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

Qiaoling Wang; Huibin Lin; Chongrong Shen; Minchun Zhang; Xingyu Wang; Miaomiao Yuan; Mingyang Yuan; Sheng Jia; Zhiwen Cao; Chao Wu; Banru Chen; Aibo Gao; Yufang Bi; Guang Ning; Weiqing Wang; Jiqiu Wang; Ruixin Liu

doi:10.1080/19490976.2023.2274124

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

Gut Microbes. 2023 Dec;15(2):2274124. doi: 10.1080/19490976.2023.2274124. Epub 2023 Nov 9.

Authors

Qiaoling Wang^{1

2}, Huibin Lin^{1

2}, Chongrong Shen^{1

2}, Minchun Zhang^{1

2}, Xingyu Wang^{1

2}, Miaomiao Yuan^{1

2}, Mingyang Yuan^{1

2}, Sheng Jia^{1

2}, Zhiwen Cao^{1

2}, Chao Wu^{1

2}, Banru Chen^{1

2}, Aibo Gao^{1

2}, Yufang Bi^{1

2}, Guang Ning^{1

2}, Weiqing Wang^{1

2}, Jiqiu Wang^{1

2}, Ruixin Liu^{1

2}

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

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.

Keywords: GLP-1; Microbiome; TGR5; bile acid; diabetes; ileum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Acids and Salts
Gastrointestinal Microbiome*
Glucagon-Like Peptide 1* / metabolism
Ileum
Mice
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Signal Transduction

Substances

Glucagon-Like Peptide 1
Receptors, G-Protein-Coupled
Bile Acids and Salts

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (92157204, 82250901, 81930021, 82088102, and 82200935). National Key Research and Development Program of China (2021YFA1301103, 2022YFC2505201), Science and Technology Commission of Shanghai Municipality (21JC1404400, 23XD1422400), Innovative Research Team of High-level Local Universities in Shanghai, and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20171903 Round 2).