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 (T_eff) 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 T_eff cells that infiltrated the siLP, but not the colon. CAR induced the expression of not only detoxifying enzymes and transporters in siLP T_eff 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.

胆汁酸是在肝细胞中合成的脂质乳化代谢物，并通过肝脏和小肠之间的肠肝循环维持在体内¹ 。作为去污剂，胆汁酸可引起肠肝组织毒性和炎症² 。核受体维持肝细胞和肠上皮细胞中的胆汁酸稳态³ ，但尚不清楚粘膜免疫细胞如何耐受小肠固有层 (siLP) 中的高浓度胆汁酸。 CD4 ⁺ T 效应 (T _eff ) 细胞上调 siLP 中异生物质转运蛋白 MDR1（由Abcb1a编码）的表达，以防止胆汁酸毒性并抑制克罗恩病样小肠炎症⁴ 。在这里，我们确定了核异生素受体 CAR（由Nr1i3编码）作为 T 细胞中 MDR1 表达的调节因子，可以防止小鼠小肠中的胆汁酸毒性和炎症。 CAR 的激活诱导了 T _eff细胞的大规模转录重编程，这些细胞浸润了 siLP，但没有浸润到结肠。与肝细胞一样，CAR 不仅诱导 siLP T _eff细胞中解毒酶和转运蛋白的表达，还诱导关键的抗炎细胞因子 IL-10 的表达。因此，T细胞中的CAR缺陷加剧了T细胞重建的Rag1 ^−/−或Rag2 ^{− / −}小鼠中胆汁酸驱动的回肠炎，而CAR的药理学激活则抑制了这种情况。这些数据表明，CAR 在浸润小肠的 T 细胞中局部发挥作用，以解毒胆汁酸并解决炎症。 该程序的激活提供了一种意想不到的治疗小肠克罗恩病的策略，并定义了小肠中淋巴细胞的亚特化。