Helminth Co-infection in Helicobacter Pylori Infected Ins- Gas Mice Attenuates Gastric Premalignant Lesions of Epithelial Dysplasia and Glandular Atrophy and Preserves Accessed Terms of Use Helminth Co-infection in Helicobacter Pylori Infected Ins-gas Mice Attenuates Gastric Premalignant Lesions of

The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Abstract Higher prevalence of helminth infections in H. pylori infected children was suggested to potentially lower the lifetime risk for gastric adenocarcinoma. In rodent models, helminth co-infection does not reduce Helicobacter-induced inflammation but delays progression of pre-malignant gastric lesions. Because gastric cancer in INS-GAS mice is promoted by intestinal microflora, the impact of Heligmosomoides polygyrus co-infection on H. pylori-associated gastric lesions and microflora were evaluated. Male INS-GAS mice co-infected with H. pylori and H. polygyrus for 5 months were assessed for gastrointestinal lesions, inflammation-related mRNA expression, FoxP3 + cells, epithelial proliferation, and gastric colonization with H. pylori and Altered Schaedler Flora. Despite similar gastric inflammation and high levels of proinflammatory mRNA, helminth co-infection increased FoxP3 + cells in the corpus and reduced H. pylori-associated gastric atrophy (p<0.04), dysplasia (p<0.02) and prevented H. pylori-induced changes in the gastric flora (p<0.05). This is the first evidence of helminth infection reducing H. pylori-induced gastric lesions while inhibiting changes in gastric flora, consistent with prior observations that gastric colonization with enteric microbiota accelerated gastric lesions in INS-GAS mice. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Identifying how helminths reduce gastric premalignant lesions and impact bacterial colonization of the H. pylori infected stomach could lead to new treatment strategies to inhibit progression from chronic gastritis to cancer in humans.

[1]  A. Sheh,et al.  Draft Genome Sequences of Helicobacter pylori Strains Isolated from Regions of Low and High Gastric Cancer Risk in Colombia , 2013, Genome Announcements.

[2]  A. Sheh,et al.  The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis , 2013, Gut microbes.

[3]  L. Bravo,et al.  Serologic Evidence that Ascaris and Toxoplasma Infections Impact Inflammatory Responses to Helicobacter pylori in Colombians , 2012, Helicobacter.

[4]  M. Piazuelo,et al.  The gastric precancerous cascade , 2012, Journal of digestive diseases.

[5]  D. Morgan,et al.  Sex Hormones, Hormonal Interventions, and Gastric Cancer Risk: A Meta-analysis , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[6]  Yue Chen,et al.  The phenotype and function of naturally existing regulatory dendritic cells in nematode-infected mice. , 2011, International journal for parasitology.

[7]  R. DiPaolo,et al.  Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity , 2011, The Journal of Immunology.

[8]  J. Fox,et al.  Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice , 2011, Infection and Immunity.

[9]  Chien-wen Su,et al.  Duodenal Helminth Infection Alters Barrier Function of the Colonic Epithelium via Adaptive Immune Activation , 2011, Infection and Immunity.

[10]  L. Bravo,et al.  Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk , 2011, Gut.

[11]  J. McDougall,et al.  Infection with an intestinal helminth parasite reduces Freund's complete adjuvant-induced monoarthritis in mice. , 2011, Arthritis and rheumatism.

[12]  E. Touati When bacteria become mutagenic and carcinogenic: lessons from H. pylori. , 2010, Mutation research.

[13]  H. Sugihara,et al.  Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori , 2010, Gut.

[14]  A. Rudensky,et al.  Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway , 2010, The Journal of experimental medicine.

[15]  S. Arihiro,et al.  Heligmosomoides polygyrus Infection Can Inhibit Colitis through Direct Interaction with Innate Immunity , 2010, The Journal of Immunology.

[16]  J. Fox,et al.  Brugia filariasis differentially modulates persistent Helicobacter pylori gastritis in the gerbil model. , 2010, Microbes and infection.

[17]  T. Wang,et al.  Combination of sulindac and antimicrobial eradication of Helicobacter pylori prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. , 2009, Cancer research.

[18]  J. Fox,et al.  Concurrent Helicobacter bilis Infection in C57BL/6 Mice Attenuates Proinflammatory H. pylori-Induced Gastric Pathology , 2009, Infection and Immunity.

[19]  J. Urban,et al.  Anti-Inflammatory Mechanisms of Enteric Heligmosomoides polygyrus Infection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model , 2008, Infection and Immunity.

[20]  L. Samson,et al.  DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. , 2008, The Journal of clinical investigation.

[21]  T. Wang,et al.  Helicobacter pylori eradication prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. , 2008, Cancer research.

[22]  G. Qvigstad,et al.  Proton pump inhibitors and gastric neoplasia , 2007, Gut.

[23]  T. Wang,et al.  Inflammation, atrophy, and gastric cancer. , 2007, The Journal of clinical investigation.

[24]  J. Fox,et al.  Rapid Onset of Ulcerative Typhlocolitis in B6.129P2-IL10tm1Cgn (IL-10−/−) Mice Infected with Helicobacter trogontum Is Associated with Decreased Colonization by Altered Schaedler's Flora , 2006, Infection and Immunity.

[25]  M. Ohtani,et al.  Colonization Dynamics of Altered Schaedler Flora Is Influenced by Gender, Aging, and Helicobacter hepaticus Infection in the Intestines of Swiss Webster Mice , 2006, Applied and Environmental Microbiology.

[26]  J. Fox,et al.  Thiol-reactive compounds prevent nonspecific antibody binding in immunohistochemistry , 2006, Laboratory Investigation.

[27]  E. Purdom,et al.  Molecular analysis of the bacterial microbiota in the human stomach. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Timothy C Wang,et al.  Helicobacter pylori but not high salt induces gastric intraepithelial neoplasia in B6129 mice. , 2005, Cancer research.

[29]  L. Bravo,et al.  Intestinal Helminthiasis in Colombian Children Promotes a Th2 Response to Helicobacter pylori: Possible Implications for Gastric Carcinogenesis , 2005, Cancer Epidemiology Biomarkers & Prevention.

[30]  J. Fox,et al.  Spatial Distribution and Stability of the Eight Microbial Species of the Altered Schaedler Flora in the Mouse Gastrointestinal Tract , 2004, Applied and Environmental Microbiology.

[31]  K. Washington,et al.  Pathology of mouse models of intestinal cancer: consensus report and recommendations. , 2003, Gastroenterology.

[32]  M. Stolte,et al.  Diagnostic criteria for gastrointestinal carcinomas in Japan and Western countries: Proposal for a new classification system of gastrointestinal epithelial neoplasia , 2000, Journal of gastroenterology and hepatology.

[33]  Mark T. Whary,et al.  Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy , 2000, Nature Medicine.

[34]  T. Wang,et al.  High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. , 1999, Cancer research.

[35]  F. Dewhirst,et al.  Phylogeny of the Defined Murine Microbiota: Altered Schaedler Flora , 1999, Applied and Environmental Microbiology.

[36]  C. Ingui,et al.  A helminth-induced mucosal Th2 response alters nonresponsiveness to oral administration of a soluble antigen. , 1998, Journal of immunology.

[37]  T. Wang,et al.  Processing and proliferative effects of human progastrin in transgenic mice. , 1996, The Journal of clinical investigation.

[38]  M. Scott,et al.  Energy restriction and severe zinc deficiency influence growth, survival and reproduction of Heligmosomoides polygyrus (Nematoda) during primary and challenge infections in mice , 1995, Parasitology.

[39]  T. Wang,et al.  Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia. , 2011, Gastroenterology.

[40]  E. El-Omar,et al.  Genetics of inflammation in the gastrointestinal tract and how it can cause cancer. , 2011, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[41]  G. Rieder,et al.  Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. , 2002, Gastroenterology.

[42]  T. Wang,et al.  Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. , 2000, Gastroenterology.