Advances in bile acid metabolism-mediated immunomodulation

Bile acids (BAs) were usually recognized for their classical role in lipid emulsification and absorption. Currently BAs have emerged as multifunctional signaling metabolites that bridge host metabolism, intestinal microbiota, and immune regulation. This review aims to provide a comprehensive overview of recent advances in BA metabolism–mediated immunomodulation, highlight the bidirectional interactions between BAs and immune cells, and discuss the therapeutic opportunities stemming from BA‑related pathways. Based on the biosynthesis, enterohepatic circulation, microbial transformation, and structural classification of BAs, we discuss the modifications of BA composition and concentration and the influence on hepatic and intestinal homeostasis. Key metabolic enzymes such as CYP7A1, CYP8B1, and CYP27A1, as well as transporters including BSEP and NTCP, govern the dynamic BA pool and thereby shape metabolic and inflammatory responses. Then, we review how BAs modulate innate immunity by acting on diverse myeloid cell subsets. Through nuclear receptors such as FXR and VDR, and membrane receptors such as TGR5, BAs regulate monocyte–macrophage polarization, support anti‑inflammatory phenotypes, and attenuate cytokine production. In dendritic cells, BA‑activated FXR, RAR‑α, and TGR5 pathways influence antigen presentation and cytokine expression, thereby shaping T‑cell priming. Furthermore, FXR activation promotes the expansion and suppressive activity of myeloid‑derived suppressor cells, while BA‑dependent modulation of neutrophil recruitment and activation contributes to tissue‑specific inflammatory outcomes. The effects of primary and secondary BAs on NK cells and NKT cells further illustrate the intricate role of BA signaling in liver immunity and tumor surveillance. In addition, we address the impact of BAs on adaptive immunity. BAs and their microbial metabolites regulate CD4+ T cell fate, favoring regulatory T‑cell differentiation and restraining pro‑inflammatory Th17 responses. For CD8+ T cells, distinct BA species exert divergent effects. Primary BAs may impair cytotoxic T‑cell survival through oxidative stress, whereas certain secondary BAs induce endoplasmic reticulum stress and functional exhaustion. Conversely, ursodeoxycholic acid (UDCA) mitigates these detrimental effects and enhances antitumor immunity, highlighting the therapeutic potential of modulating BA composition. Finally, we discuss key regulatory nodes including FXR, TGR5, and PPARs, and summarize recent drug development strategies targeting BA receptors and transporters. FXR agonists such as obeticholic acid have already entered clinical use for cholestatic liver diseases, while emerging TGR5 modulators, NTCP inhibitors, and CYP enzyme regulators are being explored for metabolic, inflammatory, and oncologic indications. Understanding the interplay between BA metabolism, gut microbiome, and immune pathways will facilitate the identification of biomarkers and accelerate the development of precision therapeutics. Overall, BA‑mediated immunoregulation represents a rapidly evolving field at the intersection of metabolism, microbiology, and immunology. Continued mechanistic insights will support innovative therapeutic strategies for autoimmune liver diseases, inflammatory bowel disease, metabolic disorders, and cancer.