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.
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.
Authors: Katharine H Banner; Christophe Cattaneo; Jean-Loic Le Net; Aleksandar Popovic; David Collins; Jeremy D Gale Journal: Br J Pharmacol Date: 2004-10-04 Impact factor: 8.739
Authors: Jürgen Glas; Julia Seiderer; Daniel Fischer; Barbara Tengler; Simone Pfennig; Martin Wetzke; Florian Beigel; Torsten Olszak; Maria Weidinger; Burkhard Göke; Thomas Ochsenkühn; Matthias Folwaczny; Bertram Müller-Myhsok; Julia Diegelmann; Darina Czamara; Stephan Brand Journal: Inflamm Bowel Dis Date: 2010-12-03 Impact factor: 5.325
Authors: Stephen Ph Alexander; Doriano Fabbro; Eamonn Kelly; Neil Marrion; John A Peters; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; Christopher Southan; Jamie A Davies Journal: Br J Pharmacol Date: 2015-12 Impact factor: 8.739
Authors: Grace M Hudson; Kyle L Flannigan; Sarah L Erickson; Fernando A Vicentini; Alexandra Zamponi; Christina L Hirota; Laurie Alston; Christophe Altier; Subrata Ghosh; Kevin P Rioux; Sridhar Mani; Thomas K Chang; Simon A Hirota Journal: Br J Pharmacol Date: 2017-04-19 Impact factor: 8.739
Authors: Stephen J Keely; Andreacarola Urso; Alexandr V Ilyaskin; Christoph Korbmacher; Nigel W Bunnett; Daniel P Poole; Simona E Carbone Journal: Am J Physiol Gastrointest Liver Physiol Date: 2021-11-10 Impact factor: 4.052
Authors: Dennis R Warner; Jeffrey B Warner; Josiah E Hardesty; Ying L Song; Taylor N King; Jing X Kang; Chih-Yu Chen; Shanfu Xie; Fang Yuan; Md Aminul Islam Prodhan; Xipeng Ma; Xiang Zhang; Eric C Rouchka; Krishna Rao Maddipati; Joan Whitlock; Eric C Li; Gary P Wang; Craig J McClain; Irina A Kirpich Journal: J Lipid Res Date: 2019-10-04 Impact factor: 5.922
Authors: Jennifer K Heppert; James M Davison; Cecelia Kelly; Gilberto Padilla Mercado; Colin R Lickwar; John F Rawls Journal: Nat Rev Gastroenterol Hepatol Date: 2020-10-06 Impact factor: 46.802
Authors: Timothy S Jayme; Gabriella Leung; Arthur Wang; Matthew L Workentine; Sruthi Rajeev; Adam Shute; Blanca E Callejas; Nicole Mancini; Paul L Beck; Remo Panaccione; Derek M McKay Journal: Sci Adv Date: 2020-06-05 Impact factor: 14.136