TY - JOUR T1 - Bariatric surgery reveals a gut-restricted TGR5 agonist that exhibits anti-diabetic effects JF - bioRxiv DO - 10.1101/2020.01.10.902346 SP - 2020.01.10.902346 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 Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/01/11/2020.01.10.902346.abstract N2 - 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. ER -