Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling

• Published in: Gut microbes Vol. 15; no. 2; p. 2274124
• Main Authors: Wang, Qiaoling, Lin, Huibin, Shen, Chongrong, Zhang, Minchun, Wang, Xingyu, Yuan, Miaomiao, Yuan, Mingyang, Jia, Sheng, Cao, Zhiwen, Wu, Chao, Chen, Banru, Gao, Aibo, Bi, Yufang, Ning, Guang, Wang, Weiqing, Wang, Jiqiu, Liu, Ruixin
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 18.12.2023; Taylor & Francis Group
• Subjects: Animals; bile acid; Bile Acids and Salts; diabetes; Gastrointestinal Microbiome; GLP-1; Glucagon-Like Peptide 1 - metabolism; Ileum; Mice; Microbiome; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Research Paper; Signal Transduction; TGR5; ileum; TGR5; GLP-1; bile acid; diabetes; Microbiome
• ISSN: 1949-0976; 1949-0984; 1949-0984
• DOI: 10.1080/19490976.2023.2274124

The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.