Project description:Bile acids (BAs) are a fundamental class of lipid emulsifying metabolites that are synthesized by hepatocytes, important for fat-soluble vitamin absorption, and maintained in vivo through enterohepatic circulation between the liver and ileum1. However, BAs are also lipophilic detergents and can be cytotoxic in enterohepatic tissues2. Whereas several nuclear receptors are known to prevent BA-driven toxicity in hepatocytes and intestinal enterocytes3, the mechanisms by which mucosal immune cells protect themselves from BAs in the ileum remains poorly understood. We recently reported that CD4+ T effector (Teff) cells upregulate expression of the xenobiotic transporter, MDR1, in the ileum to protect against BA toxicity and suppress Crohn’s disease-like small bowel inflammation4. Here, we identify the BA- and xenobiotic-sensing nuclear receptor, constitutive androstane receptor (CAR/NR1I3), as a key regulator of MDR1 expression in mucosal Teff cells. CAR promotes large-scale transcriptional reprogramming of Teff cells in the small intestine lamina propria (siLP), which shares similarities with CAR-dependent gene expression in hepatocytes and involves the induction of both detoxifying enzymes and transporters, as well as anti-inflammatory cytokines, such as Il10. Accordingly, loss of CAR in Teff cells exacerbates, whereas pharmacologic CAR activation suppresses, BA-driven ileitis in T cell-reconstituted Rag1-/- mice. Further, CAR transcriptional activity is evident in human CD4+ T cells, but only in 4+7+CCR9+ Teff cells that are licensed for small bowel homing. In these cells, CAR activation also promotes cyto-protective and anti-inflammatory gene expression, including a core set of transcriptional targets that are similarly regulated by CAR in mouse mucosal Teff cells and hepatocytes. Together, these results suggest that mucosal T cells rely on CAR to activate a hepatocyte-like transcriptional response in the ileum that detoxifies BAs and safeguards immune homeostasis. Pharmacologic activation of this program may offer an unexpected strategy to treat small bowel Crohn’s disease.

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The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids [shMdr1 RNA-seq in vivo]

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