Constitutive androstane receptor regulates the intestinal mucosal response to injury.
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.



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.



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.



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.
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Grace M
GM
Hudson
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Kyle L
KL
Flannigan
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Sarah L
SL
Erickson
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Fernando A
FA
Vicentini
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Alexandra
A
Zamponi
Department of Medicine, University of Calgary, Calgary, Canada.
Christina L
CL
Hirota
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Laurie
L
Alston
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.
Christophe
C
Altier
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Subrata
S
Ghosh
Department of Medicine, University of Calgary, Calgary, Canada.
Kevin P
KP
Rioux
Department of Medicine & Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Sridhar
S
Mani
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Thomas K
TK
Chang
Department of Physiology & Pharmacology, University of Calgary, Calgary, Canada.|Department of Microbiology, Immunology & Infectious Diseases, University of Calgary, Calgary, Canada.
Simon A
0000-0001-5782-1481
SA
Hirota
D000818:Animals; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced; D000090702:Constitutive Androstane Receptor; D016264:Dextran Sulfate; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010091:Oximes / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects
D000090702:Constitutive Androstane Receptor; D010091:Oximes; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D016264:Dextran Sulfate; C475093:6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime