Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Maggio‐Price, Lillian; Treuting, Piper M.; Bielefeldt‐Ohmann, Helle; Seamons, Audrey; Drivdahl, Rolf H.; Zeng, Weiping; Lai, LapHin; Huycke, Mark M.; Phelps, Susan; Brabb, Thea; Iritani, Brian M.

doi:10.2353/ajpath.2009.080485

Cited by 36 publications

(33 citation statements)

References 62 publications

(69 reference statements)

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“…Interestingly, lesions in H. bilis- infected Rag2 −/− mice were found solely in the proximal colon, whereas the lesions in the H. hepaticus- infected Rag2 −/− mice were noted in the cecum [50]. In contrast, Smad3 −/− (129 -Smad3 tm/Par / J) mice infected with H. bilis or coinfected with H. bilis and H. hepaticus developed severe IBD; the mean survival time for these Rag2 −/− mice was only 19 weeks [51]. …”

Section: Discussionmentioning

confidence: 99%

Helicobacter cinaedi Induced Typhlocolitis in Rag‐2‐Deficient Mice

et al. 2014

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Background Helicobacter cinaedi, an enterohepatic helicobacter species (EHS), is an important human pathogen and is associated with a wide range of diseases, especially in immunocompromised patients. It has been convincingly demonstrated that innate immune response to certain pathogenic enteric bacteria is sufficient to initiate colitis and colon carcinogenesis in recombinase-activating gene (Rag)-2-deficient mice model. To better understand the mechanisms of human IBD and its association with development of colon cancer, we investigated whether H. cinaedi could induce pathological changes noted with murine enterohepatic helicobacter infections in the Rag2−/− mouse model. Materials and Methods Sixty 129SvEv Rag2−/− mice mouse were experimentally or sham infected orally with H. cinaedi strain CCUG 18818. Gastrointestinal pathology and immune responses in infected and control mice were analyzed at 3, 6 and 9 months postinfection (MPI). H. cinaedi colonized the cecum, colon, and stomach in infected mice. Results H. cinaedi induced typhlocolitis in Rag2−/− mice by 3 MPI and intestinal lesions became more severe by 9 MPI. H. cinaedi was also associated with the elevation of proinflammatory cytokines, interferon-γ, tumor-necrosis factor-α, IL-1β, IL-10; iNOS mRNA levels were also upregulated in the cecum of infected mice. However, changes in IL-4, IL-6, Cox-2, and c-myc mRNA expressions were not detected. Conclusions Our results indicated that the Rag2−/− mouse model will be useful to continue investigating the pathogenicity of H. cinaedi, and to study the association of host immune responses in IBD caused by EHS.

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Section: Discussionmentioning

confidence: 99%

Helicobacter cinaedi Induced Typhlocolitis in Rag‐2‐Deficient Mice

et al. 2014

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“…38 Likewise, H. bilis infection or co-infection with H. hepaticus leads to both colitis development and colorectal cancer in Smad3 −/− mice and, with greater severity, in Smad3 −/− Rag2 −/− mice. 39, 40 …”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

Muthupalani

Goettel

et al. 2013

Inflammatory Bowel Diseases

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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.

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“…Moreover, colonization of mice with some bacterial species (e.g. Fusobacterium nucleatus, Helicobacter, enterotoxigenic Bacteroides fragilis) promotes cancer while colonization with specific Lactobacillus strains does not [17,19-22]. …”

Section: Perspectivementioning

confidence: 99%

Fulfilling the Promise of Microbiomics to Revolutionize Medicine

Testerman¹

2015

JMEN

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Bacterial Infection of Smad3/Rag2 Double-Null Mice with Transforming Growth Factor-β Dysregulation as a Model for Studying Inflammation-Associated Colon Cancer

Cited by 36 publications

References 62 publications

Helicobacter cinaedi Induced Typhlocolitis in Rag‐2‐Deficient Mice

Helicobacter cinaedi Induced Typhlocolitis in Rag‐2‐Deficient Mice

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

Fulfilling the Promise of Microbiomics to Revolutionize Medicine

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