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.
Article first published online 1 July 2013
*Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts;
†Harvard Medical School, Boston, Massachusetts;
‡Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, Massachusetts;
§Department of Gastroenterology/Nutrition, Boston Children’s Hospital, Boston, Massachusetts; and
‖Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.
Reprints: Scott B. Snapper, MD, PhD, Department of Gastroenterology/Nutrition, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115 (e-mail: firstname.lastname@example.org); James G. Fox, DVM, Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 16-825, Cambridge, MA 02139 (email: jgfox@MIT.edu).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).
Supported by the National Institutes of Health (K08DK083430 to D.D.N.; R01AI50950, P01 HL059561, and P30 DK34854 to S.B.S.; and R01OD011141, R01CA067529, P01CA026731, and P30ES02109 to J.G.F.) and Crohn’s and Colitis Foundation of America Career Development Award 2193 (to D.D.N.).
The authors have no conflicts of interest to disclose.
Received March 10, 2013
Accepted June 04, 2013