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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. [ABSTRACT FROM AUTHOR]

Mesalazine [5-aminosalicylic acid (5-ASA)] has been used for over 30 years in the treatment of inflammatory bowel disease (IBD). It is a highly effective, safe, and well-tolerated drug for treatment of mild to moderate ulcerative colitis, which represents most patients with this disease. Recent studies of patient adherence to 5-ASA therapies in ulcerative colitis have highlighted the need for regimens that enable long-term compliance to significantly reduce the risk of troublesome and debilitating flares in the short term, and possibly colon cancer in the long term. Indeed, much of the recent innovation in clinical use of 5-ASA in colitis has come from studies of novel delivery mechanisms and simplified oral dosing schedules. These studies have provided much needed clarity on essential matters such as starting dose, dose escalation, and efficacy in terms of the ideal clinical endpoint - mucosal healing. Various manufacturers are re-evaluating their products to determine the safety and efficacy of such dosing regimens. Although once widely employed in the treatment of Crohn’s disease (CD), the accumulated body of evidence now suggests that there is a much more limited role for 5-ASA in this particular form of inflammatory bowel disease. Recent 5-ASA randomized-controlled trials, comparative studies, and outcomes research have led to refined treatment strategies and awareness for practitioners to better inform, engage and facilitate patients in optimal use of 5-ASA in inflammatory bowel disease. [ABSTRACT FROM PUBLISHER]