Causes and consequences of interpersonal microbial variation

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Project Summary The human gastrointestinal tract harbors trillions of commensal microbes that collectively encode 150-fold more genes than the human genome; between individuals, microbiome variation far exceeds genome variation. Despite the possibility that the microbiome may represent a critical and readily modifiable component of human biology, the contribution of the gut microbiota to health, disease risk, and response to therapy remains largely undefined. The overall goal of our laboratory is to understand the principles, mechanisms, and processes that shape the interaction between gut microbial communities and their hosts. Our strategy is to combine anaerobic microbial genetics, high-throughput mass spectrometry, and gnotobiotic (germfree and ex- germfree) animal models to dissect these interactions. In recent studies, we have used these approaches to measure the contribution of the human gut microbiome to the metabolism of medical drugs and to define cooperative, competitive, and antagonistic processes in the gut microbiome. Our progress in these areas provides the basis for future studies centered on two themes. We will apply the metabolomic approaches we developed for studying microbiome-mediated drug metabolism to xenobiotic compounds that aren't drugs, including molecular components of food. Microbial genetic and gnotobiotic approaches also enable investigation of how two processes that are not readily measured in microbiome surveys, within-host evolution and phenotypic heterogeneity, contribute to host-microbiome interaction in the healthy and perturbed gut environment. If successful, these studies will define causes and consequences of host-microbiome interaction with broad implications for human health.