Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Spp.
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Fox_Colitis and.pdf
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Author(s)
Nguyen, Deanna D.
Goettel, Jeremy A.
Eston, Michelle A.
Mobley, Melissa W.
Taylor, Nancy S.
McCabe, Amanda F.
Marin, Romela
Snapper, Scott B.
Fox, James G.
Muthupalani, Sureshkumar
Alternative Title
Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Species
Date Issued
September 2013
Journal
Inflammatory Bowel Diseases
Publisher
Lippincott Williams & Wilkins
Citation
Nguyen, Deanna D., Suresh Muthupalani, Jeremy A. Goettel, Michelle A. Eston, Melissa Mobley, Nancy S. Taylor, Amanda McCabe, Romela Marin, Scott B. Snapper, and James G. Fox. “Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Species.” Inflammatory Bowel Diseases 19, no. 10 (2013): 2041–2050.
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Author's final manuscript
Abstract
Background: Wiskott–Aldrich syndrome protein–deficient patients and mice are immunodeficient and can develop inflammatory bowel disease. The intestinal microbiome is critical to the development of colitis in most animal models, in which Helicobacter spp. have been implicated in disease pathogenesis. We sought to determine the role of Helicobacter spp. in colitis development in Wiskott–Aldrich syndrome protein–deficient (WKO) mice.
Methods: Feces from WKO mice raised under specific pathogen-free conditions were evaluated for the presence of Helicobacter spp., after which a subset of mice were rederived in Helicobacter spp.–free conditions. Helicobacter spp.–free WKO animals were subsequently infected with Helicobacter bilis.
Results: Helicobacter spp. were detected in feces from WKO mice. After rederivation in Helicobacter spp.–free conditions, WKO mice did not develop spontaneous colitis but were susceptible to radiation-induced colitis. Moreover, a T-cell transfer model of colitis dependent on Wiskott–Aldrich syndrome protein–deficient innate immune cells also required Helicobacter spp. colonization. Helicobacter bilis infection of rederived WKO mice led to typhlitis and colitis. Most notably, several H. bilis–infected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls.
Conclusions: Spontaneous and T-cell transfer, but not radiation-induced, colitis in WKO mice is dependent on the presence of Helicobacter spp. Furthermore, H. bilis infection is sufficient to induce typhlocolitis and colon cancer in Helicobacter spp.–free WKO mice. This animal model of a human immunodeficiency with chronic colitis and increased risk of colon cancer parallels what is seen in human colitis and implicates specific microbial constituents in promoting immune dysregulation in the intestinal mucosa.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Division of Comparative Medicine
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DOI of Published Version
https://doi.org/10.1097/MIB.0b013e318295fd8f
