The Enterohepatic Circulatory System of Bile Acids: A Dynamic Endocrine Network Governing Metabolic and Inflammatory Balance

For centuries, bile acids (BAs) were primarily regarded as simple biological detergents, essential for the emulsification and absorption of dietary lipids and fat-soluble vitamins in the intestine. However, the last two decades have witnessed a paradigm shift in our understanding of these cholesterol-derived molecules. BAs are currently recognized as central signaling molecules responsible for orchestrating an intricate web of metabolic and inflammatory reactions in the body. This review synthesizes current research from 2020 to 2024 to describe the intricate biochemistry of BA synthesis from cholesterol that confers upon them their unique amphipathic nature. We review the molecular mechanisms by which BAs activate specific receptors, the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), to regulate glucose, lipid, and energy homeostasis. We also review the increasing role of the gut-liver axis and the gut microbiota in the regulation of the BA pool, creating a dynamic endocrine loop. Dysregulation of BA signaling is intimately intertwined with the pathology of numerous diseases, including cholestatic liver disease, metabolic syndrome, NAFLD, and inflammatory diseases. The current review highlights how the recent understanding of BAs as hormonal integrators has paved the way for fresh therapeutic possibilities, such as FXR and TGR5 agonists, which can cure such widespread diseases. Through the addition of new findings, this review emphasizes the transformation of BAs from humble gut digestive surfactants to becoming central characters in systemic physiology and disease.