Bile acids as metabolic regulators.

PURPOSE OF REVIEW: This review focuses on the latest understanding of the molecular mechanisms underlying the complex interactions between intestine and liver bile acid signaling, gut microbiota, and their impact on whole-body lipid, glucose and energy metabolism.

RECENT FINDINGS: Hepatic bile acid synthesis is tightly regulated by the bile acid negative feedback mechanisms. Modulating the enterohepatic bile acid signaling greatly impacts the whole-body metabolic homeostasis. Recently, a positive feedback mechanism through intestine farnesoid X receptor (FXR) antagonism has been proposed to link gut microbiota to the regulation of bile acid composition and pool size. Two studies identified intestine Diet1 and hepatic SHP-2 as novel regulators of CYP7A1 and bile acid synthesis through the gut-liver FXR-fibroblast growth factor 15/19-FGF receptor four signaling axis. New evidence suggests that enhancing bile acid signaling in the distal ileum and colon contributes to the metabolic benefits of bile acid sequestrants and bariatric surgery.

SUMMARY: Small-molecule ligands that target TGR5 and FXR have shown promise in treating various metabolic and inflammation-related human diseases. New insights into the mechanisms underlying the bariatric surgery and bile acid sequestrant treatment suggest that targeting the enterohepatic circulation to modulate gut-liver bile acid signaling, incretin production and microbiota represents a new strategy to treat obesity and type 2 diabetes.