Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis.
Lin Rui,Zhou Lu,Zhang Jie,Wang Bangmao
International journal of clinical and experimental pathology
BACKGROUND:Autoimmune hepatitis (AIH) is a chronic, progressive, and immunologically mediated inflammatory liver disorder. The etiology of AIH still remains unknown. The aim of this study was to investigate the changes in intestinal permeability, bacterial translocation, and intestinal microbiome in patients with AIH and to evaluate the correlations of those changes with the stages of the disease. METHODS:24 patients with autoimmune hepatitis and 8 healthy volunteers were recruited for this study. We assessed (1) the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 and occludin expression in duodenal biopsy specimens; (2) changes in the enteric microbiome by 16S rDNA quantitative PCR; and (3) the presence of bacterial translocation by the level of lipopolysaccharide (LPS) using ELISA. RESULTS:Increased intestinal permeability, derangement of the microbiome and bacterial translocation occurred in AIH, which correlated with the severity of the disease. CONCLUSIONS:Autoimmune hepatitis is associated with leaky gut and intestinal microbiome dysbiosis. The impaired intestinal barrier may play an important role in the pathogenesis of AIH.
Systematic Review: Adverse Events of Fecal Microbiota Transplantation.
Wang Sinan,Xu Mengque,Wang Weiqiang,Cao Xiaocang,Piao Meiyu,Khan Samiullah,Yan Fang,Cao Hailong,Wang Bangmao
BACKGROUND:Fecal microbiota transplantation (FMT) is a microbiota-based therapy that shows therapeutic potential in recurrent or refractory Clostridium difficile infections and other intestinal or extra-intestinal disorders. Nonetheless, adverse events (AEs) remain a major challenge in the application of FMT. AIM:To review the AEs of FMT and to address the concerns of safety during the procedure. METHODS:Publications were retrieved in the databases of Medline, Embase and Cochrane Library. AEs were classified according to their causality with FMT or their severity. RESULTS:A total of 7562 original articles about FMT were identified in this study, 50 of them fulfilled the inclusion criteria. Totally 78 kinds of AEs were revealed enrolled in these 50 selected publications. The total incidence rate of AEs was 28.5%. Among the 42 publications, 5 kinds were definitely and 38 kinds were probably related to FMT. The commonest FMT-attributable AE was abdominal discomfort, which was reported in 19 publications. For upper gastrointestinal routes of FMT, 43.6% (89/204) patients were compromised by FMT-attributable AE, while the incidence dropped to 17.7% (76/430) for lower gastrointestinal routes. In contrast, the incidences of serious adverse events (SAEs) were 2.0% (4/196) and 6.1% (40/659) for upper and lower gastrointestinal routes, respectively. A total of 44 kinds of SAEs occurred in 9.2% patients, including death (3.5%, 38/1089), infection (2.5%, 27/1089), relapse of inflammatory bowel diseases (0.6%, 7/1089) and Clostridium difficile infection (0.9%, 10/1089). CONCLUSION:Consequently, both AEs and SAEs are not rare and should be carefully monitored throughout FMT. However, high quality randomized controlled trials are still needed for the more definite incidence of AEs of FMT.
Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis.
Cao Hailong,Xu Mengque,Dong Wenxiao,Deng Baoru,Wang Sinan,Zhang Yujie,Wang Shan,Luo Shenhui,Wang Weiqiang,Qi Yanrong,Gao Jianxin,Cao Xiaocang,Yan Fang,Wang Bangmao
International journal of cancer
The gut microbiota plays an important role in maintaining intestinal homeostasis. Dysbiosis is associated with intestinal tumorigenesis. Deoxycholic acid (DCA), a secondary bile acid increased by a western diet, correlates with intestinal carcinogenesis. However, evidence relating bile acids, intestinal microbiota and tumorigenesis are limited. In our study, we investigated the effect of DCA on induction of intestinal dysbiosis and its roles in intestinal carcinogenesis. Alteration of the composition of the intestinal microbiota was induced in DCA-treated APC mice, which was accompanied by impaired intestinal barrier, gut low grade inflammation and tumor progression. The transfer of fecal microbiota from DCA-treated mice to another group of Apc mice increased tumor multiplicity, induced inflammation and recruited M2 phenotype tumor-associated macrophages. Importantly, the fecal microbiota transplantation activated the tumor-associated Wnt/β-catenin signaling pathway. Moreover, microbiota depletion by a cocktail of antibiotics was sufficient to block DCA-induced intestinal carcinogenesis, further suggesting the role of dysbiosis in tumor development. Our study demonstrated that alteration of the microbial community induced by DCA promoted intestinal carcinogenesis.
Intestinal microbiome and permeability in patients with autoimmune hepatitis.
Cai Wangfeng,Ran Ying,Li Yanni,Wang Bangmao,Zhou Lu
Best practice & research. Clinical gastroenterology
Autoimmune hepatitis (AIH) is a severe inflammatory liver disease. The underlying mechanisms remain unclear, but recent studies provided new perspectives on altered intestinal microbiome and permeability in AIH animal models and patients, highlighting gut-liver crosstalk in the pathogenesis of AIH. Transgenic AIH mice carrying HLA-DR3 showed reduced diversity and total load of gut microbiota. Germ-free mice are resistant to concanavalin A-induced liver injury, whereas enterogenouss antigens induce the activation of natural killer T cells participating in concanavalin A-induced liver injury, supporting the close relationship between microbiota and AIH. Moreover, 'molecular mimicry' provides a plausible interpretation of the immune reactions between microorganic antigens and liver autoantigens, for instance, cytochrome P4502D6, the target of cross-reactivity between virus and self. Nevertheless, direct evidence for the intestinal microbiome and permeability in AIH is still limited. The relationship between AIH susceptibilities and an intestinal microbiome shaped by drugs, diets or genes needs further study.
Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine.
Cao Hailong,Liu Xiang,An Yingying,Zhou Guoqiong,Liu Yanrong,Xu Mengque,Dong Wenxiao,Wang Sinan,Yan Fang,Jiang Kui,Wang Bangmao
Chronic constipation is a prevalent functional gastrointestinal disorder accompanied with intestinal dysbiosis. However, causal relationship between dysbiosis and constipation remains poorly understood. Serotonin transporter (SERT) is a transmembrane transport protein which re-uptakes excessive 5-hydroxytryptamine (5-HT) from effective location to terminate its physiological effects and involves in regulating gastrointestinal motility. In this study, fecal microbiota from patients with constipation and healthy controls were transplanted into the antibiotic depletion mice model. The mice which received fecal microbiota from patients with constipation presented a reducing in intestinal peristalsis and abnormal defecation parameters including the frequency of pellet expulsion, fecal weight and fecal water content. After fecal microbiota transplantation, the SERT expression in the colonic tissue was significantly upregulated, and the content of 5-HT was decreased which negatively correlated with the gastrointestinal transit time. Moverover, fecal microbiota from the mice which received fecal microbiota from patients with constipation also upregulated SERT in Caco-2 cells. Besides, this process accompanied with the decreased abundance of Clostridium, Lactobacillus, Desulfovibrio, and Methylobacterium and an increased tend of Bacteroides and Akkermansia, which also involved in the impairment of intestinal barrier after FMT. Taken together, intestinal dysbiosis may upregulate the SERT expression and contribute to the development of chronic constipation.
Diammonium Glycyrrhizinate Protects against Nonalcoholic Fatty Liver Disease in Mice through Modulation of Gut Microbiota and Restoration of Intestinal Barrier.
Li Yun,Liu Tianyu,Yan Chen,Xie Runxiang,Guo Zixuan,Wang Sinan,Zhang Yujie,Li Zhengxiang,Wang Bangmao,Cao Hailong
Nonalcoholic fatty liver disease (NAFLD), as a common chronic liver disorder, is prevalent in the world. Recent evidence demonstrates that the "gut-liver axis" is related well to the progression of NAFLD, which regards gut microbiota and the intestinal barrier as two critical factors correlated with NAFLD. Diammonium glycyrrhizinate (DG), a compound of the natural bioactive pentacyclic triterpenoid glycoside, is the main component of licorice root extracts. The anti-inflammatory and liver protection effects of DG have already been reported, but to date, the mechanism has not been fully elucidated. In this research, we observed that DG reduced body weight, liver steatosis, as well as hepatic inflammation in NAFLD model mice induced by a high-fat diet. Illumina sequencing of the 16S rRNA revealed that DG intervention notably altered the composition of the gut microbiota in NAFLD mice. The richness of gut microbiota was significantly increased by DG. Specifically, DG reduced the Firmicutes-to- Bacteroidetes ratio and the endotoxin-producing bacteria such as Desulfovibrio and elevated the abundance of probiotics such as Proteobacteria and Lactobacillus. DG could augment the levels of short-chain fatty acid (SCFA)-producing bacteria such as Ruminococcaceae and Lachnospiraceae and promote SCFA production. In addition, DG supplementation dramatically alleviated the intestinal low-grade inflammation. Meanwhile, DG improved the expression of tight junction proteins, the goblet cell number, and mucin secretion and sequentially enhanced the function of intestinal barrier. Collectively, the prevention of NAFLD by DG might be mediated by modulating gut microbiota and restoring the intestinal barrier.
Sleep Quality of Functional Gastrointestinal Disorder Patients in Class-Three Hospitals: A Cross-Sectional Study in Tianjin, China.
Zhao Wei,Jin Hong,Xu Mengque,Wang Dongxu,Liu Yandi,Tang Yanping,Zhang Qiuzan,Hua Jianping,Wang Bangmao
BioMed research international
Background:Functional gastrointestinal disorder (FGID) patients are influenced by anxiety, depression, and low sleep quality, which reduce the quality of their life. However, epidemiological data on the quality of sleep in FGID patients were lacking. This study aims to explore the sleep quality and influencing factors of the sleep quality in FGID patients. Methods:1200 subjects, diagnosed as FGID in one of the six class-three hospitals in Tianjin, China, from January to December 2014, were recruited. The information about demographic information, the severity of clinical symptoms, psychological status (Zung self-rating depression scale), and sleep quality (evaluated with Pittsburgh sleep quality index) was gathered. Results:The questionnaires from 1117 participants were collected including 920 of functional dyspepsia (FD) patients, 77 of irritable bowel disease (IBS) patients, 26 of functional constipation (FC) patients, and 94 other FGID patients. The results showed that morbidity rate for FD patients who had sleep disorders was higher than those who suffered from IBS or FC ( < 0.001). The proportion of elderly patients suffering from low sleep quality was higher than that of middle-aged and young patients ( < 0.001). The binary logistic regression analysis showed that age, education, and the severity of FGID symptom were influencing factors for poor sleep quality in FGID patients. Conclusion:The issue of poor sleep quality in FGID patients in Tianjin area is prominent, and elderly patients suffer lower sleep quality than other FGID patients. Age, education, and the severity of FGID symptoms are critical influencing factors which result in a drop-in sleep quality.
Maternal High Fat Diet Alters Gut Microbiota of Offspring and Exacerbates DSS-Induced Colitis in Adulthood.
Xie Runxiang,Sun Yue,Wu Jingyi,Huang Shumin,Jin Ge,Guo Zixuan,Zhang Yujie,Liu Tianyu,Liu Xiang,Cao Xiaocang,Wang Bangmao,Cao Hailong
Frontiers in immunology
Accumulating evidence shows that high fat diet is closely associated with inflammatory bowel disease. However, the effects and underlying mechanisms of maternal high fat diet (MHFD) on the susceptibility of offspring to colitis in adulthood lacks confirmation. C57BL/6 pregnant mice were given either a high fat (60 E% fat, MHFD group) or control diet [10 E% fat, maternal control diet (MCD) group] during gestation and lactation. The intestinal development, mucosal barrier function, microbiota, and mucosal inflammation of 3-week old offspring were assessed. After weaning all mice were fed a control diet until 8 weeks of age when the microbiota was analyzed. Offspring were also treated with 2% DSS solution for 5 days and the severity of colitis was assessed. The offspring in MHFD group were significantly heavier than those in MCD group only at 2-4 weeks of age, while no differences were found in the body weight between two groups at other measured time points. Compared with MCD group, MHFD significantly inhibited intestinal development and disrupted barrier function in 3-week old offspring. Although H&E staining showed no obvious microscopic inflammation in both groups of 3-week old offspring, increased production of inflammatory cytokines indicated low-grade inflammation was induced in MHFD group. Moreover, fecal analysis of the 3-week old offspring indicated that the microbiota compositions and diversity were significantly changed in MHFD group. Interestingly after 5 weeks consumption of control diet in both groups, the microbiota composition of offspring in MHFD group was still different from that in MCD group, although the bacterial diversity was partly recovered at 8 weeks of age. Finally, after DSS treatment in 8-week old offspring, MHFD significantly exacerbated the severity of colitis and increased the production of proinflammatory cytokine. Our data reveal that MHFD in early life can inhibit intestinal development, induce dysbiosis and low-grade inflammation and lead to the disruption of intestinal mucosal barrier in offspring, and enhance DSS-induced colitis in adulthood.
Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis.
Wang Sinan,Dong Wenxiao,Liu Li,Xu Mengque,Wang Yu,Liu Tianyu,Zhang Yujie,Wang Bangmao,Cao Hailong
The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)-induced intestinal adenoma-adenocarcinoma sequence. Apc mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA-treated Apc mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α-dehydroxylation reaction. The intestinal adenoma-adenocarcinoma sequence was observed in CA-treated Apc mice and was accompanied by an impaired intestinal barrier function and IL-6/STAT3-related low-grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA-induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.
Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in Apc mice.
Li Lu,Li Xiaofei,Zhong Weilong,Yang Min,Xu Mengque,Sun Yue,Ma Jiaheng,Liu Tianyu,Song Xueli,Dong Wenxiao,Liu Xiang,Chen Yange,Liu Yi,Abla Zaripa,Liu Wentian,Wang Bangmao,Jiang Kui,Cao Hailong
BACKGROUND:Accumulating evidence points to a close relationship between gut dysbiosis and colorectal cancer (CRC). As >90% of CRC develop from adenoma, we aimed to investigate the crucial role of imbalanced gut microbiota on the progression of intestinal adenoma. METHODS:The Apc mice gavage with phosphate-buffered saline (PBS), feces from healthy controls or CRC patients after antibiotic cocktails. The intestinal tissues were isolated for histopathology, western blotting, and RNA-seq. The microbiota of feces and short-chain fatty acids (SCFAs) were analysed by 16S rDNA Amplicon Sequencing and gas chromatography. FINDINGS:The Apcmice gavaged by feces from CRC patients had more intestinal tumours compared with those fed with feces from healthy controls or PBS. Administration of feces from CRC patients increased tumour proliferation and decreased apoptosis in tumour cells, accompanied by impairment of gut barrier function and up-regulation the pro-inflammatory cytokines profile. The up-regulated the expression of β-catenin and cyclinD1 further indicating the activation of Wnt signalling pathway. The abundance of pathogenic bacteria was increased after FMT, while producing SCFAs bacteria and SCFAs production were decreased. INTERPRETATION:Gut microbiota of CRC patients disrupted intestinal barrier, induced low-grade inflammation and dysbiosis. The altered gut microbiota enhanced the progression of intestinal adenomas in Apcmice, suggesting that a new strategy to target gut microbiota against CRC could be noted. FUND: The study was supported by the National Natural Science Foundation of China, Tianjin Research Programme of Application Foundation and Advanced Technology of China, and China Postdoctoral Science Foundation.
The Potential Role of Gut Mycobiome in Irritable Bowel Syndrome.
Gu Yu,Zhou Guoqiong,Qin Xiali,Huang Shumin,Wang Bangmao,Cao Hailong
Frontiers in microbiology
The human gut is inhabited by diverse microorganisms that play crucial roles in health and disease. Gut microbiota dysbiosis is increasingly considered as a vital factor in the etiopathogenesis of irritable bowel syndrome (IBS), which is a common functional gastrointestinal disorder with a high incidence all over the world. However, investigations to date are primarily directed to the bacterial community, and the gut mycobiome, another fundamental part of gut ecosystem, has been underestimated. Intestinal fungi have important effects on maintaining gut homeostasis just as bacterial species. In the present article, we reviewed the potential roles of gut mycobiome in the pathogenesis of IBS and the connections between the fungi and existing mechanisms such as chronic low-grade inflammation, visceral hypersensitivity, and brain-gut interactions. Moreover, possible strategies targeted at the gut mycobiome for managing IBS were also described. This review provides a basis for considering the role of the mycobiome in IBS and offers novel treatment strategies for IBS patients; moreover, it adds new dimensions to researches on microorganism.
High-fat diet-induced dysbiosis mediates MCP-1/CCR2 axis-dependent M2 macrophage polarization and promotes intestinal adenoma-adenocarcinoma sequence.
Liu Tianyu,Guo Zixuan,Song Xueli,Liu Li,Dong Wenxiao,Wang Sinan,Xu Mengque,Yang Cheng,Wang Bangmao,Cao Hailong
Journal of cellular and molecular medicine
High-fat diet (HFD) is a well-known risk factor for gut microbiota dysbiosis and colorectal cancer (CRC). However, evidence relating HFD, gut microbiota and carcinogenesis is limited. Our study aimed to demonstrate that HFD-induced gut dysbiosis promoted intestinal adenoma-adenocarcinoma sequence. In clinical study, we found that HFD increased the incidence of advanced colorectal neoplasia (AN). The expression of monocyte chemoattractant protein 1 (MCP-1), CC chemokine receptor 2 (CCR2) and CD163 in CRC patients with HFD was significantly higher than that in CRC patients with normal diet. When it comes to the Apc mice, HFD consumption could induce gut dysbiosis and promote intestinal carcinogenesis, accompanying with activation of MCP-1/CCR2 axis that recruited and polarized M2 tumour-associated macrophages. Interestingly, transfer of faecal microbiota from HFD-fed mice to another batch of Apc mice in the absence of HFD could also enhance carcinogenesis without significant body weight gain and induced MCP-1/CCR2 axis activation. HFD-induced dysbiosis could also be transmitted. Meanwhile, antibiotics cocktail treatment was sufficient to inhibit HFD-induced carcinogenesis, indicating the vital role of dysbiosis in cancer development. Conclusively, these data indicated that HFD-induced dysbiosis accelerated intestinal adenoma-adenocarcinoma sequence through activation of MCP-1/CCR2 axis, which would provide new insight into better understanding of the mechanisms and prevention for HFD-related CRC.
Fecal microbiota transplantation in cancer management: Current status and perspectives.
Chen Danfeng,Wu Jingyi,Jin Duochen,Wang Bangmao,Cao Hailong
International journal of cancer
The human gut is home to a large and diverse microbial community, comprising about 1,000 bacterial species. The gut microbiota exists in a symbiotic relationship with its host, playing a decisive role in the host's nutrition, immunity and metabolism. Accumulating studies have revealed the associations between gut dysbiosis or some special bacteria and various cancers. Emerging data suggest that gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations with therapeutic intent has become a hot topic of cancer research, and the most dramatic manipulation of gut microbiota refers to fecal microbiota transplantation (FMT) from healthy individuals to patients. FMT has demonstrated remarkable clinical efficacy against Clostridium difficile infection (CDI) and it is highly recommended for the treatment of recurrent or refractory CDI. Lately, interest is growing in the therapeutic potential of FMT for other diseases, including cancers. We briefly reviewed the current researches about gut microbiota and its link to cancer, and then summarized the recent preclinical and clinical evidence to indicate the potential of FMT in cancer management as well as cancer-treatment associated complications. We also presented the rationale of FMT for cancer management such as reconstruction of intestinal microbiota, amelioration of bile acid metabolism, and modulation of immunotherapy efficacy. This article would help to better understand this new therapeutic approach for cancer patients by targeting gut microbiota.
Current Sampling Methods for Gut Microbiota: A Call for More Precise Devices.
Tang Qiang,Jin Ge,Wang Gang,Liu Tianyu,Liu Xiang,Wang Bangmao,Cao Hailong
Frontiers in cellular and infection microbiology
The development of next-generation sequencing technology has enabled researchers to explore and understand the gut microbiome from a broader and deeper perspective. However, the results of different studies on gut microbiota are highly variable even in the same disease, which makes it difficult to guide clinical diagnosis and treatment. The ideal sampling method should be non-invasive, involve little cross-contamination or bowel preparation, and collect gut microbiota at different sites. Currently, sequencing technologies are usually based on samples collected from feces, mucosal biopsy, intestinal fluid, etc. However, different parts of the gastrointestinal tract possess various physiological characteristics that are essential for particular species of living microbiota. Moreover, current sampling methods are somewhat defective. For example, fecal samples are just a proxy for intestinal microbiota, while biopsies are invasive for patients and not suitable for healthy controls. In this review, we summarize the current sampling methods and their advantages and shortcomings. New sampling technologies, such as the Brisbane Aseptic Biopsy Device and the intelligent capsule, are also mentioned to inspire the development of future precise description methods of the gut microbiome.
Clostridium butyricum, a butyrate-producing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota.
Chen Danfeng,Jin Duochen,Huang Shumin,Wu Jingyi,Xu Mengque,Liu Tianyu,Dong Wenxiao,Liu Xiang,Wang Sinan,Zhong Weilong,Liu Yi,Jiang Ruihuan,Piao Meiyu,Wang Bangmao,Cao Hailong
Gut microbiota dysbiosis is closely involved in intestinal carcinogenesis. A marked reduction in butyrate-producing bacteria has been observed in patients with colorectal cancer (CRC); nevertheless, the potential benefit of butyrate-producing bacteria against intestinal tumor development has not been fully investigated. We found that Clostridium butyricum (C. butyricum, one of the commonly used butyrate-producing bacteria in clinical settings) significantly inhibited high-fat diet (HFD)-induced intestinal tumor development in Apc mice. Moreover, intestinal tumor cells treated with C. butyricum exhibited decreased proliferation and increased apoptosis. Additionally, C. butyricum suppressed the Wnt/β-catenin signaling pathway and modulated the gut microbiota composition, as demonstrated by decreases in some pathogenic bacteria and bile acid (BA)-biotransforming bacteria and increases in some beneficial bacteria, including short-chain fatty acid (SCFA)-producing bacteria. Accordingly, C. butyricum decreased the fecal secondary BA contents, increased the cecal SCFA quantities, and activated G-protein coupled receptors (GPRs), such as GPR43 and GPR109A. The anti-proliferative effect of C. butyricum was blunted by GPR43 gene silencing using small interfering RNA (siRNA). The analysis of clinical specimens revealed that the expression of GPR43 and GPR109A gradually decreased from human normal colonic tissue to adenoma to carcinoma. Together, our results show that C. butyricum can inhibit intestinal tumor development by modulating Wnt signaling and gut microbiota and thus suggest the potential efficacy of butyrate-producing bacteria against CRC.
Corrigendum to 'Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in Apc mice' [EBioMedicine 48 (2019) 301-315].
Li Lu,Li Xiaofei,Zhong Weilong,Yang Min,Xu Mengque,Sun Yue,Ma Jiaheng,Liu Tianyu,Song Xueli,Dong Wenxiao,Liu Xiang,Chen Yange,Liu Yi,Abla Zaripa,Liu Wentian,Wang Bangmao,Jiang Kui,Cao Hailong
The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing.
Liu Tianyu,Song Xueli,Khan Samiullah,Li Yun,Guo Zixuan,Li Chuqiao,Wang Sinan,Dong Wenxiao,Liu Wentian,Wang Bangmao,Cao Hailong
International journal of cancer
The prevalence of colorectal cancer (CRC) has markedly increased worldwide in the last decade. Alterations of bile acid metabolism and gut microbiota have been reported to play vital roles in intestinal carcinogenesis. About trillions of bacteria have inhabited in the human gut and maintained the balance of host metabolism. Bile acids are one of numerous metabolites that are synthesized in the liver and further metabolized by the gut microbiota, and are essential in maintaining the normal gut microbiota and lipid digestion. Multiple receptors such as FXR, GPBAR1, PXR, CAR and VDR act as sensors of bile acids have been reported. In this review, we mainly discussed interplay between bile acid metabolism and gut microbiota in intestinal carcinogenesis. We then summarized the critical role of bile acids receptors involving in CRC, and also addressed the rationale of multiple interventions for CRC management by regulating bile acids-microbiota axis such as probiotics, metformin, ursodeoxycholic acid and fecal microbiota transplantation. Thus, by targeting the bile acids-microbiota axis may provide novel therapeutic modalities in CRC prevention and treatment.
Microbial Metabolites: Critical Regulators in NAFLD.
Dai Xin,Hou Huiqin,Zhang Wanru,Liu Tianyu,Li Yun,Wang Sinan,Wang Bangmao,Cao Hailong
Frontiers in microbiology
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease throughout the world. The relationship between gut microbiota and NAFLD has been extensively investigated. The gut microbiota is involved in the regulation of NAFLD by participating in the fermentation of indigestible food, interacting with the intestinal mucosal immune system, and influencing the intestinal barrier function, leading to signaling alteration. Meanwhile, the microbial metabolites not only affect the signal transduction pathway in the gut but also reach the liver far away from gut. In this review, we focus on the effects of certain key microbial metabolites such as short-chain fatty acids, trimethylamine-N-oxide, bile acids, and endogenous ethanol and indole in NAFLD, and also summarize several potential therapies targeting the gut-liver axis and modulation of gut microbiota metabolites including antibiotics, prebiotics, probiotics, bile acid regulation, and fecal microbiota transplantation. Understanding the complex interactions between microbial metabolites and NAFLD may provide crucial insight into the pathogenesis and treatment of NAFLD.
ssp. Lactis 420 Mitigates Autoimmune Hepatitis Through Regulating Intestinal Barrier and Liver Immune Cells.
Zhang Hongxia,Liu Man,Liu Xin,Zhong Weilong,Li Yanni,Ran Ying,Guo Liping,Chen Xu,Zhao Jingwen,Wang Bangmao,Zhou Lu
Frontiers in immunology
Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease of uncertain cause. Accumulating evidence shows that gut microbiota and intestinal barrier play significant roles in AIH thus the gut-liver axis has important clinical significance as a potential therapeutic target. In the present study, we found that ssp. lactis 420 (B420) significantly alleviated S100-induced experimental autoimmune hepatitis (EAH) and modulated the gut microbiota composition. While the analysis of clinical specimens revealed that the fecal SCFA quantities were decreased in AIH patients, and B420 increased the cecal SCFA quantities in EAH mice. Remarkably, B420 application improved intestinal barrier function through upregulation of tight junction proteins in both vitro and vivo experiments. Moreover, B420 decreased the serum endotoxin level and suppressed the RIP3 signaling pathway of liver macrophages in EAH mice thus regulated the proliferation of Th17 cells. Nevertheless, the inhibition effect of B420 on RIP3 signaling pathway was blunted studies. Together, our results showed that early intervention with B420 contributed to improve the liver immune homeostasis and liver injury in EAH mice, which might be partly due to the protection of intestinal barrier. Our study suggested the potential efficacy of probiotics application against AIH and the promising therapeutic strategies targeting gut-liver axis for AIH.
Maternal sucralose intake alters gut microbiota of offspring and exacerbates hepatic steatosis in adulthood.
Dai Xin,Guo Zixuan,Chen Danfeng,Li Lu,Song Xueli,Liu Tianyu,Jin Ge,Li Yun,Liu Yi,Ajiguli Aihemaiti,Yang Cheng,Wang Bangmao,Cao Hailong
BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) is considered to be associated with diet and gut dysbiosis. Excessive sucralose can induce gut dysbiosis and negatively affect host health. Maternal diet shapes the microbial communities of neonate and this effect continues in later life. We aimed to investigate the effects of maternal sucralose (MS) intake on the susceptibility of offspring to hepatic steatosis in adulthood. METHODS:C57BL/6 pregnant mice were randomized into MS group (MS during gestation and lactation) and maternal control (MC) group (MC diet). After weaning, all offspring were fed a control diet until 8 weeks of age, and then treated with a high-fat diet (HFD) for 4 weeks. The intestinal development, mucosal barrier function, and gut microbiota were assessed in the 3-week-old offspring. Moreover, the severity of hepatic steatosis, serum biochemistry, lipid metabolism, and gut microbiota was then assessed in the 12th week. RESULTS:MS significantly inhibited intestinal development and disrupted barrier function in 3-week-old offspring. MS also induced intestinal low-grade inflammation, significantly changed the compositions and diversity of gut microbiota including reducing butyrate-producing bacteria and cecal butyrate production with down-regulation of GPR43. Mechanically, blocking GPR43 blunted the anti-inflammatory effect of one of the butyrate-producing bacteria, . After HFD treatment, MS exacerbated hepatic steatosis, and disturbed fatty acid biosynthesis and metabolism, accompanied by inducing gut dysbiosis compared with MC group. CONCLUSIONS:MS intake inhibits intestinal development, induces gut dysbiosis in offspring through down-regulation of GPR43, and exacerbates HFD-induced hepatic steatosis in adulthood.
Cartilage Oligomeric Matrix Protein promotes epithelial-mesenchymal transition by interacting with Transgelin in Colorectal Cancer.
Zhong Weilong,Hou Huiqin,Liu Tianyu,Su Shuai,Xi Xiaonan,Liao Yusheng,Xie Runxiang,Jin Ge,Liu Xiang,Zhu Lanping,Zhang Hongxia,Song Xueli,Yang Cheng,Sun Tao,Cao Hailong,Wang Bangmao
The role of the cartilage oligomeric matrix protein (COMP) in epithelial-mesenchymal transition (EMT) in tumor progression has been studied, but its exact regulatory mechanism remains unknown. The interaction between COMP and the actin-binding protein transgelin (TAGLN) was identified by interaction protein prediction and co-immunoprecipitation and verified through the stochastic optical reconstruction microscopy (STORM) and duolink experiments. Western blot and immunofluorescence analyses were conducted to detect the changes in EMT-related markers after COMP overexpression and knockdown. Molecular docking and Biacore of the interaction interface of COMP/TAGLN revealed that Chrysin directly targeted COMP. The promotion of COMP and the Chrysin inhibition of EMT were detected through the cell migration, invasion, apoptosis, and xenotransplantation of nude mice. COMP interacts with TAGLN in EMT in colorectal cancer to regulate cytoskeletal remodeling and promote malignant progression. COMP is highly expressed in highly malignant colorectal cancer and positively correlated with TAGLN expression. COMP knockdown can inhibit colorectal cancer metastasis and invasion, whereas COMP overexpression promotes EMT in colorectal cancer. Through virtual screening of the protein interaction interface, Chrysin, a flavonoid compound extracted from , was found to have the highest docking score to the COMP/TAGLN complex. Chrysin inhibited COMP, thereby preventing EMT and the malignant progression of colorectal cancer. This study illustrated the role of COMP in EMT and suggested that COMP/TAGLN may be a potential tumor therapeutic target. Chrysin exhibits obvious antitumor effects. This work provides a preliminary antitumor therapy to target COMP or its interaction protein to inhibit EMT.
Deglycosylated Azithromycin Targets Transgelin to Enhance Intestinal Smooth Muscle Function.
Zhong Weilong,Sun Bo,Ruan Hao,Yang Guang,Qian Baoxin,Cao Hailong,He Lingfei,Fan Yunjing,Roberts Arthur G,Liu Xiang,Hu Xuejiao,Liang Yuan,Ye Qing,Yin Tingting,Wang Bangmao,Yang Cheng,Sun Tao,Zhou Honggang
Azithromycin (AZM) has been widely used as an antibacterial drug for many years. It has also been used to treat delayed gastric emptying. However, it exerts several side effects. We found that deglycosylated AZM (Deg-AZM or CP0119), an AZM metabolite, is a positively strong intestinal agonist that may result in the intestinal mobility experienced by patients after AZM administration. We confirmed that Deg-AZM can function strongly on intestinal peristalsis and identified transgelin as its potential molecular target. Furthermore, our pharmacological studies showed that the binding of Deg-AZM to transgelin enhanced the contractility of intestinal smooth muscle cells by facilitating the assembly of actin filaments into tight bundles and stress fibers. Specifically, Deg-AZM promoted intestinal peristaltic activity in wild-type mice but not in transgelin (-/-) mice. Moreover, Deg-AZM did not exert antibacterial activity and did not disrupt intestinal flora. Thus, Deg-AZM may become a potential drug for slow-transit constipation treatment.
The effect of intermittent hypoxia and fecal microbiota of OSAS on genes associated with colorectal cancer.
Gao Jia,Cao Hailong,Zhang Qiang,Wang Bangmao
Sleep & breathing = Schlaf & Atmung
PURPOSE:Colorectal cancer (CRC) is one of the common causes of cancer death worldwide. Obstructive sleep apnea syndrome (OSAS), sharing many risk factors in common with CRC, is prevalent among CRC patients. OSAS may promote the CRC development independently but the mechanism is still unknown. Intermittent hypoxia (IH) is one of the characteristics of OSAS, and hypoxia may influence the genes associated with CRC. Intestinal microbiota plays important role in CRC carcinogenesis, and OSAS patients have been shown to have intestinal microbiota dysbiosis. We hypothesized that IH and intestinal microbiota dysbiosis may be involved for CRC in patients with OSAS. METHODS:We established precancerous cell models of CRC with Immorto-Min colonic epithelial (IMCE) cells. First, the cells were exposed to IH in a special chamber for 4 h, 8 h, and 12 h. Feces from 6 patients with OSAS and 6 healthy controls were collected and made into sterile fecal fluid for incubation with IMCE cells for 12 h. The cells were then exposed to IH for 4 h, 8 h, and 12 h. After IH exposure, the expressions of genes and inflammation cytokines associated with CRC, such as β-catenin, STAT3, HIF-1α, IL-6, TNF-α, c-myc, and cyclinD1, were tested. RESULTS:IH activated the expression of HIF-1α and STAT3 both in mRNA and protein level (HIF-1α: P = 0.015 for mRNA level, P = 0.027 for protein level; STAT3: P = 0.023 for mRNA level, P = 0.023 for protein level), and promoted p-STAT3 shifting to the nucleus (P = 0.023). The mRNA of β-catenin (P = 0.022) and cyclinD1 (P = 0.023) was elevated, but there was no change for the β-catenin protein in the nucleus. Gut microbiota of OSAS patients promoted the expression of STAT3 (protein level: 0 h: P = 0.037; 4 h: P = 0.046; 8 h: P = 0.049; 12 h: P = 0.037), promoted p-STAT3 (4 h: P = 0.049; 8 h: P = 0.046; 12 h: P = 0.046) shifting to the nucleus, and also elevated the expression of IL-6 and TNF-α in mRNA level at 4 h (IL-6: P = 0.037, TNF-α: P = 0.037) and 8 h (IL-6: P = 0.037, TNF-α: P = 0.037). The protein of β-catenin in the nucleus was not affected by IH and gut microbiota from OSAS. CONCLUSIONS:Our study demonstrated that IH and gut microbiota of patients with OSAS activated HIF-1α expression and STAT3 pathway in IMCE cells, with no influence on β-catenin pathway, which suggested that IH, STAT3 pathway, chronic inflammation, and intestinal microbiota dysbiosis may be involved in CRC carcinogenesis correlated with OSAS These findings must be interpreted cautiously and further research is necessary to clarify the causative steps in CRC development.
The role of Bacillus acidophilus in osteoporosis and its roles in proliferation and differentiation.
Chen Chen,Dong Baokang,Wang Yuming,Zhang Qiang,Wang Bangmao,Feng Shuzhi,Zhu Yu
Journal of clinical laboratory analysis
BACKGROUND:Osteoporosis is one of the most closely related diseases associated with the elderly. In recent years, the studies found that gut microbiota can cause osteoporosis. We evaluated the role of Bacillus acidophilus in osteoporosis and its roles in proliferation and differentiation. METHODS:We selected 5 healthy people and 10 osteoporosis patients and analyzed their level of 25-hydroxyvitamin D and procollagen type I N-terminal peptide (PINP), the characteristic of gut microbiota. The effect of lactobacillus acidophilus and Lactobacillus rhamnosus supernatant and butanoic acids on proliferation, differentiation, and maturity of osteoblasts MC3T3-E1 and osteoclasts RAW 264.7 cells and the activity of alkaline phosphatase, concentration of osteocalcin, and the expression of RUNX2, RANK, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 were measured in the above cell lines. RESULTS:The diversity of gut microbiota in osteoporosis patients is decreased and imbalanced with lower abundance of lactobacillus and butyric acid bacteria; meanwhile, 25-hydroxyvitamin D and PINP of osteoporosis patient were significantly lower than the normal group. The proliferation, differentiation, and maturity of MC3T3-E1 cells were stimulated; the activity of alkaline phosphatase, concentration of osteocalcin, and the expression of RUNX2, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 were improved by supernatant of lactobacillus acidophilus, Lactobacillus rhamnosus and butanoic acids; however, the proliferation, differentiation, maturity, and the expression of RANK, NFATc1, cathepsin K, DC-STAMP, OSCAR, WNT2, and CTNNB1 in RAW 264.7 cells were suppressed. CONCLUSIONS:The lactobacillus acidophilus and Lactobacillus rhamnosus supernatant could stimulate the proliferation, differentiation, and maturation of osteoblasts; the production of butyric acid may be the potential mechanism.
Gut mycobiome: A promising target for colorectal cancer.
Qin Xiali,Gu Yu,Liu Tianyu,Wang Chen,Zhong Weilong,Wang Bangmao,Cao Hailong
Biochimica et biophysica acta. Reviews on cancer
The human gut is mainly habited by a staggering amount and abundance of bacteria as well as fungi. Gut dysbiosis is believed as a pivotal factor in colorectal cancer (CRC) development. Lately increasing evidence from animal or clinical studies suggested that fungal disturbance also contributed to CRC development. This review summarized the current status of fungal dysbiosis in CRC and highlighted the potential tumorigenic mechanisms of fungi. Then the fungal markers and some therapeutic strategies for CRC were discussed. It would provide a better understanding of the correlation of mycobiota and CRC, and modulating fungal community would be a promising target against CRC.