Constitutive androstane receptor regulates the intestinal mucosal response to injury

Abstract

Background and Purpose The pathogenesis of the inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), involves aberrant interactions between a genetically susceptible individual, their microbiota and environmental factors. Alterations in xenobiotic receptor expression and function are associated with increased risk for IBD. Here, we have assessed the role of the constitutive androstane receptor (CAR), a xenobiotic receptor closely related to the pregnane X receptor, in the regulation of intestinal mucosal homeostasis. Experimental Approach CAR expression was assessed in intestinal mucosal biopsies obtained from CD and UC patients, and in C57/Bl6 mice exposed to dextran sulphate sodium (DSS; 3.5% w/v in drinking water) to evoke intestinal inflammation and tissue damage. CAR‐deficient mice were exposed to DSS and mucosal healing assessed. Modulation of wound healing by CAR was assessed in vitro. The therapeutic potential of CAR activation was evaluated, using 3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene (TCPOBOP), a selective rodent CAR agonist. Key Results CAR expression was reduced in CD and UC samples, compared with expression in healthy controls. This was reproduced in our DSS studies, where CAR expression was reduced in colitic mice. CAR‐deficient mice exhibited reduced healing following DSS exposure. In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration. Lastly, treating mice with TCPOBOP, following induction of colitis, enhanced mucosal healing. Conclusion and Implications Our results support the notion that xenobiotic sensing is altered during intestinal inflammation, and suggest that CAR activation may prove effective in enhancing mucosal healing in patients with IBD.

Emerging roles of bile acids in mucosal immunity and inflammation

“…151 As with PXR and VDR, polymorphisms in the CAR (NR1I3) locus have been associated with IBDs, and the expression of CAR and a number of its target genes have been found to be reduced in inflamed mucosal biopsies from CD and UC patients. 152 In mice, the small molecule CAR agonist, TCPOBOP, reduces severity of DSSinduced colitis, which is associated with reductions in both monocyte and macrophage mucosal infiltration and in proinflammatory cytokine expression ( Fig. 2).…”

“…153 Like PXR, CAR is thought to regulate IEC function in the context of wound healing; the selective human CAR agonist 6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) 154 increases IEC migratory activity. 152 In addition, a series of recent studies suggest that CAR-dependent transcriptional activity in IECs is influenced by the enteric flora. For example, dysbiosis induced by a high-fat diet leads to elevated expression of CAR target genes in the mouse intestine.…”

The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: An old story, yet mesmerizing

“…145 Decreased expression of CAR was found in the colon of both colitis mice models and IBD patients. 146 Cytosolic sulfotransferasesmediated sulfation is necessary for the detoxification of bile acids and may avoid colon cancer. Activation of CAR was associated with the induction of sulfotransferases to facilitate detoxification.…”

The xenobiotic sensing pregnane X receptor regulates tissue damage and inflammation triggered byC difficiletoxins

“…However, these receptors can also act as important regulators of inflammation and immunity, especially in the intestine. 27,[39][40][41] The PXR, a master regulator of the human drug metabolism enzyme CYP3A4 (CYP3A11 in mice), is expressed throughout the intestine and liver where it can "sense" endogenous and exogenous substances. At these sites, activation of the PXR can also exert anti-inflammatory and pro-healing effects.…”