bidirectional two-sample Mendelian randomization (MR) analysis to explore potential causal associations between gut microbiota and TC risk. Methods:Utilizing data from the MiBioGen consortium's genome-wide association studies (GWAS) meta-analysis involving a sample size of 18,340, we identified instrumental variables for 211 gut microbiota taxa. The summary statistics for TC was from relevant large-scale GWAS conducted by the FinnGen consortium. In the first stage, the Inverse-variance weighted (IVW) method was used as the primary estimate method, and the stability of estimations was tested by a battery of sensitivity analyses. In the second stage, a reverse MR analysis was applied to determine whether reverse causality existed. Results:According to the IVW method, we identified 9 genetically predicted gut microbiota that were causally correlated with TC risk. Among them, we observed a positive causal effect of (OR = 1.664, 95% CI: 1.103-2.511, = 0.015), (OR = 1.268, 95% CI: 1.009-1.594, = 0.042), (OR = 1.505, 95% CI: 1.049-2.159, = 0.027), (OR = 1.846, 95% CI: 1.261-2.704, = 0.002), (OR = 1.907, 95% CI: 1.165-3.121, = 0.010), (OR = 1.309, 95% CI: 1.027-1.668, = 0.029) on TC risk, while (OR = 0.522, 95% CI: 0.310-0.879, = 0.015), (OR = 0.753, 95% CI: 0.577-0.983, = 0.037), (OR = 0.596, 95% CI: 0.381-0.933, = 0.024) might be correlated with a decreased risk of TC. Subsequently, various sensitivity analyses indicated no heterogeneity, directional pleiotropy or outliers. In addition, reverse analysis demonstrated a negative causal effect of TC risk on the abundance of the gut microbiota (, OR = 0.947, 95% CI: 0.907-0.989, = 0.014). Conclusion:Genetic evidence suggested that bidirectional causal associations of specific bacteria taxa and the risk of TC, highlighting the association of the "gut-thyroid" axis. Further exploration of the potential microbiota-related mechanisms might have profound implications for public health in terms of the early prevention and treatment of TC. 10.3389/fendo.2024.1284472
Assessing causal relationships between gut microbiota and psoriasis: evidence from two sample Mendelian randomization analysis. Scientific reports Mounting data hints that the gut microbiota's role may be pivotal in understanding the emergence of psoriasis. However, discerning a direct causal link is yet elusive. In this exploration, we adopted a Mendelian randomization (MR) strategy to probe the prospective causal interplay between the gut's microbial landscape and the predisposition to psoriasis. Genetic markers acting as instrumental variables for gut microbiota were extrapolated from a genome-wide association study (GWAS) encompassing 18,340 individuals. A separate GWAS yielded summary data for psoriasis, which covered 337,159 patients and 433,201 control subjects. The primary analysis hinged on inverse variance weighting (IVW). Additional methods like the weighted median approach and MR-Egger regression were employed to validate the integrity of our findings. Intriguing correlations emerged between psoriasis risk and eight specific bacterial traits. To illustrate: Mollicutes presented an odds ratio (OR) of 1.003 with a 95% confidence interval (CI) spanning 1.001-1.005 (p = 0.016), while the family. Victivallaceae revealed an OR of 0.998 with CI values between 0.997 and 0.999 (p = 0.023). Eubacterium (coprostanoligenes group) revealed an OR of 0.997 with CI values between 0.994 and 0.999 (p = 0.027). Eubacterium (fissicatena group) revealed an OR of 0.997 with CI values between 0.996 and 0.999 (p = 0.005). Holdemania revealed an OR of 1.001 with CI values 1-1.003 (p = 0.034). Lachnospiraceae (NK4A136 group) revealed an OR of 0.997 with CI values between 0.995 and 0.999 (p = 0.046). Lactococcus revealed an OR of 0.998 with CI values between 0.996 and 0.999 (p = 0.008). Tenericutes revealed an OR of 1.003 with CI values between 1.001 and 1.006 (p = 0.016). Sensitivity analysis for these bacterial features yielded congruent outcomes, reinforcing statistically significant ties between the eight bacterial entities and psoriasis. This comprehensive probe underscores emerging evidence pointing towards a plausible causal nexus between diverse gut microbiota and the onset of psoriasis. It beckons further research to unravel the intricacies of how the gut's microbial constituents might sway psoriasis's pathogenesis. 10.1038/s41598-024-59603-5
Mendelian randomization analysis to investigate the gut microbiome in oral and oropharyngeal cancer. Frontiers in cellular and infection microbiology Background:Evidence supports an observational association between the gut microbiome and susceptibility to extraintestinal cancers, but the causal relationship of this association remains unclear. Methods:To identify the specific causal gut microbiota of oral and oropharyngeal cancer, we performed two-sample Mendelian randomization (MR) analysis of gut microbiota on oral and oropharyngeal cancer using a fixed-effects inverse-variance-weighted model. Gut microbiota across five different taxonomical levels from the MiBioGen genome-wide association study (GWAS) were used as exposures. Oral cancer, oropharyngeal cancer and a combination of the two cancers defined from three separate data sources were used as the outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher abundance of microbiome. Results & Conclusions:There was little evidence for a causal effect of gut microbiota on oral and oropharyngeal cancer when using a genome-wide p-value threshold for selecting instruments. Secondary analyses using a more lenient p-value threshold indicated that there were 90 causal relationships between 58 different microbial features but that sensitivity analyses suggested that these were possibly affected by violations of MR assumptions and were not consistent across MR methodologies or data sources and therefore are also to unlikely reflect causation. These findings provide new insights into gut microbiota-mediated oral and oropharyngeal cancers and warrant further investigation. 10.3389/fcimb.2023.1210807
Genetic Insights into the Gut-Lung Axis: Mendelian Randomization Analysis on Gut Microbiota, Lung Function, and COPD. International journal of chronic obstructive pulmonary disease Background:Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with a complex etiology involving genetic and environmental factors. The dysbiosis of gut microbiota has been implicated in COPD. Mendelian Randomization (MR) provides a tool to investigate causal links using genetic variants as instrumental variables. This study aims to employ MR analysis to explore the causal relationship between gut microbiota, lung function, and COPD. Methods:We utilized genome-wide association study (GWAS) data from MiBioGen, UK Biobank and FinnGen, which were related to gut microbial taxa, lung function parameters including forced vital capacity in one second (FEV), forced vital capacity (FVC), and percentage of predicted FEV (FEV%pred), as well as GWAS data for COPD. MR analysis was conducted to assess the causal effects of gut microbiota on lung function and the risk of COPD. Sensitivity analysis was utilized to examine the stability of the causal relationships. Multiple testing and reverse analysis were employed to evaluate the robustness of these relationships. Results:Using the IVW method, 64 causal correlations were identified. Through conducting sensitivity analysis, multiple testing, and reverse analysis, we identified 14 robust and stable causal relationships. The bacterial taxa that showed a positive association with lung function included , Erysipelotrichales, Desulfovibrionales, Clostridiales, and , while Selenomonadales and showed a negative association with lung function. The abundance of were positively correlated with the risk of COPD, while exhibited a negative correlation with the risk of COPD. Conclusion:Several microbial taxa were discovered to have a positive causal correlation with lung function, offering potential insights into the development of probiotics. The presence of microbial taxa negatively correlated with lung function and positively correlated with COPD emphasized the potential impact of gut microbiota dysbiosis on respiratory health. 10.2147/COPD.S441242
Exploring the role of gut microbiota in migraine risk: a two-sample Mendelian randomization study. Scandinavian journal of gastroenterology OBJECTIVES:The presence of intestinal flora in the gut has been linked to migraines in recent studies, but whether the association is causal or due to bias remains to be clarified. We aimed to explore whether there is a potential causal relationship between gut microbiota and migraine risk with this study. MATERIALS AND METHODS:We conducted a two-sample Mendelian randomized analysis study to explore whether gut microbiota has a causal relationship with migraine using publicly available data from large-scale genome-wide association studies. The inverse variance weighting was used as the main method, and weighted median and MR-Egger were used as supplementary methods for causal inference. Sensitivity analyses, including leave-one-out analysis, Cochran Q test, and MR-Egger intercept test, were used to verify the robustness of the results. RESULTS:After rigorous quality control of the results, we identified that genetic predisposition towards a higher abundance of genus.Lactobacillus was causally associated with higher of migraine (IVW OR = 1.10, 95% CI = 1.03 - 1.18,  = .004), whereas the higher abundance of family.Prvotellaceae predicted a decreased risk of migraine (IVW OR = 0.89, 95% CI = 0.80 - 0.98,  = .02). Sensitivity analyses indicated the results were not biased by pleiotropy. CONCLUSION:According to our research, there is evidence showing that gut microbiota may be involved in migraine development, which suggested that a stool examination might be helpful to recognize those with a higher risk of migraine. Further mechanisms remained to be elucidated in future studies. 10.1080/00365521.2023.2298370
The predictive, preventive, and personalized medicine of insomnia: gut microbiota and inflammation. The EPMA journal Background:The human gut microbiota (GM) has been recognized as a significant factor in the development of insomnia, primarily through inflammatory pathways, making it a promising target for therapeutic interventions. Considering the principles of primary prediction, targeted prevention, and personalized treatment medicine (PPPM), identifying specific gut microbiota associated with insomnia and exploring the underlying mechanisms comprehensively are crucial steps towards achieving primary prediction, targeted prevention, and personalized treatment of insomnia. Working hypothesis and methodology:We hypothesized that alterations in the composition of specific GM could induce insomnia through an inflammatory response, which postulates the existence of a GM-inflammation-insomnia pathway. Mendelian randomization (MR) analyses were employed to examine this pathway and explore the mediative effects of inflammation. We utilized genetic proxies representing GM, insomnia, and inflammatory indicators (including 41 circulating cytokines and C-reactive protein (CRP)), specifically identified from European ancestry. The primary method used to identify insomnia-related GM and examine the medicative effect of inflammation was the inverse variance weighted method, supplemented by the MR-Egger and weighted median methods. Our findings have the potential to identify individuals at risk of insomnia through screening for GM imbalances, leading to the development of targeted prevention and personalized treatment strategies for the condition. Results:Nine genera and three circulating cytokines were identified to be associated with insomnia; only the associations of ( group) and β-NGF on insomnia remained significant after the FDR test, OR = 1.08 (95% CI = 1.04-1.12,  = 1.45 × 10,  = 0.02) and OR = 1.06 (95% CI = 1.02-1.10,  = 1.06 × 10,  = 0.04), respectively. CRP was associated with an increased risk of insomnia, OR = 1.05 (95% CI = 1.01-1.10,  = 6.42 × 10). CRP mediated the association of 1, , and ( group) with insomnia. No heterogeneity or pleiotropy were detected. Conclusions:Our study highlights the role of specific GM alterations in the development of insomnia and provides insights into the mediating effects of inflammation. Targeting these specific GM alterations presents a promising avenue for advancing the transition from reactive medicine to PPPM in managing insomnia, potentially leading to significant clinical benefits. Supplementary Information:The online version contains supplementary material available at 10.1007/s13167-023-00345-1. 10.1007/s13167-023-00345-1
The causal relationship between gut microbiota and biliary tract cancer: comprehensive bidirectional Mendelian randomization analysis. Frontiers in cellular and infection microbiology Background:Growing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore the causal relationship between gut microbiota and BTC, conduct an appraisal of the gut microbiome's utility in facilitating the early diagnosis of BTC. Methods:We acquired the summary data for Genome-wide Association Studies (GWAS) pertaining to BTC (418 cases and 159,201 controls) from the Biobank Japan (BBJ) database. Additionally, the GWAS summary data relevant to gut microbiota (N = 18,340) were sourced from the MiBioGen consortium. The primary methodology employed for the analysis consisted of Inverse Variance Weighting (IVW). Evaluations for sensitivity were carried out through the utilization of multiple statistical techniques, encompassing Cochrane's Q test, the MR-Egger intercept evaluation, the global test of MR-PRESSO, and a leave-one-out methodological analysis. Ultimately, a reverse Mendelian Randomization analysis was conducted to assess the potential for reciprocal causality. Results:The outcomes derived from IVW substantiated that the presence of (OR = 0.44, = 0.034), (OR = 0.46, = 0.018), and (OR = 0.29, = 0.041) exerted a protective influence against BTC. Conversely, (OR = 2.21, = 0.017), (OR = 2.30, = 0.013), and (OR = 2.21, = 0.017) were associated with an adverse impact. To assess any reverse causal effect, we used BTC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between BTC and five different types of gut microbiota. The sensitivity analysis disclosed an absence of empirical indicators for either heterogeneity or pleiotropy. Conclusion:This investigation represents the inaugural identification of indicative data supporting either beneficial or detrimental causal relationships between gut microbiota and the risk of BTC, as determined through the utilization of MR methodologies. These outcomes could hold significance for the formulation of individualized therapeutic strategies aimed at BTC prevention and survival enhancement. 10.3389/fcimb.2024.1308742
The gut microbiota-constipation connection: Insights from a two sample bidirectional Mendelian randomization study. Microbial pathogenesis OBJECTIVE:The dysbiosis of the gut microbiota has been implicated in various maladies. Research has identified an association between the dysbiosis of the gut microbiota and the risk of constipation, prompting this study to elucidate the potential causal relationship between gut microbiota imbalance with constipation through a two sample bidirectional Mendelian randomization (MR) study, shedding light on the genetic mechanisms underlying the connection between gut microbiota and constipation. METHODS:The forward MR analysis aimed to scrutinize whether alterations in the composition and abundance of gut microbiota impact the risk of constipation, while the reverse MR analysis explored whether the genetic predisposition to constipation influences the abundance of gut microbiota. Genomic correlation data for the gut microbiota were sourced from the comprehensive statistics of the MiBioGen consortium. Genomic correlation data for constipation were obtained from the IEU database, encoded as the dataset ebi-a-GCST90018829. The correlation was assessed using various analytical techniques, including inverse variance weighting (IVW), Mendelian randomization-Egger regression (MR-Egger), and weighted median and mode methodologies. To ensure the robustness of the results, a meticulous sensitivity analysis was conducted, incorporating Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and a Leave-one-out analysis. RESULTS:In the forward Mendelian randomization analyses, a negative correlation was discerned between the abundance of Coprococcus in the gut microbiota and the occurrence of constipation (IVW: OR = 0.74, 95 % CI = 0.64-0.86, p = 0.0001), whereas a positive correlation was observed between the abundance of Bacteroidetes in the gut microbiota and constipation (IVW: OR = 1.22, 95 % CI = 1.00-1.50, p = 0.04). In the forward Mendelian randomization analyses, we were unsuccessful in obtaining valid instrumental variables for scrutiny, and we deemed that constipation exerts no influence on the composition of the gut microbiota. CONCLUSION:Genetic predisposition towards increased abundance of Coprococcus and decreased abundance of Bacteroidetes is correlated with a diminished susceptibility to constipation. This investigation showed that alterations in the gut microbiota precipitated the onset of constipation, rather than constipation inducing modifications in the microbial flora. 10.1016/j.micpath.2024.106667
Putative causal relations among gut flora, serums metabolites and arrhythmia: a Mendelian randomization study. BMC cardiovascular disorders BACKGROUND:The pathogenesis of cardiac arrhythmias is multifaceted, encompassing genetic, environmental, hemodynamic, and various causative factors. Emerging evidence underscores a plausible connection between gut flora, serum metabolites, and specific types of arrhythmias. Recognizing the role of host genetics in shaping the microbiota, we employed two-sample Mendelian randomization analyses to investigate potential causal associations between gut flora, serum metabolites, and distinct arrhythmias. METHODS:Mendelian randomization methods were deployed to ascertain causal relationships between 211 gut flora, 575 serum metabolites, and various types of arrhythmias. To ensure the reliability of the findings, five complementary Mendelian randomization methods, including inverse variance weighting methods, were employed. The robustness of the results was scrutinized through a battery of sensitivity analyses, incorporating the Cochran Q test, leave-one-out test, and MR-Egger intercept analysis. RESULTS:Eighteen gut flora and twenty-six serum metabolites demonstrated associations with the risk of developing atrial fibrillation. Moreover, ten gut flora and fifty-two serum metabolites were linked to the risk of developing supraventricular tachycardia, while eight gut flora and twenty-five serum metabolites were associated with the risk of developing tachycardia. Additionally, six gut flora and twenty-one serum metabolites exhibited associations with the risk of developing bradycardia. CONCLUSION:This study revealed the potential causal relationship that may exist between gut flora, serum metabolites and different cardiac arrhythmias and highlights the need for further exploration. This study provides new perspectives to enhance diagnostic and therapeutic strategies in the field of cardiac arrhythmias. 10.1186/s12872-023-03703-z
Mendelian Randomization Studies in Atopic Dermatitis: A Systematic Review. The Journal of investigative dermatology Prior studies have found associations between atopic dermatitis (AD) and comorbidities, including depression, obesity, asthma, and allergic rhinitis. Although observational studies often cannot establish robust causality between potential risk factors and AD, Mendelian randomization minimizes confounding when exploring causality by relying on random allelic assortment at birth. In this study, we systematically reviewed 30 Mendelian randomization studies in AD. Body mass index, gut microbial flora, the IL-18 signaling pathway, and gastroesophageal reflux disease were among the causal factors for AD, whereas AD was causal for several medical conditions, including heart failure, rheumatoid arthritis, and conjunctivitis. These insights may improve preventive counseling in AD. 10.1016/j.jid.2023.10.016
Causal associations between human gut microbiota and osteomyelitis: a Mendelian randomization study. Frontiers in cellular and infection microbiology Background:Recent studies have emphasized the role of gut microbiota in the onset and progression of osteomyelitis. However, the exact types of gut microbiota and their mechanisms of action remain unclear. Additionally, there is a lack of theoretical support for treatments that improve osteomyelitis by altering the gut microbiota. Methods:In our study, we utilized the largest genome-wide association study (GWAS) meta-analysis to date from the MiBioGen consortium, involving 13,400 participants. The GWAS data for osteomyelitis were sourced from the UK Biobank, which included 4,836 osteomyelitis cases and 486,484 controls. We employed a two-sample Mendelian randomization framework for a detailed investigation into the causal relationship between gut microbiota and osteomyelitis. Our methods included inverse variance weighting, MR-Egger, weighted median, and weighted mode approaches. Additionally, we applied Cochran's Q statistic to assess the heterogeneity of the instrumental variable. Results:At the class level, Bacilli and Bacteroidia were positively correlated with the risk of osteomyelitis. At the order level, only showed a positive association with osteomyelitis. At the genus level, an increased abundance of , , and was positively associated with the risk of osteomyelitis, whereas was negatively associated. Sensitivity analyses showed no evidence of heterogeneity or pleiotropy. Conclusion:This study reveals that classes Bacilli and Bacteroidia, order Bacteroidales, and genera , , and are implicated in increasing the risk of osteomyelitis, while the genus is associated with a reduced risk. Future investigations are warranted to elucidate the precise mechanisms through which these specific bacterial groups influence the pathophysiology of osteomyelitis. 10.3389/fcimb.2024.1338989
Genetically predicted causal effects of gut microbiota on spinal pain: a two-sample Mendelian randomization analysis. Frontiers in microbiology Background:Observational studies have hinted at a correlation between the gut microbiota and spinal pain (SP). However, the impact of the gut microbiota on SP remains inconclusive. Methods:In this study, we employed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between the gut microbiota and SP, encompassing neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). The compiled gut microbiota data originated from a genome-wide association study (GWAS) conducted by the MiBioGen consortium ( = 18,340). Summary data for NP were sourced from the UK Biobank, TSP from the FinnGen Biobank, and LBP from both the UK Biobank and FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. The primary analytical approach for assessing causal relationships was the Inverse Variance Weighted (IVW) method, supplemented by various sensitivity analyses to ensure result robustness. Results:The IVW analysis unveiled 37 bacterial genera with a potential causal relationship to SP. After Benjamini-Hochberg corrected test, four bacterial genera emerged with a strong causal relationship to SP. Specifically, (OR: 1.143, 95% CI 1.061-1.232, = 0.0004) and (OR: 1.145, 95% CI 1.059-1.238, = 0.0007) were identified as risk factors for LBP, while (OR: 0.859, 95% CI 0.791-0.932, = 0.0003) was marked as a protective factor for LBP, and (OR: 0.893, 95% CI 0.839-0.951, = 0.0004) was recognized as a protective factor for low back pain or/and sciatica. No significant heterogeneity or horizontal pleiotropy was observed through alternative testing methods. Conclusion:This study establishes a causal relationship between the gut microbiota and SP, shedding light on the "gut-spine" axis. These findings offer novel perspectives for understanding the etiology of SP and provide a theoretical foundation for potential interventions targeting the gut microbiota to prevent and treat SP. 10.3389/fmicb.2024.1357303
A Mendelian Randomization Study: Roles of Gut Microbiota in Sepsis - Who is the Angle? Polish journal of microbiology Gut microbiota (GM) is a crucial underlying player during sepsis pathogenesis. However, the causal relationship is unclear and remains to be determined. A two-sample Mendelian randomization study was implemented. The statistical data about sepsis together with GM summarized from genome-wide association studies were evaluated. Instrumental variables were defined as single-nucleotide polymorphisms with prominent correlations with exposure. The inverse-variance-weighted test was employed as a major approach of Mendelian randomization analysis to estimate of causal relationships. The inverse-variance-weighted analysis results demonstrated that at different taxa levels, Actinobacteria and influence sepsis. Actinobacteria had negative relationships to sepsis risk at the phylum (β = -0.34, SE = 0.10, = 0.0008) and class (β = -0.23, SE = 0.07, = 0.0011) levels in outcome coded ieu-b-69. Actinobacteria at the phylum level (β = -0.22, SE = 0.10, = 0.027) was also negatively associated with sepsis in outcome coded ieu-b-4980. at the order (β = -0.20, SE = 0.06, = 0.0021), family (β = -0.20, SE = 0.06, = 0.0021), and genus (β = -0.20, SE = 0.06, = 0.0007) levels were all negatively correlated with the risk of sepsis in outcome coded ieu-b-69. The results of the Wald ratio model showed that genus (OR (95%CI) = 0.6902[0.4907,0.9708], = 0.0331) and Gastranaerophilales order (OR (95%CI) = 0.5907[0.3516,0.9926], = 0.0468) were negatively connected with sepsis. This study implied at different taxa levels Actinobacteria and , genus, and Gastranaerophilales order have a causal relationship with sepsis, indicating that they are protective factors for the incidence of sepsis. 10.33073/pjm-2024-006
Causal relationship between gut microbiota and rheumatoid arthritis: a two-sample Mendelian randomisation study. Clinical and experimental rheumatology OBJECTIVES:To assess whether there is a bidirectional causal relationship between the composition of gut microbiota and rheumatoid arthritis (RA), and to identify specific pathogenic bacterial taxa via the Mendelian randomisation (MR) analysis. METHODS:We acquired single nucleotide polymorphisms (SNPs) associated with the composition of gut microbiota (n=18,340) and with RA (n=331,313) from publicly available genome-wide association studies (GWAS). The genome-wide threshold was 1 × 10-5 in the forward MR analysis and was 5 × 10-8 in the reverse MR analysis. Inverse variance weighted (IVW) was the main method to analyse causality, and MR results were verified by several sensitivity analyses including weighted median, MR Egger, and MR Pleiotropy Residual Sum and Outlier (PRESSO). RESULTS:The IVW method suggested that eight taxa were positively correlated with RA, including: MollicutesRF9 (pIVW <0.01), Alphaproteobacteria (pIVW <0.01), Betaproteobacteria (p IVW =0.04), Bacteroidaceae (pIVW <0.01), Adlercreutzia (pIVW <0.01), Bacteroides (pIVW <0.01), Butyricimonas (p IVW =0.03) and Holdemanella (pIVW =0.03). Six bacterial taxa were negatively correlated with RA, including Desulfovibrionales (pIVW = 0.01), Methanobacteriales (pIVW <0.01), Methanobacteria (PIVW <0.01), Desulfovibrionaceae (pIVW <0.01), Methanobacteriaceae (pIVW <0.01) and Butyrivibrio (pIVW =0.02). Heterogeneity (p>0.05) and pleiotropy (p>0.05) analysis confirmed the robustness of the MR results. CONCLUSIONS:We identified some specific bacterial taxa that were causally associated with the risk of RA, providing new insights into prevention and diagnosis of RA. 10.55563/clinexprheumatol/p9ig7c
Gut microbiota and risk of coronary heart disease: a two-sample Mendelian randomization study. Frontiers in cardiovascular medicine Background:The relationship between gut microbiota composition and coronary heart disease (CHD) has been recently reported in several observational studies. However, the causal effect of gut microbiota on coronary heart disease is uncharted. Objective:This study attempted to investigate the effect of gut microbiota on coronary heart disease by Mendelian randomization (MR) analysis. Methods:Through the two-sample MR method, single-nucleotide polymorphisms relevant to gut microbiota were selected as instrument variables to evaluate the causal association between gut microbiota and the risk of CHD. Results:According to the selection criteria of the inverse variance-weighted average method, Class Actinobacteria, Class Lentisphaeria, Family Clostridiales vadinBB60group, Genus group, Genus , Genus , Genus , Genus , and Order Victivallales, presented a suggestive association with coronary heart disease. Conclusion:This two-sample Mendelian randomization study found that gut microbiota was causally associated with coronary heart disease. Further randomized controlled trials are needed to clarify the protective effect of probiotics on coronary heart disease and their specific protective mechanisms. 10.3389/fcvm.2024.1273666
Univariable and multivariable Mendelian randomization study identified the key role of gut microbiota in immunotherapeutic toxicity. European journal of medical research BACKGROUND:In cancer patients receiving immune checkpoint inhibitors (ICIs), there is emerging evidence suggesting a correlation between gut microbiota and immune-related adverse events (irAEs). However, the exact roles of gut microbiota and the causal associations are yet to be clarified. METHODS:To investigate this, we first conducted a univariable bi-directional two-sample Mendelian randomization (MR) analysis. Instrumental variables (IVs) for gut microbiota were retrieved from the MiBioGen consortium (18,340 participants). GWAS summary data for irAEs were gathered from an ICIs-treated cohort with 1,751 cancer patients. Various MR analysis methods, including inverse variance weighted (IVW), MR PRESSO, maximum likelihood (ML), weighted median, weighted mode, and cML-MA-BIC, were used. Furthermore, multivariable MR (MVMR) analysis was performed to account for possible influencing instrumental variables. RESULTS:Our analysis identified fourteen gut bacterial taxa that were causally associated with irAEs. Notably, Lachnospiraceae was strongly associated with an increased risk of both high-grade and all-grade irAEs, even after accounting for the effect of BMI in the MVMR analysis. Akkermansia, Verrucomicrobiaceae, and Anaerostipes were found to exert protective roles in high-grade irAEs. However, Ruminiclostridium6, Coprococcus3, Collinsella, and Eubacterium (fissicatena group) were associated with a higher risk of developing high-grade irAEs. RuminococcaceaeUCG004, and DefluviitaleaceaeUCG011 were protective against all-grade irAEs, whereas Porphyromonadaceae, Roseburia, Eubacterium (brachy group), and Peptococcus were associated with an increased risk of all-grade irAEs. CONCLUSIONS:Our analysis highlights a strong causal association between Lachnospiraceae and irAEs, along with some other gut microbial taxa. These findings provide potential modifiable targets for managing irAEs and warrant further investigation. 10.1186/s40001-024-01741-7
Towards understanding the link between gut microbiota and heart failure in the heart-gut axis. European journal of preventive cardiology 10.1093/eurjpc/zwad200
Causal Relationship Between Gut Microbiota and Liver Cirrhosis: 16S rRNA Sequencing and Mendelian Randomization Analyses. Journal of clinical and translational hepatology Background and Aims:Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis. However, the role of the gut microbiota in liver cirrhosis remains unclear. Methods:We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing. We then performed a two-sample Mendelian randomization (MR) analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis. Causal relationships were analyzed using primary inverse variance weighting (IVW) and other supplemental MR methods. Furthermore, fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis. Results:Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups. IVW analyses suggested that Alphaproteobacteria, Bacillales, NB1n, Rhodospirillales, , , and were positively correlated with the risk of liver cirrhosis, whereas , , , and displayed the opposite effects. However, the weighted median and MR-PRESSO estimates further showed that only and presented stable negative associations with liver cirrhosis. No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis. Furthermore, the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of and than liver cirrhosis patients. Conclusions:Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis, which may contribute to the discovery of novel strategies to prevent liver cirrhosis. 10.14218/JCTH.2023.00259
Relationships among gut microbiota, plasma metabolites, and juvenile idiopathic arthritis: a mediation Mendelian randomization study. Frontiers in microbiology Objective:The objective of this study is to investigate the causal relationship between gut microbiota and juvenile idiopathic arthritis, and to identify and quantify the potential role of plasma metabolites as mediators. Methods:Using summary-level data from genome-wide association studies, a two-sample Mendelian randomization was conducted involving 131 gut microbiota genus, 1,400 plasma metabolites, and juvenile idiopathic arthritis. Additionally, a two-step approach was employed to quantify the proportion of the effect of gut microbiota on juvenile idiopathic arthritis mediated by plasma metabolites. Effect estimation primarily utilized Inverse Variance Weighting, with further validation using Bayesian weighted Mendelian randomization. Results:In our MR analysis, a positive correlation was observed between and the risk of juvenile idiopathic arthritis, while showed a negative correlation with juvenile idiopathic arthritis risk. Mediation analysis indicated that Furaneol sulfate levels acted as a mediator between and juvenile idiopathic arthritis, with an indirect effect proportion of 19.94, 95% CI [8.86-31.03%]. Conclusion:Our study confirms a causal relationship between specific microbial genus and juvenile idiopathic arthritis, and computes the proportion of the effect mediated by plasma metabolites, offering novel insights for clinical interventions in juvenile idiopathic arthritis. 10.3389/fmicb.2024.1363776
Association between the gut microbiota, inflammatory factors, and colorectal cancer: evidence from Mendelian randomization analysis. Frontiers in microbiology Background:Colorectal cancer (CRC) is one of the most common malignant tumors primarily affecting individuals over the age of 50 years. Recent studies have suggested that the dysbiosis of the gut microbiota, a community of microorganisms in the human gut, is closely associated with the occurrence and development of CRC. Additionally, inflammatory factors (IFs) have also been reported to play a significant role in the development of CRC. However, the causal relationships between the gut microbiota, IFs, and CRC remain unclear. Methods:In this study, we performed Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) data to explore the causal relationship between the gut microbiota, IFs, and CRC. The gut microbiota GWAS data were obtained from the MiBioGen study, while the IFs GWAS data were derived from the comprehensive analysis of three independent cohorts. Causal relationship analysis was conducted using appropriate instrumental variables (IVs) and statistical models. Results:MR analysis of the gut microbiota and CRC revealed a negative correlation between the species in the gut and CRC risk, while a positive correlation was observed between species, UCG010 genus, genus, and genus in the gut, and CRC risk. Additionally, we observed a causal relationship between IL-10 and CRC risk. These findings suggest that the dysbiosis of the gut microbiota might be associated with an increased risk of CRC and that specific bacterial groups may play a crucial role in the occurrence and development of CRC. Conclusion:Using MR analysis, this study revealed the causal relationships between the gut microbiota, IFs, and CRC. The negative correlation between the species in the gut and CRC risk, as well as the causal relationship between IL-10 and CRC, provide important clues for the potential roles of gut microbiota regulation and inflammatory factor control in the prevention and treatment of CRC. 10.3389/fmicb.2024.1309111
Causal relationship between gut and risk of sepsis: a two-sample Mendelian randomization and clinical retrospective study in the framework of predictive, preventive, and personalized medicine. The EPMA journal Objective:Gut microbiota is closely related to sepsis. Recent studies have suggested that could be associated with intestinal inflammation; however, the causal relationship between and sepsis remains uncertain. From the perspective of predictive, preventive, and personalized medicine (PPPM), exploring the causal relationship between gut and sepsis could provide opportunity for targeted prevention and personalized treatment. Methods:The genome-wide association study (GWAS) summary-level data of ( = 7738) and sepsis were obtained from the Dutch Microbiome Project and the UK Biobank (sepsis, 1380 cases; 429,985 controls). MR analysis was conducted to estimate the associations between and sepsis risk. The 16S rRNA sequencing analysis was conducted to calculate the relative abundance of in sepsis patients to explore the relationship between relative abundance and the 28-day mortality. Results:Genetic liability to f__ (OR, 1.91; CI, 1.35-2.71;  = 0.0003) was associated with a high risk of sepsis with inverse-variance weighted (IVW). The median relative abundance in non-survivors was significantly higher than in survivors (2.34% vs 0.17%,  < 0.001). Multivariate analysis confirmed that relative abundance (OR, 1.10; CI, 1.03-1.22;  = 0.027) was an independent factor of 28-day mortality in sepsis patients. ROC curve analysis indicated that relative abundance (AUC: 0.787, 95% CI: 0.671-0.902,  = 0.0003) could predict the prognosis of sepsis patients. Conclusion:Our results revealed that was causally associated with sepsis and affected the prognosis of sepsis patients. These findings may provide insights to clinicians on developing improved sepsis PPPM strategies. Supplementary Information:The online version contains supplementary material available at 10.1007/s13167-023-00340-6. 10.1007/s13167-023-00340-6
A Mendelian randomization investigation of the causal association between the gut microbiota and sleep disorders. Frontiers in microbiology Background:Increasing numbers of people are suffering from sleep disorders. The gut microbiota of these individuals differs significantly. However, no reports are available on the causal associations between specific gut microbiota and sleep disorders. Methods:Data on gut genera were obtained from the MiBioGen consortium. Twenty-four cohorts with 18,340 individuals of European origin were included. Sleep disorder data, which included 216,454 European individuals, were retrieved from the FinnGen Biobank. Subsequently, two-sample Mendelian randomization was performed to analyze associations between sleep disorders and specific components of the gut microbiota. Results:Inverse variance weighting (IVW) revealed a negative correlation between and sleep disorders (OR = 0.797, 95% CI = 0.66-0.96, and  = 0.016), a positive correlation between and sleep disorders (OR = 1.429, 95% CI = 1.03-1.98, and  = 0.032), a negative association between and sleep disorders (OR = 0.745, 95% CI = 0.56-0.98, and  = 0.038), and a negative association between and sleep disorders (OR = 0.858, 95% CI = 0.74-0.99,  = 0.039). Conclusion:A significant causal relationship was found between four specific gut microbiota and sleep disorders. One family, , was observed to increase the risk of sleep disorders, while three genera, namely, , and , could reduce the risk of sleep disorders. However, further investigations are needed to confirm the specific mechanisms by which the gut microbiota affects sleep. 10.3389/fmicb.2024.1372827
Assessing the relationship between gut microbiota and endometriosis: a bidirectional two-sample mendelian randomization analysis. BMC women's health BACKGROUND:An increasing body of observational studies have indicated an association between gut microbiota and endometriosis. However, the causal relationship between them is not yet clear. In this study, we employed Mendelian randomization method to investigate the causal relationship between 211 gut microbiota taxa and endometriosis. METHODS:Independent genetic loci significantly associated with the relative abundance of 211 gut microbiota taxa, based on predefined thresholds, were extracted as instrumental variables. The primary analytical approach employed was the IVW method. Effect estimates were assessed primarily using the odds ratio and 95% confidence intervals. Supplementary analyses were conducted using MR-Egger regression, the weighted median method, the simple mode and the weighted mode method to complement the IVW results. In addition, we conducted tests for heterogeneity, horizontal pleiotropy, sensitivity analysis, and MR Steiger to assess the robustness of the results and the strength of the causal relationships. RESULTS:Based on the IVW method, we found that the family Prevotellaceae, genus Anaerotruncus, genus Olsenella, genus Oscillospira, and order Bacillales were identified as risk factors for endometriosis, while class Melainabacteria and genus Eubacterium ruminantium group were protective factors. Additionally, no causal relationship was observed between endometriosis and gut microbiota. Heterogeneity tests, pleiotropy tests, and leave-one-out sensitivity analyses did not detect any significant heterogeneity or pleiotropic effects. CONCLUSIONS:Our MR study has provided evidence supporting a potential causal relationship between gut microbiota and endometriosis, and it suggests the absence of bidirectional causal effects. These findings could potentially offer new insights for the development of novel strategies for the prevention and treatment of endometriosis. 10.1186/s12905-024-02945-z
Causal effects between gut microbiota and pulmonary arterial hypertension: A bidirectional Mendelian randomization study. Heart & lung : the journal of critical care BACKGROUND:Multiple studies have highlighted a potential link between gut microbes and the onset of Pulmonary Arterial Hypertension (PAH). Nonetheless, the precise cause-and-effect relationship remains uncertain. OBJECTIVES:In this investigation, we utilized a two-sample Mendelian randomization (TSMR) approach to probe the presence of a causal connection between gut microbiota and PAH. METHODS:Genome-wide association (GWAS) data for gut microbiota and PAH were sourced from MiBioGen and FinnGen research, respectively. Inverse variance weighting (IVW) was used as the primary method to explore the causal effect between gut flora and PAH, supplemented by MR-Egger, weighted median (WM). Sensitivity analyses examined the robustness of the MR results. Reverse MR analysis was used to rule out the effect of reverse causality on the results. RESULTS:The results indicate that Genus Ruminococcaceae UCG004 (OR = 0.407, P = 0.031) and Family Alcaligenaceae (OR = 0.244, P = 0.014) were protective factors for PAH. Meanwhile Genus Lactobacillus (OR = 2.446, P = 0.013), Class Melainabacteria (OR = 2.061, P = 0.034), Phylum Actinobacteria (OR = 3.406, P = 0.010), Genus Victivallis (OR = 1.980, P = 0.010), Genus Dorea (OR = 3.834, P = 0.024) and Genus Slackia (OR = 2.622, P = 0.039) were associated with an increased Prevalence of PAH. Heterogeneity and pleiotropy were not detected by sensitivity analyses, while there was no reverse causality for these nine specific gut microorganisms. CONCLUSIONS:This study explores the causal effects of eight gut microbial taxa on PAH and provides new ideas for early prevention of PAH. 10.1016/j.hrtlng.2024.01.002
Causal associations between gut microbiota and cutaneous melanoma: a Mendelian randomization study. Frontiers in microbiology Background:Cutaneous melanoma (CM) of the skin stands as the leading cause of mortality among skin cancer-related deaths. Despite the successes achieved with novel therapies such as immunotherapy and targeted therapy, their efficacy remains limited, necessitating further exploration of new treatment modalities. The gut microbiota and CM may be linked, as indicated by a growing body of preclinical and observational research. Nevertheless, the exact correlation between the intestinal microbiota and CM remains to be determined. Therefore, this study aims to assess the potential causal relationship between the gut microbiota and CM. Methods:The study utilized exposure data obtained from the MiBioGen consortium's microbiome GWAS, which included a total of 18,340 samples gathered from 24 population-based cohorts. Data at the summary level for CM were acquired from the UK Biobank investigation. The main analytical strategy utilized in this research was the inverse variance weighted (IVW) technique, supported by quality assurance measures like the weighted median model, MR-Egger, simple model, and weighted model approaches. The Cochran's Q test was used to evaluate heterogeneity. To ascertain potential pleiotropy, we employed both the MR-Egger regression and the MR-PRESSO test. Sensitivity analysis was conducted using the leave-one-out method. Results:The study found that the class (OR = 0.997, 95% CI: 0.995-0.999, = 0.027), genus (OR = 0.997, 95% CI: 0.994-0.999, = 0.037), order (OR = 0.997, 95% CI: 0.995-0.999, = 0.027), and genus (OR = 0.998, 95% CI: 0.996-0.999, = 0.046) have protective effects on CM. On the order hand, the genus (OR = 1.003, 95% CI: 1-1.006, = 0.001) and phylum (OR = 1.002, 95% CI: 1-1.004, = 0.04) are identified as risk factors for CM. Conclusion:We comprehensively assessed the potential causal relationship between the gut microbiota and CM and identified associations between six gut microbiota and CM. Among these, four gut microbiota were identified as protective factors for CM, while two gut microbiota were identified as risk factors for CM. This study effectively established a causal relationship between the gut microbiota and CM, thereby providing valuable insights into the mechanistic pathways through which the microbiota impacts the progression of CM. 10.3389/fmicb.2024.1339621
Mendelian randomization suggests a causal relationship between gut microbiota and nonalcoholic fatty liver disease in humans. Medicine Targeting the gut microbiota is an emerging strategy to treat nonalcoholic fatty liver disease (NAFLD). Nonetheless, the causal relationship between specific gut microbiota and NAFLD remains unclear. We first obtained genome-wide association study statistics on gut microbiota and NAFLD from publicly available databases. We then performed the Mendelian randomization (MR) analysis to determine the potential causal relationship between the gut microbiota and NAFLD by 5 different methods, and conducted a series of sensitivity analyses to validate the robustness of the MR analysis results. Furthermore, we investigated the direction of causality by bidirectional MR analysis. For 211 gut microbiota, 2 MR methods confirmed that phylum Tenericutes, class Deltaproteobacteria and class Mollicutes were significantly associated with the risk of NAFLD. Heterogeneity (P > .05) and pleiotropy (P > .05) analyses validated the robustness of the MR results. There was no causal effect of NAFLD on these bacterial taxa in the reverse MR analysis. We identified specific gut microbiota with causal effects on NAFLD through gene prediction, which may provide useful guidance for targeting the gut microbiota to intervene and treat NAFLD. 10.1097/MD.0000000000037478
Gut Microbiota and Lung Cancer: A Mendelian Randomization Study. Zhou Huaqiang,Liu Jiaqing,Shen Jiayi,Fang Wenfeng,Zhang Li JTO clinical and research reports 10.1016/j.jtocrr.2020.100042
Causal relationship between gut microbiota with subcutaneous and visceral adipose tissue: a bidirectional two-sample Mendelian Randomization study. Frontiers in microbiology Background:Numerous studies have revealed associations between gut microbiota and adipose tissue. However, the specific functional bacterial taxa and their causal relationships with adipose tissue production in different regions of the body remain unclear. Methods:We conducted a bidirectional two-sample Mendelian Randomization (MR) study using aggregated data from genome-wide association studies (GWAS) for gut microbiota and adipose tissue. We employed methods such as inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode to assess the causal relationships between gut microbiota and subcutaneous adipose tissue (SAT) as well as visceral adipose tissue (VAT). Cochran's Q test, MR-Egger regression intercept analysis, and MR-PRESSO were used to test for heterogeneity, pleiotropy, and outliers of the instrumental variables, respectively. Reverse MR was employed to evaluate the reverse causal relationships between SAT, VAT, and gut microbiota with significant associations. Results:IVW results demonstrated that were protective factors for SAT production (OR = 0.88, 95% CI: 0.80-0.96,  = 0.005) and VAT production (OR = 0.91, 95% CI: 0.83-0.99,  = 0.030). Various bacterial taxa including (OR = 0.94, 95% CI: 0.89-0.99,  = 0.017), (OR = 0.96, 95% CI: 0.92-1.00,  = 0.029), and (OR = 0.90, 95% CI: 0.83-0.98,  = 0.012) were associated only with decreased SAT production. (OR = 1.05, 95% CI: 1.02-1.10,  = 0.005), (OR = 1.08, 95% CI: 1.01-1.15,  = 0.028), (OR = 1.08, 95% CI: 1.01-1.17,  = 0.034), and (OR = 1.05, 95% CI: 1.00-1.10,  = 0.047) were risk factors for SAT production. Meanwhile, (OR = 0.95, 95% CI: 0.91-0.99,  = 0.019), (OR = 0.93, 95% CI: 0.88-0.99,  = 0.022), and Defluviitaleaceae UCG011 (OR = 0.94, 95% CI: 0.89-0.99,  = 0.024) were protective factors for VAT production. Furthermore, (OR = 1.09, 95% CI: 1.01-1.17,  = 0.018), (OR = 1.09, 95% CI: 1.01-1.19,  = 0.037), Alloprevotella (OR = 1.05, 95% CI: 1.00-1.10,  = 0.038), and (OR = 1.07, 95% CI: 1.00-1.15,  = 0.042) were associated with VAT accumulation. Additionally, reverse MR revealed significant associations between SAT, VAT, and (IVW: OR = 1.57, 95% CI: 1.18-2.09,  = 0.002) as well as (IVW: OR = 1.14, 95% CI: 1.01-1.29,  = 0.029), both acting as risk factors. Sensitivity analyzes during bidirectional MR did not identify heterogeneity or pleiotropy. Conclusion:This study unveils complex causal relationships between gut microbiota and SAT/VAT, providing novel insights into the diagnostic and therapeutic potential of gut microbiota in obesity and related metabolic disorders. 10.3389/fmicb.2023.1285982
Association between gut microbiota and menstrual disorders: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with gynecological diseases. However, the causal relationship between gut microbiota and menstrual disorders remains to be determined. Methods:We obtained summary data of gut microbiota from the global consortium MiBio-Gen's genome-wide association study (GWAS) dataset and data on menstrual disorders from the IEU Open GWAS project. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were used to examine the causal association between gut microbiota and menstrual disorders. Thorough sensitivity studies were performed to confirm the data's horizontal pleiotropy, heterogeneity, and robustness. Results:Through MR analysis of 119 kinds of gut microbiota and 4 kinds of clinical phenotypes, it was discovered that 23 different kinds of gut microbiota were loosely connected to menstrual disorders. After FDR correction, the results showed that only Escherichia/Shigella ( = 0.00032,  = 0.0382, OR = 1.004, 95%CI = 1.002-1.006) is related to menstrual disorders. Conclusion:According to our MR Analysis, there are indications of a causal relationship between menstrual disorders and gut microbiota. This finding could lead to new discoveries into the mechanisms behind menstrual disorders and clinical research involving the microbiota. 10.3389/fmicb.2024.1321268
Association between gut microbiota and Hirschsprung disease: a bidirectional two-sample Mendelian randomization study. Frontiers in microbiology Background:Several studies have pointed to the critical role of gut microbiota (GM) and their metabolites in Hirschsprung disease (HSCR) pathogenesis. However, the detailed causal relationship between GM and HSCR remains unknown. Methods:In this study, we used two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between GM and HSCR, based on the MiBioGen Consortium's genome-wide association study (GWAS) and the GWAS Catalog's HSCR data. Reverse MR analysis was performed subsequently, and the sensitivity analysis, Cochran's Q-test, MR pleiotropy residual sum, outlier (MR-PRESSO), and the MR-Egger intercept were used to analyze heterogeneity or horizontal pleiotropy. 16S rDNA sequencing and targeted mass spectrometry were developed for initial validation. Results:In the forward MR analysis, inverse-variance weighted (IVW) estimates suggested that Eggerthella (OR: 2.66, 95%CI: 1.23-5.74, = 0.01) was a risk factor for HSCR, while Peptococcus (OR: 0.37, 95%CI: 0.18-0.73, = 0.004), Ruminococcus2 (OR: 0.32, 95%CI: 0.11-0.91, = 0.03), Clostridiaceae1 (OR: 0.22, 95%CI: 0.06-0.78, = 0.02), Mollicutes RF9 (OR: 0.27, 95%CI: 0.09-0.8, = 0.02), Ruminococcaceae (OR: 0.16, 95%CI: 0.04-0.66, = 0.01), and Paraprevotella (OR: 0.45, 95%CI: 0.21-0.98, = 0.04) were protective factors for HSCR, which had no heterogeneity or horizontal pleiotropy. However, reverse MR analysis showed that HSCR (OR: 1.02, 95%CI: 1-1.03, = 0.049) is the risk factor for Eggerthella. Furthermore, some of the above microbiota and short-chain fatty acids (SCFAs) were altered in HSCR, showing a correlation. Conclusion:Our analysis established the relationship between specific GM and HSCR, identifying specific bacteria as protective or risk factors. Significant microbiota and SCFAs were altered in HSCR, underlining the importance of further study and providing new insights into the pathogenesis and treatment. 10.3389/fmicb.2024.1366181
The causal relationship between gut microbiota and neuroblastoma: a bidirectional Mendelian randomization analysis and meta-analysis. Microbiology spectrum Neuroblastoma (NB) is a type of neuroectodermal tumor that originates from primitive sympathetic ganglion cells. Although many risk factors contributing to the occurrence of NB have been reported in recent years, the role of the gut microbiota in its development remains unclear. A bidirectional Mendelian randomization (MR) analysis was conducted to elucidate the causal relationship between the gut microbiota and NB. In the MR analysis, we employed the inverse-variance weighted (IVW) method as the primary criterion for assessing causality, while also utilizing three additional approaches, including MR-Egger, weighted median model, and weighted mode, for comprehensive evaluation. For gut microbiota that were causally associated with NB, a reverse MR was also used to assess the stability of this causal relationship. Finally, we also used external cohorts for validation and performed a meta-analysis of the results. The IVW results indicated a causal relationship between six gut microbiota and NB. Among the six gut microbiota, genus [IVW odds ratio (OR): 2.66, 95% confidence interval (CI): 1.09-6.51, value: 0.03] exhibited a detrimental effect against NB. On the other hand, the class (IVW OR: 0.24, 95% CI: 0.07-0.77, value: 0.02), the family (IVW OR: 0.40, 95% CI: 0.17-0.96, value: 0.04), the genus (IVW OR: 0.50, 95% CI: 0.25-0.97, value: 0.04), the genus (IVW OR: 0.39, 95% CI: 0.16-0.92, value: 0.03), and the genus (IVW OR: 0.55, 95% CI: 0.31-0.97, value: 0.04) displayed a protective effect on NB. A reverse MR analysis did not reveal a causality between NB and the six gut microbiota. Meta-analysis showed that genus (meta OR: 0.41, 95% CI: 0.22-0.75, < 0.01) and genus (meta OR: 2.20, 95% CI: 1.01-4.79, < 0.05) were still significant. IMPORTANCE:Bidirectional Mendelian randomization was used to explore the causality between gut microbiota and neuroblastoma (NB). The results showed that there is a causal relationship between the six gut microbiota and NB, of which two gut microbiota were further confirmed in the meta-analysis. This may provide a new perspective on the prevention and treatment of NB. 10.1128/spectrum.03656-23
Dissecting the association between gut microbiota and hypertrophic scarring: a bidirectional Mendelian randomization study. Frontiers in microbiology Hypertrophic scars affect a significant number of individuals annually, giving rise to both cosmetic concerns and functional impairments. Prior research has established that an imbalance in the composition of gut microbes, termed microbial dysbiosis, can initiate the progression of various diseases through the intricate interplay between gut microbiota and the host. However, the precise nature of the causal link between gut microbiota and hypertrophic scarring remains uncertain. In this study, after compiling summary data from genome-wide association studies (GWAS) involving 418 instances of gut microbiota and hypertrophic scarring, we conducted a bidirectional Mendelian randomization (MR) to investigate the potential existence of a causal relationship between gut microbiota and the development of hypertrophic scar and to discern the directionality of causation. By utilizing MR analysis, we identified seven causal associations between gut microbiome and hypertrophic scarring, involving one positive and six negative causal directions. Among them, , , , , , and act as protective factors against hypertrophic scarring, while suggests a potential role as a risk factor for hypertrophic scars. Additionally, sensitivity analyses of these results revealed no indications of heterogeneity or pleiotropy. The findings of our MR study suggest a potential causative link between gut microbiota and hypertrophic scarring, opening up new ways for future mechanistic research and the exploration of nanobiotechnology therapies for skin disorders. 10.3389/fmicb.2024.1345717
Pancreatitis affects gut microbiota via metabolites and inflammatory cytokines: an exploratory two-step Mendelian randomisation study. Molecular genetics and genomics : MGG Previous studies have observed relationships between pancreatitis and gut microbiota; however, specific changes in gut microbiota abundance and underlying mechanisms in pancreatitis remain unknown. Metabolites are important for gut microbiota to fulfil their biological functions, and changes in the metabolic and immune environments are closely linked to changes in microbiota abundance. We aimed to clarify the mechanisms of gut-pancreas interactions and explore the possible role of metabolites and the immune system. To this end, we conducted two-sample Mendelian randomisation (MR) analysis to evaluate the casual links between four different types of pancreatitis and gut microbiota, metabolites, and inflammatory cytokines. A two-step MR analysis was conducted to further evaluate the probable mediating pathways involving metabolites and inflammatory cytokines in the causal relationship between pancreatitis and gut microbiota. In total, six potential mediators were identified in the causal relationship between pancreatitis and gut microbiota. Nineteen species of gut microbiota and seven inflammatory cytokines were genetically associated with the four types of pancreatitis. Metabolites involved in glucose and amino acid metabolisms were genetically associated with chronic pancreatitis, and those involved in lipid metabolism were genetically associated with acute pancreatitis. Our study identified alterations in the gut microbiota, metabolites, and inflammatory cytokines in pancreatitis at the genetic level and found six potential mediators of the pancreas-gut axis, which may provide insights into the precise diagnosis of pancreatitis and treatment interventions for gut microbiota to prevent the exacerbation of pancreatitis. Future studies could elucidate the mechanism underlying the association between pancreatitis and the gut microbiota. 10.1007/s00438-024-02125-6
Mendelian randomization reveals association of gut microbiota with Henoch-Schönlein purpura and immune thrombocytopenia. International journal of hematology Gut microbiota have been linked to immune thrombocytopenia (ITP) and Henoch-Schönlein purpura (HSP) in recent studies, but a cause-and-effect relationship is unclear. We used Mendelian randomization (MR) to assess causal relationships between gut microbiota and HSP/ITP using summary statistics from the GWAS dataset of the international MiBioGen and FinnGen consortium. The IVW method was used as the main evaluation indicator. MR analysis of 196 intestinal flora and HSP/ITP/sTP phenotypes showed that 12 flora were potentially causally associated with ITP, 6 with HSP, and 9 with sTP. The genes predicted that genus Coprococcus3 (p = 0.0264, OR = 2.05, 95% CI 1.09-3.88)and genus Gordonibacter (p = 0.0073, OR = 1.38; 95% CI 1.09-1.75) were linked to a higher likelihood of developing ITP. Additionally, family Actinomycetaceae (p = 0.02, OR = 0.51, 95% CI 0.28-0.90) and order Actinomycetales (p = 0.0199, OR = 0.50, 95% CI 0.28-0.90) linked to reduced HSP risk. Genus Ruminococcaceae UCG013 (p = 0.0426, OR = 0.44, 95% CI 0.20-0.97) negatively correlated with sTP risk. Our MR analyses offer evidence of a possible cause-and-effect connection between certain gut microbiota species and the likelihood of HSP/ITP. 10.1007/s12185-024-03777-1
A Bidirectional Mendelian Randomization Study of Gut Microbiota and Cerebral Small Vessel Disease. The Journal of nutrition BACKGROUND:The causal nature of gut microbiota and cerebral small vessel disease (CSVD) is still obscure regardless of evidence supporting their observational correlations. OBJECTIVES:The primary objective of this research is to investigate the potentially pathogenic or protective causal impacts of specific gut microbiota on various neuroimaging subtypes of CSVD. METHODS:We obtained the latest summary-level genome-wide databases for gut microbiota and 9 CSVD traits. The univariable and multivariable Mendelian randomization (MR) studies were conducted to examine the possible causal link between exposure and outcome. Meanwhile, we conducted sensitivity analyses sequentially, containing the heterogeneity, pleiotropy, and leave-one-out analysis. Additionally, to clarify the potential bidirectional causality, the causality from CSVD traits to the identified gut microbiota was implemented through reverse MR analysis. RESULTS:The univariable MR analysis identified 22 genetically predicted bacterial abundances that were correlated with CSVD traits. Although conditioning on macronutrient dietary compositions, 2 suggestive relationships were retained using the multivariable MR analysis. Specifically, the class Negativicutes and order Selenomonadales exhibited a negative causal association with strictly lobar cerebral microbleeds, one neuroimaging trait of CSVD. There is insufficient evidence indicating the presence of heterogeneity and horizontal pleiotropy. Furthermore, the identified causal relationship was not driven by any single nucleotide polymorphism. The results of the reverse MR analysis did not reveal any statistically significant causality from CSVD traits to the identified gut microbiota. CONCLUSIONS:Our study indicated several suggestive causal effects from gut microbiota to different neuroimaging subtypes of CSVD. These findings provided a latent understanding of the pathogenesis of CSVD from the perspective of the gut-brain axis. 10.1016/j.tjnut.2024.04.024
Causal link between gut microbiota and osteoporosis analyzed via Mendelian randomization. European review for medical and pharmacological sciences OBJECTIVE:Osteoporosis (OP) is closely associated with gut microbiota (GM), yet the nature of their causal relationship remains elusive. Therefore, this study aims to reverse causality between GM and OP by using population cohorts and two-sample MR (TSMR) analysis. MATERIALS AND METHODS:In this study, we conducted an extensive genome-wide association study (GWAS) using publicly accessible summary statistics data for GM and OP. Employing rigorous criteria (p < 1*e-5), we identified independent genetic loci that exhibited significant associations with GM relative abundances as instrumental variables (IVs). A causal evaluation was primarily carried out using the inverse variance-weighted (IVW) method, supplemented by additional analyses such as MR-Egger, weighted median, simple mode, and weighted mode. RESULTS:We unveiled that increased abundances of the family Pasteurellaceae, order Pasteurellales, and genus Ruminococcaceae UCG004 were linked to an increased risk of OP. Conversely, the family Oxalobacteraceae, unknown family id.1000006161, genus Lachnospiraceae NK4A136 group, unknown genus id.1000006162, and order NB1n were associated with a reduced risk of OP. To ensure the reliability of our findings, we conducted quality assessments through Cochrane's Q test and a leave-one-out analysis. Furthermore, the stability and consistency of the results were confirmed by the MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, and sensitivity analysis (p > 0.05). Our study reveals the causal relationships between 211 GM taxa and OP, pinpointing specific GM taxa associated with the risk of OP. This research sheds light on the genetic mechanisms that underlie GM-mediated OP and opens up promising avenues for identifying valuable biomarkers and potential therapeutic targets in future OP research. CONCLUSIONS:This study establishes a substantial GM-OP link with specific taxa being identified, offering biomarkers for early detection, tailored interventions, and improved patient education. These findings enhance OP diagnosis, prevention, and treatment, promising more effective, individualized care and inspiring future research. 10.26355/eurrev_202401_35052
Associations between gut microbiota and gynecological cancers: A bi-directional two-sample Mendelian randomization study. Medicine Growing evidence has suggested that gut microbiota is associated with gynecologic cancers. However, whether there is a causal relationship between these associations remains to be determined. A two-sample Mendelian randomization (MR) evaluation was carried out to investigate the mechanism associating gut microbiota and 3 prevalent gynecological cancers, ovarian cancer (OC), endometrial cancer, and cervical cancer as well as their subtypes in individuals of European ancestry. The Genome-wide association studies statistics, which are publically accessible, were used. Eligible instrumental single nucleotide polymorphisms that were significantly related to the gut microbiota were selected. Multiple MR analysis approaches were carried out, including inverse variance weighted, MR-Egger, Weighted Median methods, and a range of sensitivity analyses. Lastly, we undertook a reverse MR analysis to evaluate the potential of reverse causality. We sifted through 196 bacterial taxa and identified 33 suggestive causal relationships between genetic liability in the gut microbiota and gynecological cancers. We found that 11 of these genera could be pathogenic risk factors for gynecological cancers, while 19 could lessen the risk of cancer. In the other direction, gynecological cancers altered gut microbiota composition. Our MR analysis revealed that the gut microbiota was causally associated with OC, endometrial cancer, and cervical cancer. This may assist in providing new insights for further mechanistic and clinical studies of microbiota-mediated gynecological cancer. 10.1097/MD.0000000000037628
Ischaemic stroke patients present sex differences in gut microbiota. European journal of neurology BACKGROUND:Gut microbiota plays a role in the pathophysiology of ischaemic stroke (IS) through the bidirectional gut-brain axis. Nevertheless, little is known about sex-specific microbiota signatures in IS occurrence. METHODS:A total of 89 IS patients and 12 healthy controls were enrolled. We studied the taxonomic differences of the gut microbiota between men and women with IS by shotgun metagenomic sequencing. To evaluate the causal effect of several bacteria on IS risk, we performed a two-sample Mendelian randomisation (MR) with inverse-variance weighting (IVW) using genome-wide association analysis (GWAS) summary statistics from two cohorts of 5959 subjects with genetic and microbiota data and 1,296,908 subjects with genetic and IS data, respectively. RESULTS:α-Diversity analysis measured using Observed Species (p = 0.017), Chao1 (p = 0.009) and Abundance-based Coverage Estimator (p = 0.012) indexes revealed that IS men have a higher species richness compared with IS women. Moreover, we found sex-differences in IS patients in relation to the phylum Fusobacteria, class Fusobacteriia, order Fusobacteriales and family Fusobacteriaceae (all Bonferroni-corrected p < 0.001). MR confirmed that increased Fusobacteriaceae levels in the gut are causally associated with an increased risk of IS (IVW p = 0.02, β = 0.32). CONCLUSIONS:Our study is the first to indicate that there are gut microbiome differences between men and women with IS, identifying high levels of Fusobacteriaceae in women as a specific risk factor for IS. Incorporating sex stratification analysis is important in the design, analysis and interpretation of studies on stroke and the gut microbiota. 10.1111/ene.15931
Causal relationships between gut microbiota, immune cell, and Non-small cell lung cancer: a two-step, two-sample Mendelian randomization study. Journal of Cancer Regulating the immune system is a crucial measure of gut microbiota (GM) that influences the development of diseases. The causal role of GM on Non-small cell lung cancer (NSCLC) and whether it can be mediated by immune cells is still unknown. We performed a two-step, two-sample Mendelian randomization study with an Inverse variance weighted (IVW) approach to investigate the causal role of GM on NSCLC and the mediation effect of immune cells between the association of GM and NSCLC. MR analyses determined the protective effects of 6 genera on NSCLC (Bacteroides, Roseburia, Alistipes, Methanobrevibacter, Ruminococcus gauvreauii group, and Peptococcus). In addition, 38 immune cell traits were suggestively associated with NSCLC. Of note, the mediation MR illustrated the causal role of Genus-Peptococcus on NSCLC (Total effect IVW: OR = 0.790, 95% CI [0.657, 0.950], P = 0.012) was to a large proportion mediated by CD45 on HLA DR CD4 in TBNK panel (-034 (95% CI [-0.070, -0.005]; P = 0.037), accounting for 14.4% of Total effect). The study suggested a causal relationship between GM and NSCLC, which may be mediated by immune cells. 10.7150/jca.92699
Roles of 21 Genera of Human Gut Microbiota in Barrett's Esophagus Risk: A Mendelian Randomization Study. Frontiers in genetics Lack of definitive evidence supports the putative hypothesis that gut microbiota dysbiosis is associated with Barrett's esophagus (BE). We conducted a two-sample Mendelian randomization study to assess the associations of 21 genera of human gut microbiota with BE. We identified independent genetic instruments for 21 genera of gut microbiota (including nine dominant genera, four core genera among individuals of European ancestry, and eight esophagus-specific genera of gut microbiota) from MiBioGen (up to 18,340 participants). We applied them to summary statistics from the largest publicly available genome-wide association study on BE (9,680 cases and 31,211 controls). We obtained the causal estimates of genetically predicted higher genera of gut microbiota and BE using the inverse variance weighting method. Sensitivity analyses included weighted median, MR-Egger, MR-RAPS, and MR-PRESSO. We found that genetically predicted higher (OR: 0.76 per unit increase in log odds of having BE, 95% CI: 0.70-0.83) and higher (OR: 0.75, 95% CI: 0.63-0.90) were significantly associated with a lower risk of BE. No associations of other genera of gut microbiota with BE were noted, apart from suggestive associations of higher (OR: 0.77; 95% CI: 0.61-0.99), higher (OR: 0.89; 95% CI: 0.80-0.99), and higher (OR: 0.76; 95% CI: 0.56-1.02) with a lower risk of BE, and higher (OR: 1.15; 95% CI: 0.99-1.33) with a higher risk of BE. This study suggests that higher and higher might protect against BE. 10.3389/fgene.2022.894900
Causal relationship between gut microbiota and chronic renal failure: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Observational studies and some experimental investigations have indicated that gut microbiota are closely associated with the incidence and progression of chronic renal failure. However, the causal relationship between gut microbiota and chronic renal failure remains unclear. The present study employs a two-sample Mendelian randomization approach to infer the causal relationship between gut microbiota and chronic renal failure at the genetic level. This research aims to determine whether there is a causal effect of gut microbiota on the risk of chronic renal failure, aiming to provide new evidence to support targeted gut therapy for the treatment of chronic renal failure. Methods:Employing genome-wide association study (GWAS) data from the public MiBioGen and IEU OpenGWAS platform, a two-sample Mendelian randomization analysis was conducted. The causal relationship between gut microbiota and chronic renal failure was inferred using five different methods: Inverse Variance Weighted, MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. The study incorporated sensitivity analyses that encompassed evaluations for pleiotropy and heterogeneity. Subsequently, the results of the Mendelian randomization analysis underwent a stringent correction for multiple testing, employing the False Discovery Rate method to enhance the validity of our findings. Results:According to the results from the Inverse Variance Weighted method, seven bacterial genera show a significant association with the outcome variable chronic renal failure. Of these, Ruminococcus (gauvreauii group) (OR = 0.82, 95% CI = 0.71-0.94, = 0.004) may act as a protective factor against chronic renal failure, while the genera Escherichia-Shigella (OR = 1.22, 95% CI = 1.08-1.38, = 0.001), Lactococcus (OR = 1.1, 95% CI = 1.02-1.19, = 0.013), Odoribacter (OR = 1.23, 95% CI = 1.03-1.49, = 0.026), Enterorhabdus (OR = 1.14, 95% CI = 1.00-1.29, = 0.047), Eubacterium (eligens group) (OR = 1.18, 95% CI = 1.02-1.37, = 0.024), and Howardella (OR = 1.18, 95% CI = 1.09-1.28, < 0.001) may be risk factors for chronic renal failure. However, after correction for multiple comparisons using False Discovery Rate, only the associations with Escherichia-Shigella and Howardella remain significant, indicating that the other genera have suggestive associations. Sensitivity analyses did not reveal any pleiotropy or heterogeneity. Conclusion:Our two-sample Mendelian randomization study suggests that the genera Escherichia-Shigella and Howardella are risk factors for chronic renal failure, and they may serve as potential targets for future therapeutic interventions. However, the exact mechanisms of action are not yet clear, necessitating further research to elucidate their precise roles fully. 10.3389/fmicb.2024.1356478
Roles of gut microbiota in androgenetic alopecia: insights from Mendelian randomization analysis. Frontiers in microbiology Background:Androgenetic alopecia (AGA) is the most common type of androgen-associated hair loss. Previous studies have indicated an association between the gut microbiota and AGA. To delve deeper, we executed a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between the gut microbiota and AGA. Methods:A two-sample MR investigation was utilized to delve into the intricate interplay between gut microbiota and AGA. Information regarding 211 gut microbial taxa was sourced from the MiBioGen consortium. The summary statistics of the genome-wide association studies (GWAS) for AGA were obtained from the FinnGen biobank, which included 195 cases and 201,019 controls. Various analytical approaches, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were employed to evaluate the causal impact of gut microbiota on AGA. Sensitivity analyses were subsequently conducted to affirm the robustness of the findings. Results:A two-sample MR investigation unveiled the genus , genus , and genus were identified as risk factors associated with AGA. In contrast, the family and genus , along with the genus 9, demonstrated a protective effect. The sensitivity analyses provided additional assurance that the findings of the current study were less susceptible to the influence of confounding variables and biases. Conclusion:The MR study has established a link between specific gut microbiota and AGA, offering evidence for the identification of more precisely targeted probiotics. This discovery has the potential to aid in the prevention, control, and reversal of AGA progression. 10.3389/fmicb.2024.1360445
Causal effects of the gut microbiome on COVID-19 susceptibility and severity: a two-sample Mendelian randomization study. Frontiers in immunology Background:The coronavirus disease 2019 (COVID-19) caused a global pandemic, with potential severity. We aimed to investigate whether genetically predicted gut microbiome is associated with susceptibility and severity of COVID-19 risk. Methods:Mendelian randomization (MR) analysis of two sets with different significance thresholds was carried out to infer the causal relationship between the gut microbiome and COVID-19. SNPs associated with the composition of the gut microbiome (n = 5,717,754) and with COVID-19 susceptibility (n = 14,328,058), COVID-19 severity (n = 11,707,239), and COVID-19 hospitalization (n = 12,018,444) from publicly available genome-wide association studies (GWAS). The random-effect inverse variance weighted (IVW) method was used to determine causality. Three more MR techniques-MR Egger, weighted median, and weighted mode-and a thorough sensitivity analysis were also used to confirm the findings. Results:IVW showed that 18 known microbial taxa were causally associated with COVID-19. Among them, six microbial taxa were causally associated with COVID-19 susceptibility; seven microbial taxa were causally associated with COVID-19 severity ; five microbial taxa were causally associated with COVID-19 hospitalization. Sensitivity analyses showed no evidence of pleiotropy or heterogeneity. Then, the predicted 37 species of the gut microbiome deserve further study. Conclusion:This study found that some microbial taxa were protective factors or risky factors for COVID-19, which may provide helpful biomarkers for asymptomatic diagnosis and potential therapeutic targets for COVID-19. 10.3389/fimmu.2023.1173974
Evidence for genetic causal relationships between gut microbiome, metabolites, and myasthenia gravis: a bidirectional Mendelian randomization study. Frontiers in immunology Background:Myasthenia gravis (MG) is an autoimmune disease observed to have connections with gut microbiome. We aimed to systematically assess the causal relationships between gut microbiome, gut microbiome-derived metabolites, and MG using Mendelian randomization (MR) approach. Methods:Summary-level genetic datasets from large-scale genome-wide association studies regarding 196 gut microbial taxa from the MiBioGen consortium (n=18,340), 72 derived metabolites from the TwinsUK and KORA studies (n=7,824), and antiacetylcholine receptor (AChR) antibody-positive MG (case=1,873, control=36,370) were employed for MR causal estimates. The inverse-variance weighted (IVW) method was utilized as the main analysis with MR-Egger, maximum likelihood, simple mode, and weighted median as complements. The tests of Cochran's Q, MR-Egger intercept, Steiger, MR-PRESSO and leave-one-out were implemented for sensitivity analyses. Results:The forward MR estimates of IVW revealed significant causal associations of the abundance of phylum Actinobacteria, class Gammaproteobacteria, family Defluviitaleac, family Family XIII, and family Peptococcaceae with a reduced risk of MG. Conversely, the abundance of phylum Lentisphaerae, order Mollicutes RF9, order Victivallales, and genus Faecalibacterium was causally associated with an increased risk of MG. The reversed MR analysis proved negative causal correlations between the MG and the abundance of family Peptostreptococcaceae, genus Romboutsia, and genus Subdoligranulum. Regarding the derived metabolites, the IVW estimates revealed that elevated levels of beta-hydroxyisovalerate and methionine were causally associated with a decreased risk of MG, while increased levels of choline and kynurenine were linked to an increased risk of MG. Furthermore, genetically predicted MG was associated with a decreased level of cholesterol. The results obtained from complementary MR methods were similar. These findings remained robust in all sensitivity analyses. Conclusion:Our MR findings support the causal effects of specific gut microbiome taxa and derived metabolites on AChR antibody-positive MG, and vice versa, yielding novel insights into prevention and therapy targets of MG. Future studies may be warranted for validation and pursuing the precise mechanisms. 10.3389/fimmu.2023.1279845
Causal relationship between gut microbiota and myasthenia gravis: a two-sample Mendelian randomization study. Frontiers in neurology Background:Previous observational studies have provided cumulative data linking gut microbiota to myasthenia gravis (MG). However, the causal link between the two remains unexplored. Hence, the current study was performed to explore the causal link between them. Methods:Mendelian randomization (MR) analysis was conducted using the summary statistics of 211 gut microbiota taxa and the largest genome-wide association studies (GWAS) for MG currently available. The inverse variance-weighted (IVW), MR-Egger, weighted median, and weighted mode methods were employed to ascertain the causal influence. Sensitivity studies utilizing several methodologies were then used to assess the robustness of the findings. Lastly, to evaluate reverse causality, a reverse MR analysis was performed. Results:Seven suggestive causal associations between the gastrointestinal microbiota and MG were identified based on the outcomes of the MR analysis. Specifically, phylum Actinobacteria (OR: 0.602, 95% CI: 0.405-0.896,  = 0.012), class Gammaproteobacteria (OR: 0.587, 95% CI: 0.357-0.968,  = 0.037), and families (OR: 0.695, 95% CI: 0.485-0.996,  = 0.047), (OR: 0.614, 95% CI: 0.412-0.916,  = 0.017), and (OR: 0.698, 95% CI: 0.505-0.964,  = 0.029) had suggestive protective effects on MG, while order Mollicutes RF9 (OR: 1.424, 95% CI: 1.015-1.998,  = 0.041) and genus (OR: 1.763, 95% CI: 1.220-2.547,  = 0.003) were suggestive risk factors for MG. The outcomes indicate that neither heterogeneity nor horizontal pleiotropy had any discernible impact. Nevertheless, this reverse analysis did not reveal any apparent effect of MG on the gut microbiota composition. Conclusion:The MR investigation has substantiated the suggestive causal connection between gut microbiota and MG, which may provide helpful insights for innovative therapeutic and preventative approaches for MG. Further randomized controlled trials are needed to elucidate the gut microbiota's precise role and therapeutic potential in the pathogenesis of MG. 10.3389/fneur.2024.1309530
Exploring the causal effects of the gut microbiome on serum lipid levels: A two-sample Mendelian randomization analysis. Frontiers in microbiology Background:The gut microbiome was reported to be associated with dyslipidemia in previous observational studies. However, whether the composition of the gut microbiome has a causal effect on serum lipid levels remains unclear. Objective:A two-sample Mendelian randomization (MR) analysis was conducted to investigate the potential causal relationships between gut microbial taxa and serum lipid levels, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and log-transformed triglyceride (TG) levels. Materials and methods:Summary statistics of genome-wide association studies (GWASs) for the gut microbiome and four blood lipid traits were obtained from public datasets. Five recognized MR methods were applied to assess the causal estimates, among which, the inverse-variance weighted (IVW) regression was used as the primary MR method. A series of sensitivity analyses were performed to test the robustness of the causal estimates. Results:The combined results from the five MR methods and sensitivity analysis showed 59 suggestive causal associations and four significant causal associations. In particular, genus was associated with higher LDL-C (  = 3.01 × 10) and TC levels (  = 2.11 × 10), phylum was correlated with higher LDL-C level (  = 4.10 × 10), and genus was associated with lower TG level (  = 2.19 × 10). Conclusion:This research may provide novel insights into the causal relationships of the gut microbiome on serum lipid levels and new therapeutic or prevention strategies for dyslipidemia. 10.3389/fmicb.2023.1113334
The causal relationship between gut microbiota and COVID-19: A two-sample Mendelian randomization analysis. Medicine Recent studies have shown that gut microbiota is associated with coronavirus disease 2019 (COVID-19). However, the causal impact of the gut microbiota on COVID-19 remains unclear. We performed a bidirectional Mendelian randomization. The summary statistics on the gut microbiota from the MiBioGen consortium. Summary statistics for COVID-19 were obtained from the 6th round of the COVID-19 Host Genetics Initiative genome-wide association study meta-analysis. Inverse variance weighting was used as the main method to test the causal relationship between gut microbiota and COVID-19. Reverse Mendelian randomization analysis was performed. Mendelian randomization analysis showed that Intestinimas.id.2062 was associated with an increased risk of severe COVID-19. Bifidobacterium.id.436, LachnospiraceaeUCG010.id.11330, RikenellaceaeRC9gutgroup.id.11191 increase the risk of hospitalized COVID-19. RuminococcaceaeUCG014.id.11371 shows the positive protection on hospitalized COVID-19. There is no causal relationship between gut microbiota and infection with COVID-19. According to the results of reverse Mendelian randomization analysis, no significant causal effect of COVID-19 on gut microbiota was found. The study found that gut microbiota with COVID-19 has a causal relationship. This study provides a basis for the theory of the gut-lung axis. Further randomized controlled trials are needed to clarify the protective effect of probiotics against COVID-19 and the specific protective mechanisms. This study has important implications for gut microbiota as a nondrug intervention for COVID-19. 10.1097/MD.0000000000036493
Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study. Frontiers in microbiology Background:Evidence from previous studies have implicated an important association between gut microbiota (GM) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but whether there is a definite causal relationship between GM and ME/CFS has not been elucidated. Method:This study obtained instrumental variables of 211 GM taxa from the Genome Wide Association Study (GWAS), and mendelian randomization (MR) study was carried out to assess the effect of gut microbiota on ME/CFS risk from UK Biobank GWAS (2076 ME/CFS cases and 460,857 controls). Inverse variance weighted (IVW) was the primary method to analyze causality in this study, and a series of sensitivity analyses was performed to validate the robustness of the results. Results:The inverse variance weighted (IVW) method indicated that genus (OR:1.001, 95%CI:1.000-1.003, value of < 0.05) and (OR 1.003, 95% CI 1.000 to 1.005, value of < 0.05) were positively associated with ME/CFS risk. Results from the weighted median method supported genus (OR 1.003, 95% CI 1.000 to 1.005, value of < 0.05) as a risk factor for ME/CFS. Conclusion:This study reveals a causal relationship between genus , genus and ME/CFS, and our findings provide novel insights for further elucidating the developmental mechanisms mediated by the gut microbiota of ME/CFS. 10.3389/fmicb.2023.1190894
Causal relationship between gut microbiota and hidradenitis suppurativa: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Accumulating evidence suggests that alterations in gut microbiota composition are associated with the hidradenitis suppurativa (HS). However, the causal association between gut microbiota and HS remain undetermined. Methods:We performed a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study summary data of gut microbiota and hidradenitis suppurativa from the MiBioGen consortium which concluded 18,340 individuals analyzed by the MiBioGen Consortium, comprising 211 gut microbiota. HS data were acquired from strictly defined HS data collected by FinnGenbiobank analysis, which included 211,548 European ancestors (409 HS patients, 211,139 controls). The inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model, weighted median, and MR-Egger were used to determine the changes of HS pathogenic bacterial taxa, followed by sensitivity analysis including horizontal pleiotropy analysis. The MR Steiger test evaluated the strength of a causal association and the leave-one-out method assessed the reliability of the results. Additionally, a reverse MR analysis was carried out to seek for possible reverse causality. Results:By combining the findings of all the MR steps, we identified four causal bacterial taxa, namely, Family XI, Porphyromonadaceae, group and Lachnospira. The risk of HS might be positively associated with a high relative abundance of group (Odds ratio, OR 2.17,  = 0.00038) and Lachnospira (OR 2.45,  = 0.017) but negatively associated with Family XI (OR 0.67,  = 0.049) and Porphyromonadaceae (OR 0.29,  = 0.014). There were no noticeable outliers, horizontal pleiotropy, or heterogeneity. Furthermore, there was no proof of reverse causation found in the reverse MR study. Conclusion:This study indicates that group and Lachnospira might have anti-protective effect on HS, whereas Family XI and Porphyromonadaceae might have a protective effect on HS. Our study reveals that there exists a beneficial or detrimental causal effect of gut microbiota composition on HS and offers potentially beneficial methods for therapy and avoidance of HS. 10.3389/fmicb.2024.1302822
Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer. Scientific reports The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC. We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n = 3890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results. Initial MR analysis suggested that a higher abundance of Bifidobacterium and presence of an unclassified group of bacteria within the Bacteroidales order in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits. Whilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality. 10.1038/s41598-023-31840-0
Altered Gut Microbiota as a Potential Risk Factor for Coronary Artery Disease in Diabetes: A Two-Sample Bi-Directional Mendelian Randomization Study. International journal of medical sciences The current body of research points to a notable correlation between an imbalance in gut microbiota and the development of type 2 diabetes mellitus (T2D) as well as its consequential ailment, coronary artery disease (CAD). The complexities underlying the association, especially in the context of diabetic coronary artery disease (DCAD), are not yet fully understood, and the causal links require further clarification. In this study, a bidirectional Mendelian randomization (MR) methodology was utilized to explore the causal relationships between gut microbiota, T2D, and CAD. By analyzing data from the DIAGRAM, GERA, UKB, FHS, and mibioGen cohorts and examining GWAS databases, we sought to uncover genetic variants linked to T2D, CAD, and variations in gut microbiota and metabolites, aiming to shed light on the potential mechanisms connecting gut microbiota with DCAD. Our investigation uncovered a marked causal link between the presence of and an increased incidence of both T2D and CAD. Specifically, a ten-unit genetic predisposition towards T2D was found to be associated with a 6.1% higher probability of an increase in the family's presence (β = 0.061, 95% CI = 0.002-0.119). In a parallel finding, an augmented presence of was related to an 8.2% heightened genetic likelihood of CAD (β = 0.082, 95% CI = 0.026-0.137). This evidence indicates a critical pathway by which T2D can potentially raise the risk of CAD via alterations in gut microbiota. Additionally, our analyses reveal a connection between CAD risk and , thus providing fresh perspectives on the roles of TMAO and carnitine in the etiology of CAD. The data also suggest a direct causal relationship between increased levels of certain metabolites - , , , and - and the prevalence of both T2D and CAD. Sensitivity assessments reinforce the notion that changes in could pose a risk for DCAD. There is also evidence to suggest that DCAD may, in turn, affect the gut microbiota's makeup. Notably, a surge in serum TMAO levels in individuals with CAD, coinciding with a reduced presence of methanogens, has been identified as a potentially significant factor for future examination. 10.7150/ijms.92131
Gut microbiome causal impacts on the prognosis of breast cancer: a Mendelian randomization study. BMC genomics BACKGROUND:Growing evidence has shown that gut microbiome composition is associated with breast cancer (BC), but the causality remains unknown. We aimed to investigate the link between BC prognosis and the gut microbiome at various oestrogen receptor (ER) statuses. METHODS:We performed a genome-wide association study (GWAS) to analyse the gut microbiome of BC patients, the dataset for which was collected by the Breast Cancer Association Consortium (BCAC). The analysis was executed mainly via inverse variance weighting (IVW); the Mendelian randomization (MR) results were verified by heterogeneity tests, sensitivity analysis, and pleiotropy analysis. RESULTS:Our findings identified nine causal relationships between the gut microbiome and total BC cases, with ten and nine causal relationships between the gut microbiome and ER-negative (ER-) and ER-positive (ER+) BC, respectively. The family Ruminococcaceae and genus Parabacteroides were most apparent among the three categories. Moreover, the genus Desulfovibrio was expressed in ER- BC and total BC, whereas the genera Sellimonas, Adlercreutzia and Rikenellaceae appeared in the relationship between ER + BC and total BC. CONCLUSION:Our MR inquiry confirmed that the gut microbiota is causally related to BC. This further explains the link between specific bacteria for prognosis of BC at different ER statuses. Considering that potential weak instrument bias impacts the findings and that the results are limited to European females due to data constraints, further validation is crucial. 10.1186/s12864-023-09608-7
Causal relationship between gut microbiota and risk of gastroesophageal reflux disease: a genetic correlation and bidirectional Mendelian randomization study. Frontiers in immunology Background:Numerous observational studies have identified a linkage between the gut microbiota and gastroesophageal reflux disease (GERD). However, a clear causative association between the gut microbiota and GERD has yet to be definitively ascertained, given the presence of confounding variables. Methods:The genome-wide association study (GWAS) pertaining to the microbiome, conducted by the MiBioGen consortium and comprising 18,340 samples from 24 population-based cohorts, served as the exposure dataset. Summary-level data for GERD were obtained from a recent publicly available genome-wide association involving 78 707 GERD cases and 288 734 controls of European descent. The inverse variance-weighted (IVW) method was performed as a primary analysis, the other four methods were used as supporting analyses. Furthermore, sensitivity analyses encompassing Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and leave-one-out methodology were carried out to identify potential heterogeneity and horizontal pleiotropy. Ultimately, a reverse MR assessment was conducted to investigate the potential for reverse causation. Results:The IVW method's findings suggested protective roles against GERD for the ( = 0.027), (P = 0.026), ( = 0.026), and (P = 0.019). In contrast, ( = 0.037), (P = 0.049), and ( = 0.024) emerged as potential GERD risk factors. In assessing reverse causation with GERD as the exposure and gut microbiota as the outcome, the findings indicate that GERD leads to dysbiosis in 13 distinct gut microbiota classes. The MR results' reliability was confirmed by thorough assessments of heterogeneity and pleiotropy. Conclusions:For the first time, the MR analysis indicates a genetic link between gut microbiota abundance changes and GERD risk. This not only substantiates the potential of intestinal microecological therapy for GERD, but also establishes a basis for advanced research into the role of intestinal microbiota in the etiology of GERD. 10.3389/fimmu.2024.1327503
Causal associations between gut microbiota and Cholestatic liver diseases: a Mendelian randomization study. Frontiers in medicine Background:The etiological factors of Cholestatic Liver Diseases especially primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are not fully illustrated. It has been reported in previous observational studies that gut microbiota are associated with cholestatic liver diseases. However, there is uncertainty regarding the causality of this association. By using Mendelian randomization, this study aimed to examine the causal impact of gut microbiota on cholestatic liver diseases. Methods:From large-scale genome-wide association studies, genetic instruments for each gut microbiota taxa as well as primary biliary cholangitis and primary sclerosing cholangitis were developed. Subsequently, we conducted a two-sample Mendelian randomization analysis, supplemented by multiple sensitivity analyses. Additionally, we performed reverse MR analyses to investigate the possibility of the reverse causal association. Result:This two-sample MR study indicated that the was associated with a decreased risk of developing PBC, and that may be factors that increase the risk of PBC. On the other hand, we also identified were positively associated with PSC. The , and were found negative associations with the risk of PSC. The reverse MR analysis demonstrated no statistically significant relationship between PBC, PSC and these specific gut microbial taxa. Conclusion:Our findings offered novel evidence that the abundance of particular bacteria contributes to the risk of PBC and PSC, which may contribute to more effective approaches to PBC and PSC therapy and prevention. 10.3389/fmed.2024.1342119
Exploring reciprocal causation: bidirectional mendelian randomization study of gut microbiota composition and thyroid cancer. Journal of cancer research and clinical oncology BACKGROUND:While an association between gut microbiota composition and thyroid cancer (TC) has been observed, the directionality and causality of this relationship remain unclear. METHODS:We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal effect between gut microbiota composition and TC. Gut microbiota data were derived from a diverse population encompassing various ethnicities (n = 18,340 samples), while TC data were sourced from an European population (n = 218,792 samples). Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were employed to assess the causal relationship using multiple MR methods, including inverse-variance weighting (IVW), weighted median, weighted mode, MR-Egger, and simple mode. F-statistics and sensitivity analyses were performed to evaluate the robustness of the findings. RESULTS:Our investigation identified a comprehensive set of 2934 instrumental variables significantly linked to gut microbiota composition (p < 1 × 10). The analysis illuminated notable candidates within the phylum Euryarchaeota, including families Christensenellaceae and Victivallaceae, and genera Methanobrevibacter, Ruminococcus2, and Subdoligranulum, which emerged as potential risk factors for TC. On the other hand, a protective influence against TC was attributed to class Betaproteobacteria, family FamilyXI, and genera Anaerofilum, Odoribacter, and Sutterella, alongside order Burkholderiales. Further enhancing our insights, the integration of 7 instrumental variables from TC data (p < 1 × 10) disclosed the regulatory potential of one family and five genera. Notably, the genus Coprobacter innocuum group (p = 0.012, OR = 0.944) exhibited the highest probability of regulation. Our meticulous analyses remained free from significant bias, heterogeneity, or horizontal pleiotropy concerns. CONCLUSION:Through a bidirectional two-sample Mendelian randomization approach, we elucidated a potential bidirectional causal relationship between gut microbiota composition and TC. Specific microbial taxa were associated with an increased risk or conferred protection against TC. These findings advance our understanding of the complex interplay between the gut microbiota and TC pathogenesis, offering new insights into the therapeutic potential of modulating the gut microbiota for managing TC. 10.1007/s00432-023-05535-y
Gut microbiota does not play a mediating role in the causal association between inflammatory bowel disease and several its associated extraintestinal manifestations: a Mendelian randomization study. Frontiers in immunology Background and objectives:Observational study has found inflammatory bowel disease to be associated with multiple extraintestinal manifestations. To this end, we characterized the causal association between inflammatory bowel disease and extraintestinal manifestations through a Mendelian randomization study and further explored the role of intestinal flora in inflammatory bowel disease and the extraintestinal manifestations associated with it. Materials and methods:We genetically predicted the causal relationship between inflammatory bowel disease and twenty IBD-related extraintestinal manifestations (including sarcoidosis, iridocyclitis, interstitial lung disease, atopic dermatitis, ankylosing spondylitis, psoriatic arthropathies, primary sclerosing cholangitis, primary biliary cholangitis). We used the full genome-wide association study (GWAS) summary statistics on gut microbiota in 18,340 participants from 24 cohorts to explore its role in the casual relationships between IBD and IBD-related extraintestinal manifestations. Inverse variance weighting (IVW) was used as the main analytical method to assess the causal associations. We performed Cochran's Q test to examine the heterogeneity. To assess the robustness of the IVW results, we further performed sensitivity analyses including the weighted median method, MR-Egger regression, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. The leave-one-out sensitivity analysis was further performed to monitor if significant associations were dominated by a single nucleotide polymorphism (SNP). Result:A total of eight extraintestinal manifestations were found to be at elevated risk of development due to inflammatory bowel diseases. A total of 11 causal relationships were found between IBD and gut microbiota, four of which were stable. Between gut microbiota and these eight extraintestinal manifestations, a total of 67 nominal causal associations were identified, of which 13 associations were stable, and notably 4 associations were strongly correlated. Conclusion:Through the two-sample MR analysis, we identified extraintestinal manifestations that were causally associated with inflammatory bowel disease and obtained multiple associations from inflammatory bowel disease and gut microbiota, and gut microbiota and extraintestinal manifestations in further analyses. These associations may provide useful biomarkers and potential targets for pathogenesis and treatment. 10.3389/fimmu.2023.1296889
Causal effect of air pollution on the risk of cardiovascular and metabolic diseases and potential mediation by gut microbiota. The Science of the total environment BACKGROUND:Epidemiological studies have explored the relationship between air pollution and cardiovascular and metabolic diseases (CVMDs). Accumulating evidence has indicated that gut microbiota deeply affects the risk of CVMDs. However, the findings are controversial and the causality remains uncertain. To evaluate whether there is the causal association of four air pollutants with 19 CVMDs and the potential effect of gut microbiota on these relationships. METHODS:Genetic instruments for particulate matter (PM) with aerodynamic diameter < 2.5 μm (PM), <10 μm (PM), PM absorbance, nitrogen oxides (NO) and 211 gut microbiomes were screened. Univariable Mendelian randomization (UVMR) was used to estimate the causal effect of air pollutants on CVMDs in multiple MR methods. Additionally, to account for the phenotypic correlation among pollutant, the adjusted model was constructed using multivariable Mendelian randomization (MVMR) analysis to strength the reliability of the predicted associations. Finally, gut microbiome was assessed for the mediated effect on the associations of identified pollutants with CVMDs. RESULTS:Causal relationships between NO and angina, heart failure and hypercholesterolemia were observed in UVMR. After adjustment for air pollutants in MVMR models, the genetic correlations between PM and hypertension, type 2 diabetes mellitus (T2DM) and obesity remained significant and robust. In addition, genus-ruminococcaceae-UCG003 mediated 7.8 % of PM-effect on T2DM. CONCLUSIONS:This study firstly provided the genetic evidence linking air pollution to CVMDs and gut microbiota may mediate the association of PM with T2DM. Our findings highlight the significance of air quality in CVMDs risks and suggest the potential of modulating intestinal microbiota as novel therapeutic targets between air pollution and CVMDs. 10.1016/j.scitotenv.2023.169418
Causal relationship between gut microbiota and serum vitamin D: evidence from genetic correlation and Mendelian randomization study. European journal of clinical nutrition BACKGROUND:The gastrointestinal microbiota is emerging as an important mediator in intestinal metabolism, such as vitamin D absorption. METHODS:To elucidate the causality of microbiota and vitamin D, we used linkage disequilibrium score (LDSC) regression and two-sample Mendelian randomization (MR) methods with largest genome-wide association study (GWAS) summary statistics to identify specific taxa that are linked to serum 25-hydroxyvitamin D (25(OH)D). RESULTS:We found that Ruminiclostridium9 was significantly genetically correlated with 25(OH)D at nominal significance (r = 0.43, P = 0.04). Applying the inverse variance weighted (IVW) method, we identified that doubling the genetic liability of abundance of Erysipelotrichia, Erysipelotrichaceae and Erysipelotrichales reduced the concentration of 25(OH)D by 0.06 standard deviation (SD) (β = -0.06, s.e. = 0.01, P = 1.48 × 10, P = 1.93 × 10) and, in turn, one SD increment in genetically determined serum 25(OH)D caused a 0.16 SD decrease in the relative abundance of Phascolarctobacterium (β = -0.16, s.e. = 0.04, P = 2.48 × 10, P = 0.02) after removing pleiotropic instruments and outliers. Moreover, four MR methods were also used to evaluate causality, the results of which supported these findings. Leave-one-out analyses showed that the results were robust with regard to alterations in the single nucleotide polymorphisms (SNPs) we selected. CONCLUSIONS:In conclusion, our results support the hypothesis that the gut microbiota mediates the absorption of serum vitamin D supplementation and interacts with it closely. These microbiota are potential therapeutic targets for promoting serum vitamin D homeostasis. 10.1038/s41430-021-01065-3
Genetic support of the causal association between gut microbiome and COVID-19: a bidirectional Mendelian randomization study. Frontiers in immunology Background:The association between gut microbiome and coronavirus disease 2019 (COVID-19) has attracted much attention, but its causality remains unclear and requires more direct evidence. Methods:In this study, we conducted the bidirectional Mendelian randomization (MR) analysis to assess the causal association between gut microbiome and COVID-19 based on the summary statistics data of genome-wide association studies (GWASs). Over 1.8 million individuals with three COVID-19 phenotypes (severity, hospitalization and infection) were included. And 196 bacterial taxa from phylum to genus were analyzed. The inverse-variance weighted (IVW) analysis was chosen as the primary method. Besides, false discovery rate (FDR) correction of -value was used. To test the robustness of the causal relationships with -FDR < 0.05, sensitivity analyses including the secondary MR analyses, horizontal pleiotropy test, outliers test, and "leave-one-out" analysis were conducted. Results:In the forward MR, we found that 3, 8, and 10 bacterial taxa had suggestive effects on COVID-19 severity, hospitalization and infection, respectively. The genus [odds ratio (OR) = 1.67; 95% confidence interval (95% CI), 1.32-2.11; = 1.69×10, -FDR = 2.01×10] was causally associated with a higher COVID-19 severity risk. In the reverse MR, COVID-19 severity, hospitalization and infection had suggestive effects on the abundance of 4, 8 and 10 bacterial taxa, respectively. COVID-19 hospitalization causally increased the abundance of the phylum (OR = 1.13; 95% CI, 1.04-1.22; = 3.02×10; -FDR = 2.72×10). However, secondary MR analyses indicated that the result of COVID-19 hospitalization on the phylum required careful consideration. Conclusion:Our study revealed the causal association between gut microbiome and COVID-19 and highlighted the role of "gut-lung axis" in the progression of COVID-19. 10.3389/fimmu.2023.1217615
Association between gut microbiota and autoimmune cholestatic liver disease, a Mendelian randomization study. Frontiers in microbiology Background:Previous studies have suggested that the gut microbiota (GM) is closely associated with the development of autoimmune cholestatic liver disease (ACLD), but limitations, such as the presence of confounding factors, have resulted in a causal relationship between the gut microbiota and autoimmune cholestatic liver disease that remains uncertain. Thus, we used two-sample Mendelian randomization as a research method to explore the causal relationship between the two. Methods:Pooled statistics of gut microbiota from a meta-analysis of genome-wide association studies conducted by the MiBioGen consortium were used as an instrumental variable for exposure factors. The Pooled statistics for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) were obtained from the R9 version of the FinnGen database (https://r9.finngen.fi/). Inverse-variance Weighted (IVW), cML-MA, MR-Egger regression, Weighted median (WME), Weighted mode (WM), and Simple mode (SM) were used to detect the association between intestinal flora and the causal relationship between intestinal flora and ACLD, in which IVW method was dominant, was assessed based on the effect indicator dominance ratio (odds ratio, OR) and 95% confidence interval (CI). Sensitivity analysis, heterogeneity test, gene pleiotropy test, MR pleiotropy residual sum and outlier test (MR-PRESSO) were combined to verify the stability and reliability of the results. Reverse Mendelian randomization analysis was performed on gut microbiota and found to be causally associated with ACLD. Results:The IVW results showed that the relative abundance of the genus group, genus , and genus was negatively correlated with the risk of PBC, that is, increased abundance reduced the risk of PBC and was a protective, and the relative abundance of the genus was positively correlated with the risk of PSC, which is a risk factor for PSC. Family and family were negatively correlated with the risk of PSC, which is a protective factor for PSC. Conclusion:This study found a causal relationship between gut microbiota and ACLD. This may provide valuable insights into gut microbiota-mediated pathogenesis of ACLD. It is necessary to conduct a large-sample randomized controlled trial (RCT) at a later stage to validate the associated role of the relevant gut microbiota in the risk of ACLD development and to explore the associated mechanisms. 10.3389/fmicb.2024.1348027
Causal relationship between gut microbiota and glioblastoma: a two-sample Mendelian randomization study. Journal of Cancer Observational research and medical trials have suggested a connection between gut microbiota and glioblastoma, but it remains unclear if the relationship is causal. A two-sample Mendelian randomization (MR) study was conducted by employing data from the MiBioGen consortium's largest genome-wide association study (n=18340) and the FinnGen consortium R8 release information (162 cases and 256,583 controls). Inverse variance weighted (IVW), weighted median estimator (WME), weighted model, MR-Egger, simple mode, and MR-PRESSO were used to determine the causal relationship between gut microbiota and glioblastoma. Reverse MR analysis was also performed on bacteria identified as causally related to glioblastoma. Seven causal relationships were identified between genetic liability in the gut microbiota and glioblastoma, involving various bacterial families and genera. No significant causal effect was found on gut microbiota from glioblastoma, and no significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was observed. A two-sample MR analysis reveals a causal association between the gut microbiota and glioblastoma, highlighting the need for more investigation to comprehend the processes behind this association. 10.7150/jca.90149
Insight into the Causal Relationship between Gut Microbiota and Back Pain: A Two Sample Bidirectional Mendelian Randomization Study. Advanced genetics (Hoboken, N.J.) Observational studies have shown that alterations in gut microbiota composition are associated with low back pain. However, it remains unclear whether the association is causal. To reveal the causal association between gut microbiota and low back pain, a two-sample bidirectional Mendelian randomization (MR) analysis is performed. The inverse variance weighted regression (IVW) is performed as the principal MR analysis. MR-Egger and Weighted Median is further conducted as complementary analysis to validate the robustness of the results. Finally, a reverse MR analysis is performed to evaluate the possibility of reverse causation. The inverse variance weighted (IVW) method suggests that (odds ratio [OR] 1.056, 95% confidence interval [CI] [1.015-1.098], = 0.010), and (OR 1.070, 95% CI [1.026-1.115], = 0.003) are positively associated with back pain. The (OR 0.923, 95% CI [0.849-0.997], = 0.033), (OR 0.920, 95% CI [0.868 - 0.972], = 0.002), and (OR 0.948, 95% CI [0.903-0.994], = 0.022) are negatively associated with back pain. In this study, underlying causal relationships are identified among gut microbiota and low back pain. Notably, further research is needed on the biological mechanisms by which gut microbiota influences low back pain. 10.1002/ggn2.202300192
Gut microbiome relationship with arrhythmias and conduction blocks: A two-sample Mendelian randomization study. Journal of electrocardiology INTRODUCTION:Past research based on observations has suggested that the gut microbiome (GM) could play a role in developing arrhythmias and conduction blocks. Nonetheless, the nature of this association remains uncertain due to the potential for reverse causation and confounding factors in observational research. The aim of this investigation is to elucidate the causal relationship between GM and the development of arrhythmias as well as conduction blocks. METHODS:This study collected summary statistics regarding GM, arrhythmias, and conduction blocks. Two-sample Mendelian randomization (MR) analysis was carried out employing various methods, with inverse variance weighted being the primary approach, followed by weighted median, simple mode, MR-Egger, and MR-PRESSO. Moreover, the MR findings were corroborated through multiple sensitivity analyses. RESULTS:Among them, for atrial fibrillation and flutter (AF), phylum_Actinobacteria and genus_RuminococcaceaeUCG004 demonstrated a negative correlation, while order_Pasteurellales, family_Pasteurellaceae, and genus_Turicibacter were associated with an increased risk. In the case of paroxysmal tachycardia (PT), genus_Holdemania and genus_Roseburia were found to reduce risk. For atrioventricular block (AVB), order_Bifidobacteriales, family_Bifidobacteriaceae, and genus_Alistipes exhibited a negative correlation, whereas genus_CandidatusSoleaferrea showed a positive correlation. Concerning the left bundle-branch block (LBBB), family_Peptococcaceae appeared to decrease the risk, while genus_Flavonifractor was linked to an increased risk. Lastly, no causative GM was identified in the right bundle-branch block (RBBB) context. CONCLUSION:We have uncovered potential causal links between some GM, arrhythmias, and conduction blocks. This insight may aid in designing microbiome-based interventions for these conditions and their risk factors in future trials. Additionally, it could facilitate the discovery of novel biomarkers for targeted prevention strategies. 10.1016/j.jelectrocard.2023.06.006
Causal relationship between gut microbiota and rosacea: a two-sample Mendelian randomization study. Frontiers in medicine Background:Rosacea, a chronic inflammatory skin condition affecting millions worldwide, is influenced by complex interactions between genetic and environmental factors. Although gut microbiota's role in skin health is well-acknowledged, definitive causal links between gut microbiota and rosacea remain under-explored. Methods:Using a two-sample Mendelian randomization (MR) design, this study examined potential causal relationships between gut microbiota and rosacea. Data was sourced from the largest Genome-Wide Association Study (GWAS) for gut microbiota and the FinnGen biobank for rosacea. A total of 2078 single nucleotide polymorphisms (SNPs) associated with gut microbiota were identified and analyzed using a suite of MR techniques to discern causal effects. Results:The study identified a protective role against rosacea for two bacterial genera: phylum Actinobacteria and genus Butyrivibrio. Furthermore, 14 gut microbiota taxa were discovered to exert significant causal effects on variant categories of rosacea. While none of these results met the strict False Discovery Rate correction threshold, they retained nominal significance. MR outcomes showed no pleiotropy, with homogeneity observed across selected SNPs. Directionality tests pointed toward a robust causative path from gut microbiota to rosacea. Conclusion:This study provides compelling evidence of the gut microbiota's nominal causal influence on rosacea, shedding light on the gut-skin axis's intricacies and offering potential avenues for therapeutic interventions in rosacea management. Further research is warranted to validate these findings and explore their clinical implications. 10.3389/fmed.2024.1322685
Causal effects of gut microbiome on autoimmune liver disease: a two-sample Mendelian randomization study. BMC medical genomics BACKGROUND:Epidemiological studies have indicated a potential link between the gut microbiome and autoimmune liver disease (AILD) such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The relationship between the gut microbiome and autoimmune liver disease is still uncertain due to confounding variables. In our study, we aim to shed light on this relationship by employing a two-sample Mendelian randomization approach. METHODS:We conducted a two-sample Mendelian randomization (MR) study using the R package "TwoSampleMR". The exposure data consisted of genetic variants associated with 194 bacterial traits obtained from the MiBioGen consortium. Summary statistics for AILD were obtained from the GWAS Catalog website. Furthermore, a series of sensitivity analyses were performed to validate the initial MR results. RESULTS:There were two, four and three bacteria traits associated with an increased risk of AIH. PBC, and PSC respectively. In contrast, there were five, two and five bacteria traits associated with a decreased risk for AIH, PBC and PSC. Notably, the genus_Clostridium_innocuum_group showed a negative association with AIH (OR = 0.67, 95% CI: 0.49-0.93), and the genus_Actinomyces was found to be genetically associated with a decreased risk of PSC (OR = 0.62, 95% CI: 0.42-0.90). CONCLUSIONS:Our study identified the causal impact of specific bacterial features on the risk of AILD subtypes. Particularly, the genus_Clostridium_innocuum_group and the genus_Actinomyces demonstrated significant protective effects against AIH and PSC respectively. These findings provide further support for the potential use of targeted probiotics in the management of AILD. 10.1186/s12920-023-01670-0
Revealing the Impact of Gut Microbiota on Acne Through Mendelian Randomization Analysis. Clinical, cosmetic and investigational dermatology Background:The association between acne and gut microbiota has garnered considerable attention; nevertheless, given the substantial diversity within gut microbiota, the precise cause-and-effect relationship linking specific microbial species to acne remains elusive. To address this gap in knowledge, our study utilized Mendelian randomization analysis to elucidate a potential causal link between gut microbiota composition and acne development while also investigating underlying mechanisms involving microbial factors associated with metabolic disorders. Materials and Methods:The independent single nucleotide polymorphisms (SNPs) closely associated with 196 gut microbiota samples (N=18340) were selected as variable tools. The relationship between gut microbiota and acne (N=212438) was analyzed using the Twosample package in R4.3.1, employing various methods including inverse variance weighting (IVW), weighted median, MR-Egger, Simple-mode, and Weighted-mode. To ensure the stability of the estimates, a series of sensitivity analyses were conducted, such as Cochran's Q-test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Additionally, the impact of each instrumental variable was calculated. Results:In the Mendelian randomization analysis, we identified twelve microbial taxa potentially associated with acne: family.Bacteroidaceae, family.Clostridiaceae1, genus.Allisonella, genus.Bacteroides, genus.Butyricimonas, genus.Clostridiumsensustricto1, and genus.Coprococcus3. These seven bacterial groups were found to be potential risk factors for acne. Conversely, family.Lactobacillaceae and genus.Ruminococcustorquesgroup along with genus.CandidatusSoleaferrea, genus.Fusicatenibacter, family.Lactobacillaceae, and genus.Lactobacillus exhibited a protective effect against acne. Furthermore, our investigation revealed that some of these microbial taxa have been implicated in metabolic diseases through previous studies. Importantly though, no causal relationship was observed in the reverse Mendelian randomization analysis. 10.2147/CCID.S451104
Association between gut microbiota and diabetic nephropathy: a mendelian randomization study. Frontiers in microbiology Background:The correlation between diabetic nephropathy (DN) and gut microbiota (GM) has been suggested in numerous animal experiments and cross-sectional studies. However, a causal association between GM and DN has not been ascertained. Methods:This research adopted MR analysis to evaluate the causal link between GM and DN derived from data acquired through publicly available genome-wide association studies (GWAS). The study utilized the inverse variance weighted (IVW) approach to assess causal association between GM and DN. Four additional methods including MR-Egger, weighted median, weighted mode, and simple mode were employed to ensure comprehensive analysis and robust results. The Cochran's Q test and the MR-Egger method were conducted to identify heterogeneity and horizontal pleiotropy, respectively. The leave-one-out approach was utilized to evaluate the stability of MR results. Finally, a reverse MR was performed to identify the reverse causal association between GM and DN. Results:According to IVW analysis, Class Verrucomicrobiae ( = 0.003), Order Verrucomicrobiales ( = 0.003), Family ( = 0.003), Genus ( = 0.003), Genus Catenibacterium ( = 0.031), Genus 1 ( = 0.022), Genus group ( = 0.018), and Genus ( = 0.023) were associated with a higher risk of DN. On the contrary, Class ( = 0.037), Group group ( = 0.030), Group group ( = 0.048), Order ( = 0.045), Phylum ( = 0.017) were associated with a lower risk of DN. The sensitivity analysis did not identify any substantial pleiotropy or heterogeneity in the outcomes. We found causal effects of DN on 11 GM species in the reverse MR analysis. Notably, Phylum and DN are mutually causalities. Conclusion:This study identified the causal association between GM and DN with MR analysis, which may enhance the understanding of the intestinal-renal axis and provide novel potential targets for early non-invasive diagnosis and treatment of DN. 10.3389/fmicb.2024.1309871
Causal relationships between Gut microbiota and primary open-angle Glaucoma: A Mendelian randomization and mediation analysis of Glaucoma endophenotypes. Experimental eye research Primary open-angle glaucoma (POAG) is a widespread condition responsible for irreversible blindness, and its prevalence is expected to increase substantially in the coming decades. Despite its significance, the exact cause of POAG remains elusive, necessitating a comprehensive exploration of its pathogenesis. Emerging research suggests a potential link between alterations in gut microbiota composition and POAG. However, establishing causality in these associations remains a challenge. In this study, we employed Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota (GM) and POAG. Significant bacteria taxa were further analyzed with POAG endophenotypes. We utilized data from genome-wide association studies (GWAS) for GM and POAG, as well as for glaucoma endophenotypes, including intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, vertical cup-to-disc ratio (VCDR), and central corneal thickness (CCT). Univariable, multivariable MR and mediation effect analysis were conducted. Our analysis revealed that certain taxa, including phylum Euryarchaeota, genus Odoribacter, Rumnicoccaceae UCG009, Ruminiclostridium9, unknown genus id.2071, and Eubacterium rectale group, were associated with an increased risk of POAG. On the other hand, family Victivallaceae, Lacchnospiraceae, genus Lachnoclostridium, Oscillospira, Ruminococcaceae UCG011, Alloprevotella, and Faecalibacterium were found to be associated with a decreased risk of POAG. Furthermore, some of these taxa were found to be connected to glaucoma endophenotypes. Through further multivariable MR analysis, it was determined that IOP, VCDR, and CCT might played mediating roles between GM and POAG. In conclusion, this study utilizes MR analysis to elucidate potential causal associations between GM and POAG, providing insights into specific GM taxa that influence POAG risk and related endophenotypes. These findings emphasize the potential role of the gut microbiota in the pathogenesis of POAG and pave the way for future research and therapeutic interventions. 10.1016/j.exer.2024.109788
Association between gut microbiota and seven gastrointestinal diseases: A Mendelian randomized study. The journal of gene medicine BACKGROUND:Observational research has shed light on the ability of gut microbes to influence the onset and progression of gastrointestinal diseases. The causal relationships between specific gut microbiomes and various gastrointestinal conditions, however, remain unknown. METHODS:We investigated the relationship between gut microbiota and seven specific gastrointestinal disorders using a robust two-sample Mendelian randomization (MR) approach. The inverse variance-weighted (IVW) method was used as the primary analysis tool in our study. Furthermore, we conducted multiple sensitivity analyses to strengthen the robustness of our findings and ensure the reliability of the IVW method. RESULTS:Our research has discovered significant links between the composition of gut microbiota and a variety of gastrointestinal ailments. We found compelling links between 13 gut microbiota and fatty liver, four gut microbiota and cirrhosis, eight gut microbiota and hepatocellular carcinoma, four gut microbiota and cholelithiasis, 12 gut microbiota and acute pancreatitis, eight gut microbiota and chronic pancreatitis, and 11 gut microbiota and pancreatic cancer. These findings shed light on the intricate relationship between gut microbes and the emergence of these specific gastrointestinal conditions. CONCLUSIONS:The findings of this extensive study not only validate the potential role of specific gut microbiota in gastrointestinal diseases, but also fill a critical gap in previous research. The discovery of these specific gut microbiota is a significant step forward because they may serve as novel and promising biomarkers for both the prevention and treatment of gastrointestinal conditions. 10.1002/jgm.3623
The causality between gut microbiome and liver cirrhosis: a bi-directional two-sample Mendelian randomization analysis. Frontiers in microbiology Background and aim:Previous studies have reported an association between gut microbiota and cirrhosis. However, the causality between intestinal flora and liver cirrhosis still remains unclear. In this study, bi-directional Mendelian randomization (MR) analysis was used to ascertain the potential causal effect between gut microbes and cirrhosis. Methods:Large-scale Genome Wide Association Study (GWAS) data of cirrhosis and gut microbes were obtained from FinnGen, Mibiogen consortium, and a GWAS meta-analysis of Alcoholic cirrhosis (ALC). Two-sample MR was performed to determine the causal relationship between gut microbiota and cirrhosis. Furthermore, a bi-directional MR analysis was employed to examine the direction of the causal relations. Result:In MR analysis, we found that 21 gut microbiotas were potentially associated with cirrhosis. In reverse MR analysis, 11 gut microbiotas displayed potentially associations between genetic liability in the gut microbiome and cirrhosis. We found that the family (OR: 1.59, 95% CI:1.10-2.29) might be harmful in cirrhotic conditions (ICD-10: K74). Furthermore, the genus might be a protective factor for cirrhosis (OR:0.55, 95% CI:0.34-0.88) and PBC (OR:0.68, 95% CI:0.52-0.89). Combining the results from the MR analysis and reverse MR analysis, we firstly identified the had a bi-directional causal effect on PBC (Forward: OR: 0.37, 95% CI:0.15-0.93; Reverse: OR: 1.03, 95% CI:1.00-1.05). Conclusion:We found a new potential causal effect between cirrhosis and intestinal flora and provided new insights into the role of gut microbiota in the pathological progression of liver cirrhosis. 10.3389/fmicb.2023.1256874
Exploring the impact of gut microbiota on abdominal aortic aneurysm risk through a bidirectional Mendelian randomization analysis. Journal of vascular surgery OBJECTIVE:The abdominal aortic aneurysm (AAA) is associated with alterations in the composition of the gut microbiota; however, the precise causal relationship remains unclear. Elucidating this complex interplay could provide new insights into the pathogenesis of AAA. METHODS:A bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide association study summary data on the gut microbiota (n = 18,340) and AAA (n = 353,087). A total of 196 gut microbial taxa across taxonomic levels were examined for their potential causal effects on AAA risk. Conversely, the effect of AAA on these microbial taxa was also analyzed. RESULTS:Nine microbial taxa were identified as having a causal influence on AAA risk. Specifically, increased risk were associated with genus Bilophila (odds ratio [OR], 1.359; P = .0119), genus Catenibacterium (OR, 1.348; P = .0058), genus family XIII AD3011 group (OR, 1.507; P = .004), genus Oxalobacter (OR, 1.157; P = .0449), and genus Prevotella 7 (OR, 1.194; P = .0306), whereas decreased risks were linked to class Lentisphaeria (OR, 0.829; P = .0361), order Victivallales (OR, 0.829; P = .0361), family Victivallaceae (OR, 0.814; P = .0057), and genus Anaerotruncus (OR, 0.773; P = .0497). Furthermore, AAA was found to influence the abundance of 14 microbial taxa across various taxonomic levels. Notably, bidirectional associations were observed with the class Lentisphaeria and the order Victivallales. CONCLUSIONS:This study provides novel evidence for a reciprocal causal relationship between gut microbiota and AAA risk, thereby offering new insights into the pathogenesis of AAA. These findings also suggest promising avenues for microbiome-based therapeutic interventions. 10.1016/j.jvs.2023.11.041
Causal relationship between gut microbiota and autoimmune thyroiditis: A mendelian study. Heliyon Background:Autoimmune thyroiditis (AIT), also known as Hashimoto's thyroiditis (HT) or chronic lymphocytic thyroiditis, is a prevalent autoimmune disorder. Despite its high prevalence, the pathogenesis of AIT remains unclear. Previous studies have suggested a potential association between gut microbiota and AIT. However, whether this relationship is causal or coincidental remains uncertain. To address this gap in knowledge, our study aimed to investigate the potential causal association between gut microbiota and AIT using the two-sample Mendelian randomization (MR) method. Methods:Summary-level gut microbiota data comprising 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla) were obtained from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were extracted from the UK Biobank, FinnGen study, and various extensive GWAS studies. A meticulous MR analysis was conducted to evaluate the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. Sensitivity analyses and tests for heterogeneity were systematically performed to validate the reliability of our findings. Results:Six gut microbiota species showed significant associations with AIT according to the IVW method. Among them, the following exhibited negative associations with AIT: family Alcaligenaceae, family Pasteurellaceae (ID: 3689), family Peptococcaceae, genus Lachnospira, genus Victivallis, and order Pasteurellales (ID: 3688). No evidence of pleiotropy or heterogeneity was detected. Conclusion:The MR analysis uncovered a causal relationship at the genetic prediction level between specific gut microbiota and AIT. These findings offer novel insights into the mechanisms governing the development of AIT mediated by gut microbiota. This knowledge could inform the design of future interventions, potentially involving microbiome-related strategies, to address the mechanisms associated with AIT development. 10.1016/j.heliyon.2024.e25652
Association between gut microbiota and gastric cancers: a two-sample Mendelian randomization study. Frontiers in microbiology Background:Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide, with its etiology attributed to a complex interplay of genetic, dietary, environmental factors, and infections such as . Despite the known risk factors, the role of gut microbiota in the development of gastric cancer remains insufficiently explored. This study aims to elucidate the causal relationship between gut microbiota and gastric cancer using a two-sample Mendelian Randomization (MR) approach. Methods:Utilizing genome-wide association study (GWAS) summary data from the MiBioGen consortium and gastric cancer datasets, we selected instrumental variables for MR analysis based on their association with specific microbiota. We employed several MR methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and others, to estimate the causal effects of gut microbiota diversity on the risk of developing gastric cancer. Results:Our analysis identified significant associations between certain gut microbiota and gastric cancer risk. Specifically, taxa such as (OR = 0.540, 95%CI: 0.354-0.823, = 0.004), (OR = 0.756, 95%CI: 0.613-0.932, = 0.009), (OR = 0.816, 95%CI: 0.666-1.000, < 0.05), (OR = 0.816, 95%CI: 0.666-1.000, < 0.05), (OR = 0.863, 95%CI: 0.746-0.999, = 0.048) were found to have a protective effect against gastric cancer. Conversely, an increased risk of gastric cancer was associated with the abundance of (OR = 1.342, 95%CI: 1.071-1.681, = 0.011), (OR = 1.132, 95%CI: 1.012-1.267, = 0.030), and (OR = 1.207, 95%CI: 1.074-1.355, = 0.002). The findings were robust across various MR methods and were not driven by any single SNP, indicating a genuine causal relationship. Conclusion:Our studies have shown that there is a causal relationship between intestinal flora and gastric cancer at the genetic level. , , , , , and as having a protective role against GC, while , , and were associated with an increased risk. 10.3389/fmicb.2024.1383530
Gut microbiota and risk of lower respiratory tract infections: a bidirectional two-sample Mendelian randomization study. Frontiers in microbiology Introduction:Observational studies have reported the association between gut microbiota and the risk of lower respiratory tract infections (LRTIs). However, whether the association reflects a causal relationship remains obscure. Methods:A bidirectional twosample Mendelian randomization (MR) analysis was conducted by assessing genome-wide association study (GWAS) summary statistics for gut microbiota taxa and five common LRTIs. MR methods including inverse-variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode were used to analyze the causality. Gene pleiotropy was tested using MR-Egger regression and MR-PRESSO methods. Cochran's Q test was used to check for heterogeneity. Leave-one-out analysis was used to assess the stability of effect sizes. Detected significant associations were validated by using an independent LRTI GWAS summary statistics dataset. An optional MR method of causal analysis using summary effect estimates (CAUSE) was further performed as a validation to avoid potential false-positive results. Results:According to the MR-Egger estimates in forward MR analysis, a causal effect of gut on increased odds of bronchiectasis and pneumonia was suggested. MR-Egger regression pleiotropy intercept methods detected no significant horizontal pleiotropy between the instrumental variables of these associations. MR-PRESSO global test examined no potential horizontal pleiotropy. Cochran's Q test showed that no heterogeneity biased the results. The leave-one-out sensitivity analyses suggested robust causality results. These associations with consistent effect direction were successfully replicated in IVW analysis by using the validation GWAS dataset. However, these evidence of causality did not survive after applying strict Bonferroni correction or CAUSE analysis. The reverse MR analysis failed to achieve consistent results in the effect of LRTIs on gut microbiota through comprehensive discovery and validation processes. Discussion:This study established no strong causality between genetically predicted gut microbiome and the risk of lower respiratory tract infections. However, specific subtypes of microbial genera, such as , were identified as potential influencers and require further investigation, particularly at the species or strain levels. 10.3389/fmicb.2023.1276046
Genetic support of the causal association between gut microbiota and peripheral artery disease: a bidirectional Mendelian randomization study. Aging BACKGROUND:The causal relationship between gut microbiota and peripheral artery disease (PAD) is still not clear. In this research, we employed the Mendelian randomization (MR) technique to explore the potential causal connection between 211 gut microbiota species and PAD. We also investigated whether the causal effects operate in both directions. METHODS:We used Genome-wide Association Studies (GWAS) summary statistics data from the MiBioGen and FinnGen consortia to conduct a two-sample MR analysis to explore the causal link between gut microbiota and PAD. Sensitivity analysis is conducted to assess the robustness of the MR results. In addition to that, reverse MR analysis was performed to examine the inverse causal relationship. RESULTS:The inverse variance weighted (IVW) method provided evidence supporting a causal relationship between 9 specific gut microbiota taxa and PAD. The study findings indicated that family Family XI (OR=1.11, CI 1.00-1.24, P=0.048), genus (OR=1.24, 1.02-1.50, P=0.033), and genus UCG001 (OR=1.17, 1.01-1.35, P=0.031) are risk factors associated with PAD. class (OR=0.84, 0.72-0.99, P=0.034), family (OR=0.80, 0.66-0.98, P=0.029), genus (OR=0.79, 0.64-0.98, P=0.029), genus UCG004 (OR=0.84, 0.72-0.99, P=0.032), genus UCG010 (OR=0.74, 0.58-0.96, P=0.022), and order NB1n (OR=0.88, 0.79-0.98, P=0.02) may be associated with the risk factors of PAD. Moreover, our analysis did not uncover any evidence of a reverse causal relationship between PAD and the nine specific gut microbiota taxa investigated. CONCLUSIONS:Our MR research has confirmed the potential causal relationship between gut microbiota and PAD while also identifying specific gut bacterial communities associated with PAD. 10.18632/aging.205417
Gut microbiota alterations may increase the risk of prescription opioid use, but not vice versa: A two-sample bi-directional Mendelian randomization study. Frontiers in microbiology Introduction:Gut microbiota alterations are strongly associated with prescription opioid use (POU) and multisite chronic pain (MCP). However, whether or not these associations are causal remains unknown. Therefore, we aim to explore the causal relationships between them comprehensively. Methods:A two-sample bi-directional Mendelian randomization was conducted to assess the potential associations between gut microbiota and POU/MCP using summary level Genome-wide association studies (GWASs) that were based on predominantly European ancestry. Results:Potential causal effects were identified between seven host genetic-driven traits of gut microbiota on POU, including , , , , , , and at the genus level ( < 0.05) by the Inverse-variance weighted method, with significant causal effects of ChristensenellaceaeR.7group and on POU ( < 0.025). A total of five genetically greater abundance of gut microbiota traits were identified to be possibly related to the level of MCP ( < 0.05), including genus , , order , order , and family . In the other direction, no clear evidence was found to support a significant causal relationship between POU and gut microbiota, as well as MCP and gut microbiota. In addition, evidence was also provided for the relationship between triacylglycerols and diacylglycerol elevation, and an increased risk of POU and MCP. No evidence was found across various sensitivity analyses, including reverse causality, pleiotropy, and heterogeneity. Conclusion:The findings from this study provide robust evidence that gut microbiota alterations may be a risk of POU/MCP, but not vice versa. 10.3389/fmicb.2022.994170
Causal effects of gut microbiome on hypertension: a Mendelian randomization study. Frontiers in microbiology Background:Previous observational studies have shown that there is an important relationship between gut microbiota and hypertension, we performed a two-sample Mendelian randomization analysis to examine whether the gut microbiota is causally related to hypertension in order to find a basis for potential diagnostic or intervention approaches for hypertension. Methods:We obtained significant single nucleotide polymorphisms related to gut microbiota and hypertension from publicly available genome-wide association studies for a two-sample Mendelian randomization study. A total of 18,340 individual genome-wide genotype data were included from 24 population-based cohorts. The inverse-variance weighted meta-analysis is the main analytical method for evaluating causal relationships, and the Mendelian randomization research results have been validated through a series of sensitivity analyses. Results:The inverse-variance weighted analysis results indicated that phylum (OR:0.831, 95%CI: 0.710-0.972;  = 0.021), family (OR:0.672, 95%CI: 0.496-0.911;  = 0.01), family (OR:0.709, 95%CI:0.569-0.884,  = 0.002), genus (OR: 0.991, 95%CI: 0.982-0.999,  = 0.035), genus (OR:0.819, 95%CI:0.685-0.981;  = 0.03), genus (OR:0.990, 95%CI:0.981-0.999;  = 0.025), and genus (OR:0.988, 95%CI: 0.979-0.997;  = 0.008) had protective causal effects on hypertension. The Family (OR:1.011, 95%CI:1.000-1.021,  = 0.04), Genus (OR:1.375, 95%CI:1.096-1.653;  = 0.025), Genus (OR:1.899, 95%CI:1.361-2.348;  = 0.02), and Genus (OR:1.536, 95%CI:1.072-2.202;  = 0.019) were associated with a higher risk of HTN. The reverse Mendelian randomization analysis results showed no reverse causal relationship between HTN and these bacterial taxa. Conclusion:Our Mendelian randomization analysis results indicate a potential causal relationship between these bacterial taxa and hypertension, providing a new perspective for the treatment and prevention of hypertension. 10.3389/fmicb.2023.1276050
Gut microbiota and risk of endocarditis: a bidirectional Mendelian randomization study. Frontiers in microbiology Background:The associations between gut microbiota and cardiovascular disease have been reported in previous studies. However, the relationship between gut microbiota and endocarditis remains unclear. Methods:A bidirectional Mendelian randomization (MR) study was performed to detect the association between gut microbiota and endocarditis. Inverse variance weighted (IVW) method was considered the main result. Simultaneously, heterogeneity and pleiotropy tests were conducted. Results:Our study suggests that family Victivallaceae ( = 0.020), genus group ( = 0.047), genus Escherichia Shigella ( = 0.024), genus Peptococcus ( = 0.028) and genus Sellimonas ( = 0.005) play protective roles in endocarditis. Two microbial taxa, including genus Blautia ( = 0.006) and genus Ruminococcus2 ( = 0.024) increase the risk of endocarditis. At the same time, endocarditis has a negative effect on genus group ( = 0.048). Besides, no heterogeneity or pleiotropy was found in this study. Conclusion:Our study emphasized the certain role of specific gut microbiota in patients with endocarditis and clarified the negative effect of endocarditis on gut microbiota. 10.3389/fmicb.2024.1320095
Association between gut microbiota and pan-dermatological diseases: a bidirectional Mendelian randomization research. Frontiers in cellular and infection microbiology Background:Gut microbiota has been associated with dermatological problems in earlier observational studies. However, it is unclear whether gut microbiota has a causal function in dermatological diseases. Methods:Thirteen dermatological diseases were the subject of bidirectional Mendelian randomization (MR) research aimed at identifying potential causal links between gut microbiota and these diseases. Summary statistics for the Genome-Wide Association Study (GWAS) of gut microbiota and dermatological diseases were obtained from public datasets. With the goal of evaluating the causal estimates, five acknowledged MR approaches were utilized along with multiple testing corrections, with inverse variance weighted (IVW) regression serving as the main methodology. Regarding the taxa that were causally linked with dermatological diseases in the forward MR analysis, reverse MR was performed. A series of sensitivity analyses were conducted to test the robustness of the causal estimates. Results:The combined results of the five MR methods and sensitivity analysis showed 94 suggestive and five significant causal relationships. In particular, the increased the risk of developing psoriasis vulgaris (odds ratio [OR] = 1.32, p = 4.36 × 10), (OR = 2.25, p = 4.39 × 10), (OR = 1.42, p = 1.29 × 10), and (OR = 2.25, p = 1.29 × 10) increased the risk of developing acne; and the increased the risk of urticaria (OR = 1.30, p = 9.13 × 10). A reverse MR study revealed insufficient evidence for a significant causal relationship. In addition, there was no discernible horizontal pleiotropy or heterogeneity. Conclusion:This study provides novel insights into the causality of gut microbiota in dermatological diseases and therapeutic or preventive paradigms for cutaneous conditions. 10.3389/fcimb.2024.1327083
Exploring the causal role of gut microbiota in giant cell arteritis: a Mendelian randomization analysis with mediator insights. Frontiers in immunology Background:Giant Cell Arteritis (GCA) is a complex autoimmune condition. With growing interest in the role of gut microbiota in autoimmune diseases, this research aimed to explore the potential causal relationship between gut microbiota and GCA, and the mediating effects of specific intermediaries. Methods:Using a bidirectional two-sample Mendelian randomization (MR) design, we investigated associations between 191 microbial taxa and GCA. A two-step MR technique discerned the significant mediators on this relationship, followed by Multivariable MR analyses to quantify the direct influence of gut microbiota on GCA and mediation effect proportion, adjusting for these mediators. Results:Nine taxa displayed significant associations with GCA. Among them, families like Bacteroidales and Clostridiaceae1 had Odds Ratios (OR) of 1.48 (p=0.043) and 0.52 (p=5.51e-3), respectively. Genera like Clostridium sensu stricto1 and Desulfovibrio showed ORs of 0.48 (p=5.39e-4) and 1.48 (p=0.037), respectively. Mediation analyses identified 25 hydroxyvitamin D level (mediation effect of 19.95%), CD14+ CD16- monocyte counts (mediation effect of 27.40%), and CD4+ T cell counts (mediation effect of 28.51%) as significant intermediaries. Conclusion:Our findings provide invaluable insights into the complex interplay between specific gut microbiota taxa and GCA. By highlighting the central role of gut microbiota in influencing GCA risk and long-term recurrence, and their interactions with vital immune mediators, this research paves the way for potential therapeutic interventions in GCA management. 10.3389/fimmu.2023.1280249
Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis. Frontiers in microbiology Background:Patients with DN (diabetic nephropathy) show remarkable variations in their gut microbiota composition. However, to date, no study has shown whether a causal relationship exists between gut microbiota composition and DN. Methods:Here, we performed a two-sample Mendelian randomization (MR) investigation for identifying causal associations of gut microbiota with DN. Gut microbiota genetic data were gathered from the recent genome-wide association study pooled data of the MiBioGen consortium, which included 24 cohorts and 18,340 individuals. Results:IVW(Inverse variance weighting) revealed that [odds ratio (OR) = 1.390; 95% confidence interval (CI) = 1.10-1.75; = 0.005], (OR = 1.284; 95% CI = 1.03-1.59; = 0.012), (OR = 1.390; 95% CI = 1.10-1.75; = 0.005), (OR = 1.390; 95% CI = 1.10-1.75; p = 0.005), (OR = 1.261; 95% CI = 1.02-1.55; = 0.031), (OR = 1.278; 95% CI = 1.02-1.59; = 0.030). Conclusion:Two-sample MR analysis identified 12 microbial taxa in gut microbiota (one of which is yet to be officially named) that showed significant causal associations with DN; 8 of these taxa significantly increased the risk of DN, while the remaining 4 taxa (including the one without an official name) reduced the risk of DN. The precise mechanisms influencing the interactions of gut microbiota with DN occurrence remain unclear; hence, additional investigations should be conducted to clarify these mechanisms. 10.3389/fmicb.2023.1281361
Corrigendum: Gut microbiota and chronic obstructive pulmonary disease: a Mendelian randomization study. Frontiers in microbiology [This corrects the article DOI: 10.3389/fmicb.2023.1196751.]. 10.3389/fmicb.2023.1335133
Gut microbiota in combination with blood metabolites reveals characteristics of the disease cluster of coronary artery disease and cognitive impairment: a Mendelian randomization study. Frontiers in immunology Background:The coexistence of coronary artery disease (CAD) and cognitive impairment has become a common clinical phenomenon. However, there is currently limited research on the etiology of this disease cluster, discovery of biomarkers, and identification of precise intervention targets. Methods:We explored the causal connections between gut microbiota, blood metabolites, and the disease cluster of CAD combined with cognitive impairment through two-sample Mendelian randomization (TSMR). Additionally, we determine the gut microbiota and blood metabolites with the strongest causal associations using Bayesian model averaging multivariate Mendelian randomization (MR-BMA) analysis. Furthermore, we will investigate the mediating role of blood metabolites through a two-step Mendelian randomization design. Results:We identified gut microbiota that had significant causal associations with cognitive impairment. Additionally, we also discovered blood metabolites that exhibited significant causal associations with both CAD and cognitive impairment. According to the MR-BMA results, the free cholesterol to total lipids ratio in large very low density lipoprotein (VLDL) was identified as the key blood metabolite significantly associated with CAD. Similarly, the cholesteryl esters to total lipids ratio in small VLDL emerged as the primary blood metabolite with a significant causal association with dementia with lewy bodies (DLB). For the two-step Mendelian randomization analysis, we identified blood metabolites that could potentially mediate the association between genus Butyricicoccus and CAD in the potential causal links. Conclusion:Our study utilized Mendelian randomization (MR) to identify the gut microbiota features and blood metabolites characteristics associated with the disease cluster of CAD combined with cognitive impairment. These findings will provide a meaningful reference for the identification of biomarkers for the disease cluster of CAD combined with cognitive impairment as well as the discovery of targets for intervention to address the problems in the clinic. 10.3389/fimmu.2023.1308002
Investigating the gut microbiota's influence on psoriasis and psoriatic arthritis risk: a Mendelian randomization analysis. Precision clinical medicine Background:Numerous investigations have revealed the interplay between gut microbiota (GM) and psoriasis (Ps) and psoriatic arthritis (PsA). However, the causal relationship between them remains unknown. Methods:We curated a collection of genetic variants ( < 1 × 10) associated with GM ( = 18 340) derived from the MiBioGen study. To explore the intricate relationship between GM and Ps as well as PsA, we harnessed the comprehensive resources of the FinnGen database, encompassing a vast cohort of individuals, including 4510 Ps cases and 212 242 controls and 1637 PsA cases and 212 242 controls. Mendelian randomization (MR) was used, including an inverse variance weighting method, followed by a sensitivity analysis to verify the robustness of the results. Results:For Ps, some bacterial taxa, including , and , were identified as risk factors; but demonstrated a protective effect against Ps. In the case of PsA, , and were identified as risk factors; and exhibited a protective effect against the development of PsA. Conclusion:Our study establishes a causal link between the GM and Ps and PsA. These findings provide insights into the underlying mechanisms and suggest potential therapeutic targets. 10.1093/pcmedi/pbad023
Genetic evidence on the causality between gut microbiota and various asthma phenotypes: a two-sample Mendelian randomization study. Frontiers in cellular and infection microbiology Introduction:Asthma is a multifarious disease that manifests in various phenotypes. Among the various factors that contribute to the development of asthma, the gut microbiota has recently emerged as a compelling area of investigation. This study aims to investigate the causal relationships between gut microbiota and distinct asthma phenotypes. Methods:The genome-wide association study (GWAS) summary statistics for 211 gut microbial taxa were used as study exposure. Five traits pertaining to various asthma phenotypes (asthma, allergic asthma, childhood asthma, suggestive for eosinophilic asthma and obesity-related asthma) were included as study outcome. We conducted Mendelian randomization (MR) analysis and sensitivity analysis for each bacterial taxa and asthma phenotypes. Result:We discovered a total of 58 associations that exhibited evidence of causality. Out of these, 4 associations remained significant even after applying multiple correction. An increased risk of asthma was causally associated with higher abundance of genus (OR = 1.11; CI: 1.05-1.17; p = 0.027), genus (OR = 1.09; CI: 1.04-1.15; p = 0.025) and genus (OR = 1.14; CI: 1.06-1.22; p = 0.027). Order was causally linked with an increased risk of obesity-related asthma (OR = 1.17; CI: 1.07-1.29; p = 0.015). There was limited overlap among the taxa that exhibited potential causal relationships with distinct asthma phenotypes. Conclusion:Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and distinct asthma phenotypes, supporting the role of the gut microbiota in various asthma phenotypes. It is possible that different taxa play a role in the development of distinct asthma phenotypes. The causal relationships identified in this study require further investigation. 10.3389/fcimb.2023.1270067
Genetic Connectivity of Gut Microbiota and Oral Ulcers: A Mendelian Randomization Study. International dental journal OBJECTIVES:The aim of this study was to reveal the relationship, if any, between gut microbiota and oral ulcers. METHODS:We performed a 2-sample Mendelian randomization (MR) study to estimate the roles of gut microbiota in mouth ulcers. The summary datasets of gut microbiota were from the largest genome-wide association study (GWAS) conducted by MiBioGen, and data of mouth ulcers were obtained from UK Biobank. Random effect inverse variance-weighted, weighted median, MR Egger, simple mode and weighted mode were used to estimate the relationship. Sensitivity analyses were conducted to assess the heterogeneity and pleiotropy of instrumental variables. MR Steiger filtering was also applied to orient the causal direction. RESULTS:Three gut microbiota taxa were positively associated with mouth ulcers: Holdemania (odds ratio [OR] = 1.005, 95% confidence interval [CI]: 1.001-1.009, P = .019), Oxalobacter (OR = 1.004, 95% CI: 1.000-1.007, P = .032), and Ruminococcaceae UCG011 (OR = 1.006, 95% CI: 1.001-1.011, P = .029), while 4 gut microbiota taxa were negatively associated with mouth ulcers: Actinobacteria (OR = 0.992, 95% CI: 0.985-1.000, P = .042), Lactobacillales (OR = 0.995, 95% CI: 0.990-1.000, P = .034), Oscillospira (OR = 0.990, 95% CI: 0.984-0.997, P = .007) and Phascolarctobacterium (OR = 0.992, 95% CI: 0.986-0.997, P = .003). Sensitivity analyses validated the robustness of the association in between. CONCLUSIONS:This MR study identified a strong association between the quality of gut microbiota and oral ulcers. The findings are likely to expand the therapeutic targets for mouth ulcers. 10.1016/j.identj.2024.02.007
Gut microbiota's influence on erysipelas: evidence from a two-sample Mendelian randomization analysis. Frontiers in cellular and infection microbiology Background:Previous studies have suggested a link between gut microbiota and skin diseases, including erysipelas, an inflammatory skin condition. Despite this, the precise nature of the relationship between erysipelas and gut microbiota remains unclear and subject to debate. Methods:We conducted a Mendelian Randomization (MR) analysis using publicly available summary data from genome-wide association studies (GWAS) to explore the potential causal relationship between gut microbiota and erysipelas. Instrumental variables (IVs) were identified using a comprehensive set of screening methods. We then performed MR analyses primarily using the Inverse Variance Weighted (IVW) method, complemented by alternative approaches such as MR Egger, weighted median, simple mode, and weighted mode. A series of sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test, and a leave-one-out test, were executed to ensure the robustness and validity of our findings. Results:We identified potential associations between erysipelas and various gut microbiota, including (OR 1.23; 95% CI 1.06-1.43; p=0.006), (OR 0.77; 95% CI 0.67-0.90; p=0.001), and others. Notably, associations with , , , , , and were also observed. Sensitivity analyses confirmed the robustness of these associations. Conclusion:Our MR analysis suggests both potentially beneficial and harmful causal relationships between various gut microbiota and the incidence of erysipelas. This study provides new theoretical and empirical insights into the pathogenesis of erysipelas and underscores the potential for innovative preventive and therapeutic approaches. 10.3389/fcimb.2024.1371591
Investigating causal associations among gut microbiota, metabolites and autoimmune hypothyroidism: a univariable and multivariable Mendelian randomization study. Frontiers in immunology Background:Accumulating evidence suggests that the gut microbiota and its metabolites may be involved in autoimmune hypothyroidism. However, the causal association between gut microbiota, metabolites and autoimmune hypothyroidism remains to be determined. Methods:Instrumental variables were screened from the GWAS datasets of 211 gut microbiota taxonomic groups, gut microbiota-derived metabolites, and autoimmune hypothyroidism. Univariable Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) were used to analyse the potential causal relationship between autoimmune hypothyroidism, these metabolites, or these microbiota. During the MR analysis, we alternated multiple MR methods with different model assumptions to assess the consistency and robustness of the findings: inverse variance weighted (IVW), weighted median, MR pleiotropy residual sum and outlier (MRPRESSO) and MR-Egger methods. Reverse MR analysis was performed to assess the possibility of reverse causality. Finally, enrichment analyses were used to investigate potential biofunctions. Results:The IVW results of univariable MR showed that the phyla Actinobacteria, genus DefluviitaleaceaeUCG011, genus Eggerthella, family Defluviitaleaceae, genus Subdoligranulum, genus RuminococcaceaeUCG011, and genus Intestinimonas were associated with autoimmune hypothyroidism. After FDR adjustment, the absence of a causal relationship between gut microbiota and autoimmune hypothyroidism ( > 0.05) suggested a possible marginal association. The results on gut metabolites showed that N-(3-furoyl)glycine, pipecolate, phenylalanine, allantoin, indololactate and alanine were associated with autoimmune hypothyroidism. After FDR correction, only indololactate was associated with hypothyroidism (OR=1.592; 95% CI, 1.228-2.065; = 0.036). Family Defluviitaleaceae and genus DefluviitaleaceaeUCG011 were suggestively significant in the MVMR. The results of reverse MR analysis showed no reverse causality between autoimmune hypothyroidism and the identified gut microbiota. Enrichment analysis revealed that several key regulatory pathways were significantly enriched. Conclusion:This study supported that there were beneficial or detrimental causal effects of gut microbiota and its metabolites on autoimmune hypothyroidism risk, which provides more theoretical support for mechanistic research on the "thyroid-gut" axis. 10.3389/fimmu.2023.1213159
Causal effects of gut microbiota on renal tumor: a Mendelian randomization study. International journal of surgery (London, England) 10.1097/JS9.0000000000001041
Genetic Insights into Intestinal Microbiota and Risk of Infertility: A Mendelian Randomization Study. Microorganisms BACKGROUND:The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. METHODS:In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). RESULTS:As indicated by the IVW estimator, significantly protective effects of the (OR = 0.87) and (OR = 0.85) were identified for female fertility, while (OR = 1.18), (OR = 1.18), (OR = 1.12), and (OR = 1.11) showed adverse effects on female fertility. Meanwhile, (OR = 0.57), (OR = 0.57), and (OR = 0.61) revealed protective effects on male fertility, and a causal association between (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for . No heterogeneity or pleiotropy were identified by Cochran's Q test, MR-Egger, and global test (all > 0.05). CONCLUSIONS:This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility. 10.3390/microorganisms11092319
The Causal Impact of the Gut Microbiota on Respiratory Tuberculosis Susceptibility. Infectious diseases and therapy INTRODUCTION:Recent cross-sectional research has demonstrated a substantial link between tuberculosis (TB) and gut microbiota. Nevertheless, the causal impact of the gut microbiota on TB susceptibility in humans remains unknown. METHODS:The Mendelian randomization (MR) method was utilized for investigating the causality between them. The main method used for MR analysis was the inverse variance weighted (IVW) test, with the MR-Egger, weighted median, weighted mode, and simple median methods serving as supplements. And several sensitivity tests were carried out to validate the MR findings. RESULTS:The IVW outcomes suggested that three bacterial traits exhibited associations with susceptibility to respiratory TB after Bonferroni correction, namely Lachnospiraceae UCG010 (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.17-2.55, P = 0.005), Eubacterium (brachy group) (OR 1.33, 95% CI 1.07-1.65, P = 0.009), and Ruminococcaceae UCG005 (OR 0.71, 95% CI 0.52-0.98, P = 0.034). Sensitivity analyses demonstrated that horizontal pleiotropy and heterogeneity were absent, thereby guaranteeing the reliability of the results. CONCLUSION:This research sheds light on the causal impact of gut microbiota on respiratory tuberculosis susceptibility, improving our knowledge of therapeutic strategies for managing TB. 10.1007/s40121-023-00880-4
A bidirectional two-sample Mendelian randomization using the gut microbiota to reveal potential therapeutic targets for primary sclerosing cholangitis. European journal of gastroenterology & hepatology BACKGROUND:Previous studies indicate that gut microbiota correlates to primary sclerosing cholangitis (PSC), but the causation is still unclear. We sought to reveal the causal relationship between gut microbiota and PSC with a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS:The large-scale genome-wide association study (GWAS) summary statistics and a bidirectional two-sample MR study were used to assess the causality between gut microbiota and PSC. Multiple sensitivity analyses were used to identify the robustness of our results. RESULTS:Three microbial taxa causally correlated to PSC. Genus Ruminococcaceae UCG002 (OR: 1.855, 95% CI: 1.068-3.220, P = 0.028) increased the risk of PSC. Class Betaproteobacteria (OR: 0.360, 95% CI: 0.171-0.758, P = 0.007), and genus Ruminiclostridium6 (OR: 0.474, 95% CI: 0.219-0.820, P = 0.011) had protective effects on PSC. In addition, we found the causal relationship of PSC with higher abundance of genus Dialister (beta: 0.059, 95% CI: 0.017-0.102, P = 0.006), genus Veillonella (beta: 0.065, 95% CI: 0.016-0.113, P = 0.009), class Melainabacteria (beta: 0.073, 95% CI: 0.012-0.133, P = 0.019), and order Gastranaerophilales (beta: 0.072, 95% CI: 0.011-0.113, P = 0.133). CONCLUSION:Our study reveals the causality between gut microbiota and PSC, providing new insights into the pathological mechanisms of PSC and facilitating the development of novel biomarkers and disease-modifying therapeutics for PSC from the perspective of gut microbiota. 10.1097/MEG.0000000000002666
Identification of bidirectional causal links between gut microbiota and narcolepsy type 1 using Mendelian randomization. Sleep STUDY OBJECTIVES:Narcolepsy type 1 (NT1), characterized by cataplexy and orexin deficiency, is a rare and frequently debilitating neurological disorder. It has been noted to have connections with the gut microbiota, yet the exact causal relationships remain unclear. METHODS:We conducted a comprehensive bidirectional Mendelian randomization (MR) study to rigorously investigate the causal links between the gut microbiota and NT1, utilizing genetic datasets from the MiBioGen consortium and FinnGen consortium, respectively. The inverse-variance weighted (IVW) method was employed to obtain the primary MR estimates, supplemented by several alternative methods as well as sensitivity analyses including Cochran's Q, MR-Egger, MR pleiotropy residual sum and outlier, leave-one-out, and genetic colocalization. RESULTS:Our findings indicated that an increased relative abundance of five genera including Blautia (p = 4.47E-5), Collinsella (p = 0.036), Gordonibacter (p = 0.047), Hungatella (p = 0.015), and Lachnospiraceae UCG010 (p = 0.027) may be associated with a decreased risk of NT1. Conversely, an increased relative abundance of class Betaproteobacteria (p = 0.032), genus Alloprevotella (p = 0.009), and genus Ruminiclostridium6 (p = 0.029) may potentially heighten the risk of NT1. The onset of NT1 may lead to a decrease in the relative abundance of genus Eubacterium eligens group (p = 0.022), while a increase in the family Family XI (p = 0.009), genus Hungatella (p = 0.005), genus Prevotella (p = 0.013), and unknown genus id.2001 (p = 0.019). These findings remained robust under all sensitivity analyses. CONCLUSIONS:Our results offer robust evidence for the bidirectional causal links between particular gut microbial taxa and NT1, underscoring the significance of the microbiota-gut-brain axis in the pathological process of NT1. 10.1093/sleep/zsae004
Causal relationship between gut microbiota and risk of esophageal cancer: evidence from Mendelian randomization study. Aging BACKGROUND:The causative implications remain ambiguous. Consequently, this study aims to evaluate the putative causal relationship between gut microbiota and Esophageal cancer (EC). METHODS:The genome-wide association study (GWAS) pertaining to the microbiome, derived from the MiBioGen consortium-which consolidates 18,340 samples across 24 population-based cohorts-was utilized as the exposure dataset. Employing the GWAS summary statistics specific to EC patients sourced from the GWAS Catalog and leveraging the two-sample Mendelian randomization (MR) methodology, the principal analytical method applied was the inverse variance weighted (IVW) technique. Cochran's Q statistic was utilized to discern heterogeneity inherent in the data set. Subsequently, a reverse MR analysis was executed. RESULTS:Findings derived from the IVW technique elucidated that the Family Porphyromonadaceae (P = 0.048) and Genus Candidatus Soleaferrea (P = 0.048) function as deterrents against EC development. In contrast, the Genus Catenibacterium (P = 0.044), Genus Eubacterium coprostanoligenes group (P = 0.038), Genus Marvinbryantia (P = 0.049), Genus Ruminococcaceae UCG010 (P = 0.034), Genus Ruminococcus1 (P = 0.047), and Genus Sutterella (P = 0.012) emerged as prospective risk contributors for EC. To assess reverse causal effect, we used EC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between EC and seven different types of gut microbiota. The robustness of the MR findings was substantiated through comprehensive heterogeneity and pleiotropy evaluations. CONCLUSIONS:This research identified certain microbial taxa as either protective or detrimental elements for EC, potentially offering valuable biomarkers for asymptomatic diagnosis and prospective therapeutic interventions for EC. 10.18632/aging.205547
The causal effects between gut microbiota and hemorrhagic stroke: a bidirectional two-sample Mendelian randomization study. Frontiers in microbiology Background:Recent studies have suggested that the composition of gut microbiota (GM) may change after intracerebral hemorrhage. However, the causal inference of GM and hemorrhagic stroke is unknown. Mendelian Randomization (MR) is an effective research method that removes confounding factors and investigates the causal relationship between exposure and outcome. This study intends to explore the causal relationship between GM and hemorrhagic stroke with the help of MR. Methods:Univariable and multivariable MR analyses were performed using summary statistics of the GM ( = 18,340) in the MiBioGen consortium vs. the FinnGen consortium R9 summary statistics (intracerebral hemorrhage, subarachnoid hemorrhage, and nontraumatic intracranial hemorrhage). Causal associations between gut microbiota and hemorrhagic stroke were analyzed using inverse variance weighted, MR-Egger regression, weighted median, weighted mode, simple mode, and MR-PRESSO. Cochran's statistic, MR-Egger regression, and leave-one-out analysis were used to test for multiplicity and heterogeneity of instrumental variables. Separate reverse MR analyses were performed for microbiota found to be causally associated with hemorrhagic stroke in the forward MR analysis. Also, multivariate MR analyses were conducted after incorporating common confounders. Results:Based on the results of univariable and multivariate MR analyses, (OR, 0.80; 95%CI, 0.66-0.97; = 0.025) had a protective effect against hemorrhagic stroke, while (OR, 0.81; 95%CI, 0.67-0.99; = 0.039) had a potential protective effect. Furthermore, (OR, 1.77; 95%CI, 1.27-2.46; = 0.001), (OR, 1.24; 95%CI, 1.05-1.48; = 0.013) and (OR, 1.28; 95%CI, 1.01-1.62; = 0.041) acted as potential risk factors for hemorrhagic stroke. The abundance of (β, 0.05; 95%CI, 0.002 ~ 0.101; = 0.041) may increase, and that of (β, -0.072; 95%CI, -0.137 ~ -0.007; = 0.030) decreased after hemorrhagic stroke according to the results of reverse MR analysis. No significant pleiotropy or heterogeneity was detected in any of the MR analyses. Conclusion:There is a significant causal relationship between GM and hemorrhagic stroke. The prevention, monitoring, and treatment of hemorrhagic stroke through GM represent a promising avenue and contribute to a deeper understanding of the mechanisms underlying hemorrhagic stroke. 10.3389/fmicb.2023.1290909
The causality between gut microbiota and ankylosing spondylitis: Insights from a bidirectional two-sample Mendelian randomization analysis. International journal of rheumatic diseases BACKGROUND:The association between gut microbiota and ankylosing spondylitis (AS) has been reported in the literature; however, whether the two are correlative is unclear. METHODS:Single nucleotide polymorphisms associated with the gut microbiome composition and AS (968 AS cases and 336 191 controls) were obtained from published genome-wide association studies in this two-sample Mendelian randomization (MR) study. The causal relationship between gut microbiota and AS was estimated using the inverse-variance weighted method, and the robustness of our findings was confirmed through a comprehensive series of sensitivity analyses. RESULTS:Anaerotruncus (OR = 0.9984, 95% CI, 0.9968-0.9999, p = .0405) and Ruminococcaceae UCG002 (OR = 0.9989, 95% CI, 0.9979-0.9999, p = .0375) were protective against AS. Defluviitaleaceae (OR = 1.0015, 95% CI, 1.0005-1.0025, p = .0048), Butyricicoccus (OR = 1.0016, 95% CI, 1.0001-1.0032, p = .0429), Coprococcus 3 (OR = 1.0016, 95% CI, 1.0000-1.0032, p = .0463), and Defluviitaleaceae UCG011 (OR = 1.0016, 95% CI, 1.0005-1.0027, p = .0041) exhibited significant positive correlations with heightened susceptibility to AS. Reverse MR revealed that AS does not affect the gut microbial composition. CONCLUSION:Our study has established a genetically-based causal relationship between gut microbiota and AS. This finding suggests that we may be able to target and regulate specific bacterial groups in the gut to prevent and treat AS. 10.1111/1756-185X.14938
The Causal Relationships Between Gut Microbiota, Brain Volume, and Intelligence: A Two-Step Mendelian Randomization Analysis. Biological psychiatry BACKGROUND:Growing evidence indicates that dynamic changes in gut microbiome can affect intelligence; however, whether these relationships are causal remains elusive. We aimed to disentangle the poorly understood causal relationship between gut microbiota and intelligence. METHODS:We performed a 2-sample Mendelian randomization (MR) analysis using genetic variants from the largest available genome-wide association studies of gut microbiota (N = 18,340) and intelligence (N = 269,867). The inverse-variance weighted method was used to conduct the MR analyses complemented by a range of sensitivity analyses to validate the robustness of the results. Considering the close relationship between brain volume and intelligence, we applied 2-step MR to evaluate whether the identified effect was mediated by regulating brain volume (N = 47,316). RESULTS:We found a risk effect of the genus Oxalobacter on intelligence (odds ratio = 0.968 change in intelligence per standard deviation increase in taxa; 95% CI, 0.952-0.985; p = 1.88 × 10) and a protective effect of the genus Fusicatenibacter on intelligence (odds ratio = 1.053; 95% CI, 1.024-1.082; p = 3.03 × 10). The 2-step MR analysis further showed that the effect of genus Fusicatenibacter on intelligence was partially mediated by regulating brain volume, with a mediated proportion of 33.6% (95% CI, 6.8%-60.4%; p = .014). CONCLUSIONS:Our results provide causal evidence indicating the role of the microbiome in intelligence. Our findings may help reshape our understanding of the microbiota-gut-brain axis and development of novel intervention approaches for preventing cognitive impairment. 10.1016/j.biopsych.2024.02.1012
Association of gut microbiome with risk of intracranial aneurysm: a mendelian randomization study. BMC neurology OBJECTIVE:To investigate the potential causal link between genetic variants associated with gut microbiome and risk of intracranial aneurysm (IA) using two-sample mendelian randomization (MR). METHODS:We performed two sets of MR analyses. At first, we selected the genome-wide statistical significant(P < 5 × 10) single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Then, we selected the locus-wide significant (P < 1 × 10) SNPs as IVs for the other set of analyses to obtain more comprehensive conclusions. Gut microbiome genetic association estimates were derived from a genome-wide association study (GWAS) of 18,473 individuals. Summary-level statistics for IA were obtained from 79,429 individuals, which included 7,495 cases and 71,934 controls. RESULTS:On the basis of locus-wide significance level, inverse variance weighted(IVW) showed that Clostridia [(odds ratio (OR): 2.60; 95% confidence interval (CI): 1.00-6.72, P = 0.049)], Adlercreutzia (OR: 1.81; 95% CI: 1.10-2.99, P = 0.021) and Victivallis (OR: 1.38; 95% CI: 1.01-1.88, P = 0.044) were positively related with the risk of unruptured intracranial aneurysm(UIA); Weighted median results of MR showed Oscillospira (OR: 0.37; 95% CI: 0.17-0.84, P = 0.018) was negatively with the risk of UIA and Sutterella (OR: 1.84; 95% CI: 1.04-3.23, P = 0.035) was positively related with the risk of UIA; MR-Egger method analysis indicated that Paraprevotella (OR: 0.32; 95% CI: 0.13-0.80, P = 0.035) was negatively with the risk of UIA and Rhodospirillaceae (OR: 13.39; 95% CI: 1.44-124.47, P = 0.048) was positively related with the risk of UIA. The results suggest that Streptococcus (OR: 5.19; 95% CI: 1.25-21.56; P = 0.024) and Peptostreptococcaceae (OR: 4.92; 95% CI: 1.32-18.32; P = 0.018) may increase the risk of UIA according to genome-wide statistical significance thresholds. CONCLUSION:This MR analysis indicates that there exists a beneficial or detrimental causal effect of gut microbiota composition on IAs. 10.1186/s12883-023-03288-2