Secondary bile acids and host metabolism: crosstalk, signaling pathways and therapeutic frontiers

Bile acids, traditionally regarded as detergents essential for lipid solubilization and absorption, are now recognized as potent endocrine and immunomodulatory molecules that integrate metabolic, microbial, and inflammatory pathways. Primary bile acids synthesized from cholesterol in the liver are transformed by gut microbiota into an extensive repertoire of secondary and microbially derived bile acids (MDBAs) that act as signaling mediators across multiple organs. These metabolites regulate host metabolism and immune homeostasis through activation of nuclear and membrane receptors, including FXR, GPBAR1, VDR, CAR, and RORγt. FXR-FGF19 and GPBAR1-GLP-1 pathways mediate enterohepatic and entero-pancreatic communication, modulating glucose and lipid metabolism, while GPBAR1 activation in thermogenic tissues promotes thyroid hormone conversion and energy expenditure. Moreover, lithocholic acid and related secondary bile acids engage AMPK-sirtuin signaling, mimicking the systemic benefits of caloric restriction and contributing to longevity. By shaping the gut microbial ecosystem and influencing host physiology, bile acids constitute a molecular bridge between the microbiota and systemic metabolism. In this context, understanding the signaling landscape of secondary bile acids provides crucial insights into host-microbiota communication and unveils innovative therapeutic perspectives for metabolic, immune, and age-related disorders.