Abstract
Bile acids (BAs) are lipid emulsifying metabolites synthesized in hepatocytes and maintained in vivo through enterohepatic circulation between the liver and small intestine1. As detergents, BAs can cause toxicity and inflammation in enterohepatic tissues2. Nuclear receptors maintain BA homeostasis in hepatocytes and enterocytes3, 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 inflammation4. 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.
Footnotes
This updated version contains additional information in main Figure 2d concerning genes and pathways activated downstream of CAR/Nr1i3 in small intestinal T cells. It also contains an additional supplementary table (2), which lists relevant gene sets from our statistical analyses of RNA-seq data in Figure 2a-d.
Abbreviations
- 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