Colitis and Colon Cancer in WASP-Deficient Mice Require Helicobacter Spp

Background—Wiskott-Aldrich Syndrome protein (WASP)-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 WASP-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 re-derivation 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 WASP-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. bilisinfected animals developed dysplasia with 10% demonstrating colon carcinoma, which was not observed in uninfected controls. Corresponding authors: Scott B. Snapper, M.D., Ph.D., [email protected], phone: 617-919-4973, fax 617-730-0498; and James G. Fox, DVM [email protected], phone: 617-253-1757, fax: 617-258-5708. DISCLOSURE The authors have no financial conflict of interest to declare. NIH Public Access Author Manuscript Inflamm Bowel Dis. Author manuscript; available in PMC 2014 September 01. Published in final edited form as: Inflamm Bowel Dis. 2013 September ; 19(10): 2041–2050. doi:10.1097/MIB.0b013e318295fd8f. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript 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.