How does an animal deal with toxins ingested in the diet? One potential way is through the microbiota - that is, the assemblage of microbes that are associated with an animal. Evidence is accumulating that the microbiota plays an essential role in many aspects of animal biology. While the mechanism by which the microbiota may help an animal tolerate dietary toxins is potentially straightforward - microbial breakdown of those toxins in the intestinal tract - rarely, if ever, do studies explicitly link specific members of the microiota to host health and then identify the mechanisms by which those microbes benefit their host. Answering these basic questions is necessary for a fundamental understanding of the animal-diet-microbiota interaction. This application leverages the experimental tractability of the fruit ly Drosophila melanogaster to investigate how the microbiota affects host health in response to an ingested toxin, specifically dietary ethanol. D. melanogaster has emerged as a model for investigating non-pathogenic host-microbe interactions. Particularly important to this is the ability to experimentally clear Drosophila of its microbiota and then re-introduce defined microbial communities. Ethanol is a major component of rotting fruit, the primary diet of wild D. melanogaster and overconsumption negatively affects numerous aspects of fly health. In response to ethanol, flies show similar developmental and cognitive impairment as humans, thus, general principles discovered may be relevant to human health and behavior. Preliminary work has found that, when ingesting ethanol-supplemented diets, flies colonized with their normal microbiota are healthier than flies cleared of their microbes. By associating flies with individual microbial strains, this study will identify which microbes are responsible for this benefit. It will then investigate the potential mechanisms that underlie this effect. First, the colonization level of each microbe within the host will be measured to determine if microbes that do not impart a benefit are simply unable to effectively colonize the host. Next, the ethanol concentration in fly intestines will be measured to determine if beneficial bacteria are reducing ethanol concentrations in the host gut, thus suggesting a direct mechanism for microbially-mediated host benefit. The applicant will become proficient in all experimental techniques needed to complete this project. Additionally, through interactions with his Sponsors and other members of the UC Berkeley community, the applicant will gain the skills required to secure a position as a Principle Investigator at the conclusion of this fellowship. Finally, the proposed research is sufficiently distinct from that of his Sponsors, which will allow the applicant to use t as the basis for an independent research program in his own laboratory.