Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects

Abstract

Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone GLP-1 and changes in 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 increases Tgr5 expression and induces GLP-1 secretion. Further, CA7S administration increases glucose tolerance in insulin-resistant mice in a TGR5-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.

A microbial metabolite remodels the gut-liver axis following bariatric surgery

“…Because mice post-SG displayed higher levels of LCA in the portal vein, we hypothesized that more LCA was being synthesized by bacteria in the intestine of mice post-SG. Contrary to our hypothesis, we had observed a significant decrease in levels of LCA in the cecum of mice post-SG, while the levels of DCA and total BAs were unchanged (Chaudhari et al, 2020). We observed similar changes in stool samples from human patients that had undergone SG.…”

“…GLP-1 is a major mediator of diabetes remission post-SG (Kaska et al, 2016;Larraufie et al, 2019). Consistent with our previous studies, we observed an increase in circulating levels of GLP-1 in DIO mice that were subjected to SG (Chaudhari et al, 2020) (Figure 1F). However, treatment of DIO mice with antibiotics pre-and post-SG ablated the SG-mediated increase in GLP-1 secretion ( Figure 1G).…”

“…Previous studies have documented overall changes to BA pools postsurgery (Kohli et al, 2013;Patti et al, 2009;Pournaras et al, 2012). Recently, we have demonstrated the importance of studying changes in levels of individual BAs after bariatric surgery (Chaudhari et al, 2020). We identified a specific BA, cholic acid-7-sulfate (CA7S), that is increased in both murine cecal contents and feces of human patients post-SG.…”

“…CA7S triggers the activation of TGR5 and subsequently GLP-1 secretion to improve glucose tolerance in vivo (Chaudhari et al, 2020). GLP-1 is a major mediator of diabetes remission post-SG (Kaska et al, 2016;Larraufie et al, 2019).…”

Simulating the Post-gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR

“…This is also supported by the finding that the jejunal contents of RYGB-operated rats stabilized barrier function in Caco-2 cells independently of FXR, since bile flow is redirected away from the upper/mid jejunum post-operatively. Nevertheless, future bile acid measurements of the duodenal and colonic contents of RYGB-operated rats by nuclear magnetic resonance spectroscopy are needed to identify the precise molecular mechanisms responsible for their barrier-stabilizing effects, akin to that performed for mouse cecal contents in the context of enhanced enteroendocrine cell function following VSG ( Chaudhari et al., 2020 ).…”