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

Abstract

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. 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.

Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10 −/− Mice

“…EHS infection exacerbates the onset of disease in IL-10 Ϫ/Ϫ mice and thus is a frequently used model to study pathogen-induced IBD and colon cancer. H. hepaticus and H. bilis are the most thoroughly studied EHS; however, other EHS, like H. trogontum, H. typhlonius, H. rodentium, H. mastomyrinus, and H. cinaedi, a human pathogen, can also cause IBD-like disease in immunocompromised mice (9,11,34,(38)(39)(40). Because EHS-induced colitis in IL-10 Ϫ/Ϫ mice is well characterized, we chose this mouse model to investigate the pathogenic potential of H. saguini.…”

“…H. hepaticus, H. bilis, and other EHS infections in immunocompromised mice cause chronic typhlocolitis, high-grade dysplasia, and progression to colitis-associated carcinoma (CAC) (8)(9)(10)(11). Novel Helicobacter spp., including H. macacae, have been cultured from idiopathic colitis and colon adenocarcinomas in rhesus monkeys (12)(13)(14).…”

Biology and Diseases of Mice

“…H. hepaticus and H. bilis, e.g., can cause inflammation in the gastrointestinal tract, which is expressed as IBD and colon cancer in immunodeficient mice or typhlitis in A/JCr mice infected with H. hepaticus (Ward et al, 1996;Knutson et al, 2013;Shomer et al, 1997;Erdman et al, 2003b;Nguyen et al, 2013). colonize the crypts of the lower bowel, where, depending on host genotype, the organisms can be pathogenic or nonpathogenic.…”

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…Helicobacter hepaticus induces hepatitis and hepatocellular carcinoma in the liver in A/JCr mice; causes chronic intestinal inflammation in A/JCr, germfree Swiss Webster mice and immunodeficient mice; H.hepaticus also leads to IBD, associated colon cancer in immune-dysregulated mice (1). Helicobacter bilis is associated with hepatitis in aged inbred and outbred mice; caused IBD and colon cancer in severe combined immunodeficient mice multiple-drug resistance-deficient mice, and WASP-deficient mice and increases the susceptibility for gall stone formation in C57L/J mice (2)(3)(4)(5)(6). Several novel EHS have been reported in recent years.…”