《生命科学》 2026, 38(3): 454-462
基于胆汁酸代谢介导免疫调控的研究进展
摘 要：
胆汁酸不仅参与机体脂质乳化吸收，而且作为多效性信号代谢物参与机体及微生物群相互作用，调控机体代谢平衡。近年研究发现胆汁酸还具有复杂的免疫调节功能，影响髓系细胞（单核-巨噬细胞、树突状细胞、髓源性抑制细胞、中性粒细胞）和淋巴细胞（CD4+ T 细胞、CD8+ T 细胞）的功能、表型和活化状态，调控机体免疫代谢相关通路，进而影响自身免疫性肝病、炎症性肠病和肿瘤的发生发展。基于胆汁酸代谢通路和作用机制的研究，包括对胆汁酸受体 FXR 和 PPAR、转运蛋白 BSEP 和 NTCP，以及胆汁酸代谢酶等关键因子系统分析，不仅有助于揭示胆汁酸免疫调节新机制，而且为炎症、代谢免疫及肿瘤等相关疾病的防治药物开发提供新思路和新策略。
通讯作者：杨全军 , Email:myotime@sjtu.edu.cn
Abstract:
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.
Communication Author：YANG Quan-Jun , Email:myotime@sjtu.edu.cn
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