Interactions of dietary protein intake and intestinal resident microbiota affecting susceptibility to persistent Giardia infection and Giardia mediated enteropathy

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PROJECT SUMMARY Giardia lamblia belongs to a group of gut pathogens associated with impaired child development and gut function, especially in children with inadequate nutrition. Although most Giardia infections in these children are clinically silent, Giardia may lead to longterm detriments. For reasons that are unknown, many of these children cannot clear the parasite. Further, infected children may be at risk for gut dysfunction as a result of Giardia infection, even if they are asymptomatic. We hypothesize that susceptibility to Giardia and subsequent disease result from a change in the resident intestinal microbial community as a consequence of low dietary protein. Animal models provide an opportunity to dissect how an individual pathogen like Giardia impacts early life intestinal health, and a model to understand mechanisms whereby specific nutrients support host defenses and physiology. The objective of this proposal is to use our novel mouse models of Giardia infection in a state-of-the-art environment where we can define and control for all microbial exposures in the gut (gnotobiotics). We will combine our gnotobiotics expertise with expertise in microbial metagenomics and metabolomics for a rigorous examination of how dietary influences exert a functional change in the complex community or resident intestinal microbes. In Aim 1, we will determine how resident intestinal microbes normally protect against persistent Giardia infection by transferring intestinal microbes from a well-nourished animal into susceptible hosts, and vice versa transferring permissive microbes from hosts with chronic infection into nourished mice. We will specifically examine whether the ability of microbes to metabolize bile acids are key to protection against Giardia infection, and whether microbes are necessary for effective immunity. In Aim 2, we will determine how Giardia and protein deficiency synergize to cause intestinal barrier dysfunction. Our model has a clinically relevant outcome of growth restriction and loss of intestinal barrier function during the combined insult of limited protein intake and Giardia infection. We will use our gnotobiotic model to generate metagenomic and metabolomic data that will identify pathogenic shifts in microbial communities during Giardia infection. We will specifically elucidate the role of aromatic amino acid metabolites and bile acids on gut function in the protein deficient state, as well as whether Giardia promotes pathogenic bacterial functions to cause enteropathy. Our gnotobiotic approach is innovative and will allow us to characterize critical interactions between resident intestinal bacteria and infection with Giardia that have not previously been elucidated. The proposed research will address longstanding questions related to the role of Giardia on gut function, and specifically whether Giardia exerts pathogenesis by altering microbial metabolism. Beyond Giardia pathogenesis, these results are expected to lead to new considerations for how healthy bacteria provide protection against gut infection, and how chronic enteropathogen exposures cause gut dysfunction absent diarrhea. We hope to discover new pathways that might leverage emerging microbial or molecular-based therapeutics to improve health of children vulnerable to malnutrition and intestinal infections.