Diet transformation by the microbiome and its impact on bacterial infection

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Project Summary Food contains a vast collection of bioactive small molecules that encounter enormous populations of commensal microbes in the gastrointestinal tract. Microbiome metabolism has been reported across dietary compound classes; however, the microbial enzymes that metabolize dietary small molecules can be highly substrate specific and these activities can vary widely between individuals. The impact of diet on the microbiome is also well established. Thus, the gut microbiome is likely a determining factor in an individual's dietary metabolite exposure, with implications for infection, cancer, inflammatory diseases, cardiovascular diseases, and other diseases impacted by diet. Microbes and diet directly intersect in the context of infections caused by the food-borne enteropathogens Salmonella enterica serovar Typhimurium and Campylobacter jejuni, which cause tens of millions of cases of food-borne illness every year, largely through consumption of chicken and other poultry products. Progress understanding these interactions would transform our ability to manage this major public health challenge, enabling interventions in humans and in our food chain where diet can be directly prescribed. This proposal will test the hypothesis that modification of dietary compounds by the gut microbiota, and disruption of the microbiota by dietary compounds, determines the function of these molecules in modulating colonization resistance (pathogen exclusion by the microbiome), pathogen growth, and virulence in humans and in our food chain. In Aim 1, we will generate a systematic map of the metabolism of over 100 dietary compounds by over 100 gut microbes and microbiomes from two human cohorts and chickens at the level of communities, species, enzymes, and metabolites. In Aim 2, we will determine how these compounds modulate colonization resistance in gnotobiotic mouse and gnotobiotic chicken models of S. Typhimurium and C. jejuni infections. In Aim 3, we will measure how dietary compounds and their microbial metabolites impact pathogen growth and virulence in vitro, in 2D monolayers derived from intestinal organoids, and in gnotobiotic animals. Together, these studies will define how the reciprocal interactions between diet and the microbiome determine the outcome of food-borne infections, a major public health risk.