Bile acid signaling in health and disease

Abstract

Bile acids (BAs), cholesterol-derived amphipathic metabolites which are traditionally regarded as digestive surfactants, are now recognized as pleiotropic signaling molecules that act through ligand-, receptor-, and tissue-specific mechanisms to maintain systemic homeostasis. They exert biological functions via nuclear receptors (FXR, PXR, VDR, CAR) and membrane receptors (TGR5, S1PR2, MRGPRX4). These receptors activate transcriptional and membrane-initiated programs, including FXR–SHP/FGF19 feedback, TGR5–cAMP–PKA signaling, S1PR2–ERK/AKT/RhoA pathways, MRGPRX4-dependent Ca2⁺ signaling, PXR/CAR/VDR-driven detoxification responses, and non-receptor-mediated membrane and mitochondrial stress pathways. This review discusses how the diversity of BA structures, hepatic synthesis, conjugation, transportation, enterohepatic circulation, and microbiota-mediated transformation generates receptor- and tissue-specific signals. Furthermore, we summarize the physiological functions of BA signaling in lipid, glucose, and energy metabolism, intestinal epithelial integrity, mucosal immunity, neuroendocrine regulation, musculoskeletal adaptation, and renal water-salt balance. Additionally, we discuss the effects of disrupted BA signaling on cholestatic and metabolic liver diseases, alcohol-associated liver disease, hepatocellular carcinoma, inflammatory bowel disease, BA diarrhea, colorectal cancer, obesity, type 2 diabetes, atherosclerosis, and biliary tract diseases. Finally, the therapeutic strategies that modulate BA signaling, including the use of FXR and TGR5 agonists, FGF19 analogues, transporter inhibitors, enzyme-targeting methods, microbiota-based treatments, and hydrophilic BA therapies, are evaluated. By categorizing BA biology according to the production of ligands, receptor activation, tissue responses, and disease mechanisms, this review highlights BA signaling as an integrated regulatory network and a tractable therapeutic axis in health and disease.