The diet is our sole source of nutrients, yet we are just beginning to understand how the human gut microbiota acts as an essential layer of metabolism. Resident microbes not only help to capture plant-derived carbohydrates from our diet, but also likely encounter (and modify) a steady stream of drug-like molecules from plants, a number of which are known to have important biological activity in humans (e.g. anti-inflammatory isoflavonoids and chemo preventative glucosinolates). We propose that these plant-derived small molecules mediate plant-microbe interactions not only in the rhizosphere, but also in the human gut. In this capacity, dietary compounds from plants might represent the most important environmental perturbation regularly experienced by the gut microbiota. Furthermore, we suggest that sensing and processing of dietary plant molecules by the gut microbiota generates compounds with enhanced biological activities, and therefore functions as a central mechanism for diet-based disease prevention. This project will characterize in molecular detail key plant-microbe interactions that take place in the human gut, and will elucidate the mechanisms by which gut microbes directly influence the absorption of 'plant drugs'from diet. Specific outcomes of this project will be insight into (1) how key dietary small molecules with known biological activity are processed, activated, and presented by gut microflora to the human host, and (2) how these metabolites impact microbial community dynamics in the gut. Our proposed experimental approach will draw on our expertise in chemical analysis, natural products biochemistry, and metabolic pathways. This work will be carried out in collaboration with the Sonnenburg lab in Microbiology and Immunology at Stanford who will contribute experience in gut microbiota community dynamics and gnotobiotic mouse models. We anticipate that the identification of how key dietary plant-derived molecules impact gut microbial species will enable the reprogramming of gut metabolism to maximize nutrient harvest and create a novel means of controlling a microbial niche that has a direct effect on human health and disease.