Environmental factors modify genetic susceptibility to many chronic diseases. Resident microbiota profoundly influence physiologic responses in multiple organs and are linked to many inflammatory (IBD, NASH, atherosclerosis, MS), metabolic (obesity, diabetes, metabolic syndrome, osteoporosis, hypertension), neoplastic (colon, pancreatic cancer) and behavioral (depression, autism) disorders, and responses to treatments (immunotherapies, biologic therapies). Altered microbiota (dysbiosis) and metabolites associated with these conditions and the Human Microbiome Project make this research a worldwide priority. However, functional consequences and the primary vs. secondary nature of these compositional changes and the role of individual bacterial species and combinations are poorly understood. Gnotobiotic animal models address causality and mechanisms of these host-microbe interactions. The National Gnotobiotic Rodent Resource Center (NGRRC) provides an essential resource for local and national multidisciplinary investigators to explore these key functional relationships. The NGRRC provides germ-free (GF, sterile) wild type and genetically- engineered gnotobiotic mice that are not available to most investigators due to the specialized technical expertise and stringent husbandry necessary for their creation, breeding and study beyond the resources and expertise of most NIH grantees. Our resource allows investigators to examine physiologic and pathogenic differences in GF and gnotobiotic (selectively colonized) vs. conventionally raised mice, functional relevance of bacterial genes and individual and defined groups of microbes to explore host/microbe, microbe/microbe and dietary/microbe interactions. Maintaining gnotobiotic animals is extremely labor intensive, expensive and requires considerable training to apply compulsive sterile technique, with sterility monitored by a series of quality control steps. Goal: Support broadly based gnotobiotic research by local and national NIH-funded investigators with reliable, cost-effective and easily accessed resources. Aims: 1. Provide GF and gnotobiotic WT and mutant mice, their tissues and cells to NIH-funded investigators. 2. Derive additional GF genetically engineered mouse strains. 3. Support pilot studies for new investigators to generate preliminary data for NIH grant applications. 4. Train personnel to develop murine gnotobiotic facilities in other institutions. We provide a unique, cost effective and essential resource for a large, multidisciplinary group of NIH-funded investigators to study physiologic and pathophysiologic functions of normal and dysbiotic resident microbiota, alone or in aggregate, with particular emphasis on gene/ environmental interactions in genetically altered mice (transgenic, knockout or spontaneously mutated) with altered physiology and disease phenotypes.