The function of the gut microbiota–bile acid–TGR5 axis in diarrhea-predominant irritable bowel syndrome

作者：Kai Zhan, Haomeng Wu, Yongyin Xu, Kehan Rao, Huan Zheng, Shumin Qin, Yuanming Yang, Jia Rui, Weihuan Chen, Shaogang Huang · 发表于：mSystems · 年份：2024 · DOI：10.1128/msystems.01299-23 · 被引用次数：28 · 研究领域：Gastrointestinal motility and disorders、Gut microbiota and health、Helicobacter pylori-related gastroenterology studies

ABSTRACT Imbalanced gut microbiota (GM) and abnormal fecal bile acid (BA) are thought to be the key factors for diarrhea-predominant irritable bowel syndrome (IBS-D), but the underlying mechanism remains unclear. Herein, we explore the influence of the GM–BA–Takeda G-protein-coupled receptor 5 (TGR5) axis on IBS-D. Twenty-five IBS-D patients and fifteen healthy controls were recruited to perform BA-related metabolic and metagenomic analyses. Further, the microbiota-humanized IBS-D rat model was established by fecal microbial transplantation (FMT) to investigate the GM–BA–TGR5 axis effects on the colonic barrier and visceral hypersensitivity (VH) in IBS-D. Finally, we used chenodeoxycholic acid (CDCA), an important BA screened out by metabolome, to evaluate whether it affected diarrhea and VH via the TGR5 pathway. Clinical research showed that GM associated with bile salt hydrolase (BSH) activity such as Bacteroides ovatus was markedly reduced in the GM of IBS-D, accompanied by elevated total and primary BA levels. Moreover, we found that CDCA not only was increased as the most important primary BA in IBS-D patients but also could induce VH through upregulating TGR5 in the colon and ileum of normal rats. TGR5 inhibitor could reverse the phenotype, depression-like behaviors, pathological change, and level of fecal BSH in a microbiota-humanized IBS-D rat model. Our findings proved that human-associated FMT could successfully induce the IBS-D rat model, and the imbalanced GM–BA–T...