美国哈佛医学院Jun R. Huh、纽约大学医学院Dan R. Littman和斯坦福大学Michael A. Fischbach等研究人员合作发现，胆汁酸代谢物调控T_H17和T_reg细胞的分化。2019年11月27日，《自然》在线发表了这项成果。

研究人员表示，胆汁酸在哺乳动物的肠道中很丰富，在那里它们经过细菌介导的转化而生成大量的生物活性分子。尽管已知胆汁酸会影响宿主代谢、癌症进展和先天免疫，但尚不清楚它们是否会影响适应性免疫细胞，例如表达IL-17a的辅助性T细胞（T_H17细胞）或调节性T细胞（T_reg细胞）。

研究人员筛选了胆汁酸代谢物的库，并鉴定了胆甾酸（LCA）的两种不同衍生物，即3-oxoLCA和isoalloLCA，作为小鼠中的T细胞调节剂。3-OxoLCA通过直接结合关键类视黄醇相关孤儿受体γt（RORγt）抑制T_H17细胞的分化，而isoalloLCA通过产生线粒体活性氧（mitoROS）来提高T_reg细胞的分化，从而导致FOXP3的表达增加。isoalloLCA介导的T_reg细胞分化增强需要Foxp3增强子，即保守的非编码序列（CNS）3；这代表了一种不同于先前确定的增加Treg细胞分化代谢物（需要CNS1）的作用方式。在小鼠体内注射3-oxoLCA和isoalloLCA分别降低了肠道固有层T_H17细胞分化以及提高了T_reg细胞分化。这些数据表明胆汁酸代谢物通过直接调节T_H17和T_reg细胞的平衡来控制宿主免疫反应的机制。

附：英文原文

Title: Bile acid metabolites control T H 17 and T reg cell differentiation

Author: Saiyu Hang, Donggi Paik, Lina Yao, Eunha Kim, Trinath Jamma, Jingping Lu, Soyoung Ha, Brandon N. Nelson, Samantha P. Kelly, Lin Wu, Ye Zheng, Randy S. Longman, Fraydoon Rastinejad, A. Sloan Devlin, Michael R. Krout, Michael A. Fischbach, Dan R. Littman, Jun R. Huh

Issue&Volume: 2019-11-27

Abstract: Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (TH17 cells) or regulatory T cells (Treg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of TH17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-t (RORt) and isoalloLCA increased the differentiation of Treg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of Treg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase Treg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced TH17 cell differentiation and increased Treg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of TH17 and Treg cells. Screening of a library of bile acid metabolites revealed two derivatives of lithocholic acid that act as regulators of T helper cells that express IL-17a and regulatory T cells, thus influencing host immune responses.

DOI: 10.1038/s41586-019-1785-z

Source: https://www.nature.com/articles/s41586-019-1785-z