Dipartimento di Scienze Biomediche e Chirurgiche, Università di Perugia, Piazza L. Severi 1, 06100, Perugia, Italy.
Scuola di Specializzazione in Malattie Apparato Digerente, Università di Perugia, Perugia, Italy.
Dig Dis Sci. 2021 Mar;66(3):674-693. doi: 10.1007/s10620-020-06715-3. Epub 2020 Dec 8.
Bile acids are a group of chemically different steroids generated at the host/microbial interface. Indeed, while primary bile acids are the end-product of cholesterol breakdown in the host liver, secondary bile acids are the products of microbial metabolism. Primary and secondary bile acids along with their oxo derivatives have been identified as signaling molecules acting on a family of cell membrane and nuclear receptors collectively known as "bile acid-activated receptors." Members of this group of receptors are highly expressed throughout the gastrointestinal tract and mediate the bilateral communications of the intestinal microbiota with the host immune system. The expression and function of bile acid-activated receptors FXR, GPBAR1, PXR, VDR, and RORγt are highly dependent on the structure of the intestinal microbiota and negatively regulated by intestinal inflammation. Studies from gene ablated mice have demonstrated that FXR and GPBAR1 are essential to maintain a tolerogenic phenotype in the intestine, and their ablation promotes the polarization of intestinal T cells and macrophages toward a pro-inflammatory phenotype. RORγt inhibition by oxo-bile acids is essential to constrain Th17 polarization of intestinal lymphocytes. Gene-wide association studies and functional characterizations suggest a potential role for impaired bile acid signaling in development inflammatory bowel diseases (IBD). In this review, we will focus on how bile acids and their receptors mediate communications of intestinal microbiota with the intestinal immune system, describing dynamic changes of bile acid metabolism in IBD and the potential therapeutic application of targeting bile acid signaling in these disorders.
胆汁酸是一组在宿主/微生物界面生成的化学性质不同的甾体化合物。事实上，虽然初级胆汁酸是宿主肝脏中胆固醇分解的终产物，但次级胆汁酸是微生物代谢的产物。初级和次级胆汁酸及其氧化衍生物已被确定为信号分子，作用于一组被称为“胆汁酸激活受体”的细胞膜和核受体。该受体家族的成员在整个胃肠道中高度表达，并介导肠道微生物群与宿主免疫系统的双向通讯。胆汁酸激活受体 FXR、GPBAR1、PXR、VDR 和 RORγt 的表达和功能高度依赖于肠道微生物群的结构，并受肠道炎症的负调控。基因敲除小鼠的研究表明，FXR 和 GPBAR1 对于在肠道中维持耐受表型至关重要，它们的缺失会促进肠道 T 细胞和巨噬细胞向促炎表型极化。氧化胆汁酸对 RORγt 的抑制对于限制肠道淋巴细胞中 Th17 的极化至关重要。全基因组关联研究和功能特征表明，胆汁酸信号受损可能在炎症性肠病 (IBD) 的发展中起作用。在这篇综述中，我们将重点讨论胆汁酸及其受体如何介导肠道微生物群与肠道免疫系统的通讯，描述 IBD 中胆汁酸代谢的动态变化，以及靶向这些疾病中胆汁酸信号的潜在治疗应用。
