美国斯克里普斯研究所Mark S. Sundrud、加州大学伯克利分校David D. Moore等研究人员合作发现，CAR指导T细胞适应小肠中的胆汁酸。这一研究成果于2021年4月7日在线发表在国际学术期刊《自然》上。

研究人员表示，胆汁酸是在肝细胞中合成的脂质乳化代谢产物，通过肝脏和小肠之间的肝肠循环在体内得以维持。作为清洁剂，胆汁酸可引起肠肝组织的毒性和炎症。核受体维持肝细胞和肠细胞中的胆汁酸稳态，但是尚不清楚粘膜免疫细胞如何耐受小肠固有层（siLP）中高浓度的胆汁酸。CD4⁺T效应（T_eff）细胞上调siLP中异源生物转运蛋白MDR1（由Abcb1a编码）的表达，从而防止胆汁酸中毒并抑制克罗恩病样小肠炎症。

研究人员发现，核异源生物受体CAR（由Nr1i3编码）是T细胞中MDR1表达的调节因子，其可以预防小鼠小肠的胆汁酸毒性和炎症。CAR的激活在渗透siLP但未渗透结肠的T_eff细胞中诱导大规模转录重编程。在siLP T_eff细胞中，CAR不仅像在肝细胞中一样诱导解毒酶和转运蛋白的表达，而且还诱导关键的抗炎细胞因子IL-10的表达。因此，在T细胞中，CAR缺乏会加剧重组T细胞的Rag1^-/-或Rag2^-/-小鼠的胆汁酸驱动性回肠炎，而CAR的药理学激活会抑制这个过程。这些数据表明，CAR在渗透小肠的T细胞中发挥局部作用，从而解毒胆汁酸并缓解炎症。该程序的激活提供了一种治疗小肠克罗恩病的新策略，并定义了小肠中的淋巴细胞亚分化。 

附：英文原文

Title: CAR directs T cell adaptation to bile acids in the small intestine

Author: Mei Lan Chen, Xiangsheng Huang, Hongtao Wang, Courtney Hegner, Yujin Liu, Jinsai Shang, Amber Eliason, Huitian Diao, HaJeung Park, Blake Frey, Guohui Wang, Sarah A. Mosure, Laura A. Solt, Douglas J. Kojetin, Alex Rodriguez-Palacios, Deborah A. Schady, Casey T. Weaver, Matthew E. Pipkin, David D. Moore, Mark S. Sundrud

Issue&Volume: 2021-04-07

Abstract: Bile acids are lipid-emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, bile acids can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain bile acid homeostasis in hepatocytes and enterocytes3, but it is unclear how mucosal immune cells tolerate high concentrations of bile acids in the small intestine lamina propria (siLP). CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1 (encoded by Abcb1a) in the siLP to prevent bile acid toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here we identify the nuclear xenobiotic receptor CAR (encoded by Nr1i3) as a regulator of MDR1 expression in T cells that can safeguard against bile acid toxicity and inflammation in the mouse small intestine. Activation of CAR induced large-scale transcriptional reprogramming in Teff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine IL-10. Accordingly, CAR deficiency in T cells exacerbated bile acid-driven ileitis in T cell-reconstituted Rag1/ or Rag2/ mice, whereas pharmacological activation of CAR suppressed it. These data suggest that CAR acts locally in T cells that infiltrate the small intestine to detoxify bile acids and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn’s disease and defines lymphocyte sub-specialization in the small intestine.

DOI: 10.1038/s41586-021-03421-6

Source: https://www.nature.com/articles/s41586-021-03421-6