CAR/Nr1i3 directs T cell adaptation to bile acids in the small intestine

Bile acids (BAs) are lipid emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine[1][1]. As detergents, BAs can cause toxicity and inflammation in enterohepatic tissues[2][2]. Nuclear receptors maintain BA homeostasis in hepatocytes and enterocytes[3][3], but it is unclear how mucosal immune cells tolerate high BA concentrations in the small intestine lamina propria (siLP). We previously reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter MDR1/ ABCB1 in the siLP to prevent BA toxicity and suppress Crohn’s disease-like small bowel inflammation[4][4]. Here, we identify the nuclear xenobiotic receptor, constitutive androstane receptor (CAR/ NR1I3 ), as a regulator of MDR1 expression in T cells, and safeguard against BA toxicity and inflammation in the small intestine. CAR was activated and induced large-scale transcriptional reprograming in Teff cells infiltrating the siLP, but not the colon. CAR induced expression of detoxifying enzymes and transporters in siLP Teff cells, as in hepatocytes, but also the key anti-inflammatory cytokine, Il10 . Accordingly, CAR-deficiency in T cells exacerbated, whereas pharmacologic CAR activation suppressed, BA-driven ileitis in T cell-reconstituted Rag −/− mice. These data suggest that CAR acts locally in small intestinal T cells to detoxify BAs and resolve inflammation. Activation of this program offers an unexpected strategy to treat small bowel Crohn’s disease, and provides evidence of lymphocyte sub-specialization within the small intestine. ### Competing Interest Statement M.S.S. is a consultant to Sigilon Therapeutics and Sage Therapeutics. * MDR1 : multidrug resistance 1 IFNγ : interferon gamma IL-10 : interleukin-10 IL-17 : interleukin-17 Abcb1a : ATP-binding cassette subfamily B, member 1a Abcb1b : ATP-binding cassette subfamily B, member 1b Rag1/2 : recombination-activating gene 1 or 2 [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4