PT  - JOURNAL ARTICLE
AU  - Snehal N. Chaudhari
AU  - David A. Harris
AU  - Hassan Aliakbarian
AU  - Matthew T. Henke
AU  - Renuka Subramaniam
AU  - Ashley H. Vernon
AU  - Ali Tavakkoli
AU  - Eric G. Sheu
AU  - A. Sloan Devlin
TI  - Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects
AID  - 10.1101/2020.01.10.902346
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.10.902346
4099  - http://biorxiv.org/content/early/2020/01/11/2020.01.10.902346.short
4100  - http://biorxiv.org/content/early/2020/01/11/2020.01.10.902346.full
AB  - Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.