The effects of a helminth-altered gut metabolome and deworming on host immunity




Brosschot, Tara Pauline

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Helminths are parasitic worms that can establish long-lived infections by modulating host immune responses. Helminth infection has been associated with a reduced prevalence of allergic disease in human populations, and impaired immunity to co-infecting pathogens. Several human and mouse studies suggest that helminths may impair host responses to concurrent bacterial infection. In this thesis, we study the extent to which helminth infection affects Salmonella colonization and how anthelmintic treatment (deworming) impacts immunity to Salmonella in a mouse model of co-infection. We find that helminth co-infection allows Salmonella to establish in the lumen of the small intestine. Further, we find that deworming prior to bacterial infection restores impaired immunity to Salmonella in the small intestine, however, deworming after Salmonella has established during helminth co-infection does not revert elevated bacterial burdens. To ensure their longevity in the host, helminths release immunomodulatory molecules, and modulate immunity through changes in the gut microbiota. The microbiota is known to influence mucosal immunity through the production of metabolites, but metabolites have not received much attention in the context of helminth modification of immune responses. This thesis uncovers the impact of helminth infection on levels of short-chain fatty acids (SCFAs) and bile acids, two groups of metabolites with immunomodulatory potential. We found that helminth infection increases small intestinal levels of the branched-chain SCFA isovalerate and lowers the small intestinal bile acid concentration. We next explored the consequences of these metabolite shifts on susceptibility to bacterial infection, helminth fitness and regulatory T cells. Collectively, these results contribute to the understanding of host-pathogen interactions in a co-infection scenario, which ultimately, will help to inform strategies for disease control in helminth-endemic areas. Further, our data contributes to the characterization of the helminth-modified intestinal metabolome, which future work can build on to reveal novel immunomodulatory pathways that can be targeted to relieve symptoms in inflammatory diseases such as allergic asthma.



Microbiology, Parasitology, Immunology, Metabolomics, Infectious disease