Bile Acids and the Gut-X Axis: TCM-Mediated Systemic Protection and Therapeutic Opportunities for Multi-Organ...

The gut microbiota regulates host physiology and drives extraintestinal diseases through the gut-X axis. Bile acids (BAs) function as key mediators of this interorgan crosstalk by activating nuclear and membrane receptors (FXR, TGR5, PXR, VDR). Traditional Chinese Medicine (TCM) demonstrates efficacy across multiple organ systems through multi-component formulations. This narrative review synthesizes evidence from preclinical and clinical studies supporting that TCM exerts systemic protection via strategic modulation of the microbiota-BA-host receptor axis, which functions as a core regulatory circuit within a larger network of microbial metabolites. Mechanistically, representative TCM formulas remodel gut microbial ecology and reinforce intestinal barrier integrity, leading to optimized BA profiles. These favorable BA signatures engage tissue-specific receptor signaling to resolve inflammation, mitigate fibrosis, and restore metabolic homeostasis across the gut-heart, gut-kidney, gut-liver, gut-bone, and gut-endocrine axes. Support for this causal relationship is provided by microbiota depletion, fecal transplantation, and multi-omics studies, collectively suggesting that TCM's benefits are microbiota-dependent and at least partially BA-mediated. Moreover, context-dependent modulation of BA receptors, such as differential regulation of FXR, enables TCM to achieve pathology-specific outcomes. Current evidence is derived predominantly from preclinical models, and clinical data remain lacking. Nonetheless, the microbiota-BA-organ axis thus provides a potential framework for understanding TCM's systemic actions and establishes a molecular basis for developing microbiome-informed precision therapeutics. Future directions include patient stratification and precision intervention design inspired by TCM's ecological modulation strategies.