Hyocholic Acid Species Improve Glucose Homeostasis Through a Distinct TGR5 and FXR Signaling Mechanism

Hyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 71% of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that BA depletion in pig models suppresses secretion of glucagon-like peptide-1 (GLP-1) and increases blood glucose levels. Oral administration of HCA species increased serum fasting GLP-1 secretion levels to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, 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 was associated with diabetes and were closely related to glycemic markers.