Mechanism of H. pylori-induced risk reduction for inflammatory bowel disease

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Helicobacter pylori infection is widely prevalent as more than half of the world's population is colonized with this organism. H. pylori infection has clearly been linked to the development of gastritis, peptic ulcer disease and certain gastric malignancies, yet close to 90% of infected individuals will remain asymptomatic despite lack of treatment. The prospect of H. pylori infection offering protective benefits, however, has not been well studied. The broad long-term objective of this proposal is to elucidate how H. pylori infection may aid in the prevention of inflammatory bowel disease. We hypothesize that H. pylori will direct a regulatory T cell (T reg) skewing in the Th17:Treg axis mediated by dendritic cells leading to immunoregulation against inflammatory bowel disease. The specific aims of this research include investigation into the mechanisms H. pylori genomic DNA is able to induce dendritic cell Treg skewing. Furthermore, this research proposal will examine the impact of H. pylori DNA on mouse susceptibility to chronic dextran sulfate sodium-colitis. Briefly, by using H. pylori genomic DNA and TLR9 knockout mice and small interfering RNA to knockdown TLR-9, we will examine the role of bacterial DNA-TLR-9 interaction in shaping the phenotype of murine bone marrow- derived and tissue isolated gastric mucosal dendritic cells, and Its influence on an experimental model of IBD. PUBLIC HEALTH RELEVANCE: The results of this research will impact further our understanding of the potential benefits of H. pylori colonization in lowering the risk of chronic inflammatory conditions such as inflammatory bowel disease and asthma. If indeed there is mechanistic evidence to support the epidemiological data suggesting H. pylori is protective against the development of inflammatory bowel disease, further thought regarding completely eliminating this infection, an infection which produces symptoms in only 10% of infected individuals, will need to be re-addressed. Furthermore, by elucidating the mechanism by which H. pylori does protect against IBD, insight can be gained into the development of more effective treatment for inflammatory bowel disease.