The bacterium Vibrio cholerae causes cholera, a devastating diarrhea disease that affects millions of people worldwide each year. Cholera is endemic in many areas that suffer from poor sanitation, and imposes an immense burden in terms of mortality and illness, often on those countries least able to afford it. Despite advances in understanding how V. cholerae causes disease, there is still a lack of mechanisms to prevent the spread of cholera. Our previous studies have found that specific configurations of the gut microbiome, or the community of resident bacteria in the gastrointestinal tract of all humans, mediate susceptibility to V. cholerae infection. We hypothesize that individual differences in commensal microbes may be a risk factor for cholera. This proposal aims to determine the relationship between the structure of the gut microbiome and the ability of V. cholerae to colonize and cause disease. Studies of pathogen-microbiome interactions are limited by a lack of suitable animal models, a problem that is particularly acute for cholera research, as the behavior of the pathogen differs between many animal models and humans, while other models are limited by cost and availability. We have begun to adapt a popular and readily accessible animal model of V. cholerae pathogenesis, the suckling mouse model, to allow for the establishment of human microbiomes prior to infection. Using these and gnotobiotic adult colonization models, we will determine how human gut microbiomes drive the biochemical milieu of the gut into pathogen-resistant or susceptible states. These mechanisms may determine the establishment and composition of the adult gut microbial community, and thus determine personalized infectious disease risk. These studies will improve the accessibility of models for studying how gut microbiomes influence bacterial infections of the gut, and identify new targets for prophylactic and therapeutic manipulations of the gut microbiome to combat V. cholerae.