Fiorucci Stefano, Marchianò Silvia, Distrutti Eleonora, Biagioli Michele
Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy.
Liver Res. 2025 Jan 28;9(1):1-16. doi: 10.1016/j.livres.2025.01.005. eCollection 2025 Mar.
Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.
与传统类固醇类似，胆汁酸作为信号分子发挥作用，作用于一系列膜受体和核受体。研究最为充分的胆汁酸调节受体是法尼醇X受体，它由初级胆汁酸激活；还有G蛋白偶联胆汁酸受体1（也称为武田G蛋白偶联受体5），它由次级胆汁酸激活，如石胆酸（LCA）和脱氧胆酸。法尼醇X受体和G蛋白偶联胆汁酸受体1均在先天免疫细胞、单核细胞/巨噬细胞和自然杀伤细胞中表达。它们在这些细胞中的激活提供了具有抑制性质的反调节信号，并减轻炎症。然而，近年来，人们越来越认识到肠道微生物群对胆汁酸的生物转化会导致形成化学性质不同的次级胆汁酸，这些次级胆汁酸能有效调节适应性免疫。两种LCA衍生物3-氧代LCA和异别alloLCA可结合仅由淋巴细胞表达的受体，如视黄酸受体相关孤儿受体γt（RORγt）和维生素D受体（VDR），从而将胆汁酸的调节作用扩展到T细胞，包括辅助性T细胞17和3型固有淋巴细胞（ILC3）。在这个新的概念框架中，胆汁酸已成为后生生物群的主要成分之一，后生生物群是肠道微生物群产生的化学介质废物阵列。解读这些介质与肠道和肝脏免疫系统之间的相互作用是胆汁酸复兴的一个新颖而迷人的领域。
