Constitutive androstane receptor regulates the intestinal mucosal response to injury

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1857-1871
Number of pages15
JournalBritish Journal of Pharmacology
Volume174
Issue number12
DOIs
StatePublished - 2017

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Wounds and Injuries
Xenobiotics
Ulcerative Colitis
Inflammatory Bowel Diseases
Crohn Disease
Wound Healing
constitutive androstane receptor
Inflammation
Dextran Sulfate
Microbiota
Colitis
Benzene
Drinking Water
Cell Movement
Rodentia
Homeostasis
Biopsy

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hudson, G. M., Flannigan, K. L., Erickson, S. L., Vicentini, F. A., Zamponi, A., Hirota, C. L., ... Hirota, S. A. (2017). Constitutive androstane receptor regulates the intestinal mucosal response to injury. British Journal of Pharmacology, 174(12), 1857-1871. https://doi.org/10.1111/bph.13787

Constitutive androstane receptor regulates the intestinal mucosal response to injury. / Hudson, Grace M.; Flannigan, Kyle L.; Erickson, Sarah L.; Vicentini, Fernando A.; Zamponi, Alexandra; Hirota, Christina L.; Alston, Laurie; Altier, Christophe; Ghosh, Subrata; Rioux, Kevin P.; Mani, Sridhar; Chang, Thomas K.; Hirota, Simon A.

In: British Journal of Pharmacology, Vol. 174, No. 12, 2017, p. 1857-1871.

Research output: Contribution to journalArticle

Hudson, GM, Flannigan, KL, Erickson, SL, Vicentini, FA, Zamponi, A, Hirota, CL, Alston, L, Altier, C, Ghosh, S, Rioux, KP, Mani, S, Chang, TK & Hirota, SA 2017, 'Constitutive androstane receptor regulates the intestinal mucosal response to injury', British Journal of Pharmacology, vol. 174, no. 12, pp. 1857-1871. https://doi.org/10.1111/bph.13787
Hudson GM, Flannigan KL, Erickson SL, Vicentini FA, Zamponi A, Hirota CL et al. Constitutive androstane receptor regulates the intestinal mucosal response to injury. British Journal of Pharmacology. 2017;174(12):1857-1871. https://doi.org/10.1111/bph.13787
Hudson, Grace M. ; Flannigan, Kyle L. ; Erickson, Sarah L. ; Vicentini, Fernando A. ; Zamponi, Alexandra ; Hirota, Christina L. ; Alston, Laurie ; Altier, Christophe ; Ghosh, Subrata ; Rioux, Kevin P. ; Mani, Sridhar ; Chang, Thomas K. ; Hirota, Simon A. / Constitutive androstane receptor regulates the intestinal mucosal response to injury. In: British Journal of Pharmacology. 2017 ; Vol. 174, No. 12. pp. 1857-1871.
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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.",
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AU - Flannigan, Kyle L.

AU - Erickson, Sarah L.

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AU - Zamponi, Alexandra

AU - Hirota, Christina L.

AU - Alston, Laurie

AU - Altier, Christophe

AU - Ghosh, Subrata

AU - Rioux, Kevin P.

AU - Mani, Sridhar

AU - Chang, Thomas K.

AU - Hirota, Simon A.

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AB - 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.

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