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.

Automated summary

This study reveals that high levels of hyocholic acid (HCA) in pigs contribute to their resistance against type 2 diabetes, as depletion of bile acids (BA) in pigs leads to reduced glucagon-like peptide-1 (GLP-1) secretion and increased blood glucose levels. HCA administration in diabetic mouse models effectively improves GLP-1 secretion and glucose homeostasis by activating TGR5 and inhibiting FXR in enteroendocrine cells, a mechanism not seen in other BA species. Clinical findings also show a correlation between lower levels of HCA species and diabetes, indicating its importance in glycemic control.