Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism

Hyocholic acid (HCA) and its derivatives are found in trace amounts in human blood but constitute approximately 76% of the bile acid (BA) pool in pigs, a species known for its exceptional resistance to type 2 diabetes. Here, we show that BA depletion in pigs suppressed secretion of glucagon-like peptide-1 (GLP-1) and increased blood glucose levels. HCA administration in diabetic mouse models improved serum fasting GLP-1 secretion and glucose homeostasis to a greater extent than tauroursodeoxycholic acid. HCA upregulated GLP-1 production and secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor (FXR), a unique mechanism that is not found in other BA species. We verified the findings in TGR5 knockout, intestinal FXR activation, and GLP-1 receptor inhibition mouse models. Finally, we confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers. [Display omitted] •HCA is the primary BA in pigs, a species known for its exceptional resistance to T2DM•Serum HCA levels are inversely correlated with glucose levels in humans with T2DM•HCA exhibit strong effects on glucose regulation in the pig and diabetic mouse models•HCA promote GLP-1 secretion via simultaneously activating TGR5 and inhibiting FXR Pigs are routinely raised on obesogenic diets yet are resistant to the development of T2DM. Zheng et al. report that a group of bile acids, hyocholic acid and its derivatives (HCAs), the primary bile acids in pigs, are inversely correlated with glucose levels in subjects with T2DM. They further discover that HCAs promote GLP-1 production and secretion through a distinct TGR5 and FXR signaling mechanism.