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How chemotaxis and endogenous microbiota alter the disease outcome of Helicobacter pylori infection


The gastric pathogen Helicobacter pylori infects 50% of the world's population. Infection can lead to a range of diseases from asymptomatic gastritis to gastric or duodenal ulcers to gastric cancer. The reason for this disparity in disease development is an outstanding question in H. pylori pathogenesis. This thesis examines three components affecting disease outcome: H. pylori stomach localization, the immune response to H. pylori, and the host endogenous microbiota.

Some H. pylori strains preferentially colonize in the antrum, the distal region of the stomach. Inflammation in the antrum leads to duodenal ulcers--one of the most common disease outcomes of H. pylori infection. This suggests that H. pylori stomach localization may contribute to disease progression. H. pylori antral localization is affected by chemotaxis, or movement in response to chemical cues. Using standard microbiological techniques and H. pylori chemotaxis mutants (Che-) we found that chemotaxis, and specifically the chemoreceptor TlpD, is necessary for bacterial survival and/or growth in the increased inflammatory environment of the antrum.

Che- mutants also cause less overall stomach inflammation than wild-type H. pylori, which makes Che- infections a good model for asymptomatic H. pylori infections. Thus we compared immune responses in Che- mutant versus wild-type H. pylori infected mouse stomachs using immunohistochemistry, flow cytometry, and quantitative PCR. Increased virulence factor expression, host cell apoptosis, and T-helper type 17 (Th17) cells characterized the inflammatory wild-type H. pylori infection. We concluded that chemotaxis drives H. pylori to interact with the host and induce pathological Th17 immune responses that promote chronic inflammation.

Lastly, one previously unappreciated parameter influencing H. pylori disease outcome is variation in pre-infection host microbiota. We altered the gut microbiota in mice by antibiotic treatment and found that microbiota alterations resulted in significantly reduced CD4+ T-helper cells and Ifng transcript in gastric tissue after H. pylori infection. The altered bacterial communities had significantly more cluster IV and XIVa Clostridium spp., bacteria known to increase regulatory T cell populations. Our findings suggest that microbiota composition contributes to the variable disease outcome of H. pylori infection by promoting specific immune cell recruitment or differentiation.

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