Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography–mass spectrometry-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 Takeda G-protein receptor 5 (TGR5) agonist that increases Tgr5 expression and induces GLP-1 secretion. Furthermore, 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 the circulation. By studying changes in individual metabolites after surgery, the present study has revealed a naturally occurring TGR5 agonist that exerts systemic glucoregulatory effects while remaining confined to the gut.

减肥手术是治疗肥胖症和 2 型糖尿病最有效的方法，它与肠促胰岛素激素胰高血糖素样肽-1 (GLP-1) 水平升高和循环胆汁酸水平变化有关。然而，手术后胃肠道 (GI) 中单个胆汁酸的水平在很大程度上仍未得到研究。使用基于超高效液相色谱-质谱的定量分析，我们观察到袖状胃切除术后小鼠和人类胃肠道内源性胆汁酸、7-硫酸胆酸 (CA7S) 的增加。我们证明 CA7S 是一种武田 G 蛋白受体 5 (TGR5) 激动剂，可增加Tgr5表达并诱导 GLP-1 分泌。此外，CA7S 给药以 TGR5 依赖性方式增加胰岛素抵抗小鼠的葡萄糖耐量。CA7S 仍然受到肠道限制，最大限度地减少先前观察到的 TGR5 激动剂吸收到循环中的脱靶效应。通过研究手术后个体代谢物的变化，本研究揭示了一种天然存在的 TGR5 激动剂，它在发挥全身性血糖调节作用的同时仍局限于肠道。