DESCRIPTION (provided by applicant): Environmental factors, especially microbiota, modify genetic susceptibility to many chronic diseases. The NGRRC provides an essential resource for local, regional, national and international multidisciplinary investigators to explore the hypothess that commensal bacteria strongly influence physiologic processes in normal hosts and pathogenic inflammatory, metabolic and neoplastic responses in genetically susceptible hosts. This unit provides a resource for broadly based NIH-funded investigators to examine physiologic and pathophysiologic differences in germ-free (sterile) vs. gnotobiotic (known life, selectively colonized) vs. specific pathogen-free mice of different genetic backgrounds, to explore the functional alterations of normal vs. dysbiotic bacterial communities in murine models and human diseases, and to define the functional relevance of bacterial genes. The microbiota can be precisely manipulated by colonizing germ-free rodents with single or multiple commensal or pathogenic bacterial, viral or fungal species using isogenic wild type or genetically engineered bacterial strains. In addition, fecal transplants can be performed from murine models or human donors. Specific aims: 1. Provide germ-free or selectively colonized wild type and mutant mice or their tissues and cells to NIH-funded investigators. 2. Derive additional GF genetically engineered mouse strains for NIH-funded investigators. 3. Support pilot studies for investigators with novel hypotheses to generate preliminary data for NIH grant applications. 4. Train personnel to develop gnotobiotic facilities in other institutions, 5. Develop innovative techniques to improve our gnotobiotic resource. We provide a unique and essential resource for a multidisciplinary group of NIH-funded investigators to study the physiologic and pathophysiologic function of normal and dysbiotic commensal bacteria, with particular emphasis on gene/environmental interactions in genetically altered mice (transgenic, knockout or spontaneously mutated) with altered physiology and disease phenotypes. In the past 4 years of funding, the NGRRC provided 8930 gnotobiotic mice to 73 investigators in 46 institutions. 62 funded and 11 submitted NIH grants (in 6 Institutes) by 52 investigators depend on gnotobiotic mice from the NGRRC.

PUBLIC HEALTH RELEVANCE: Altered microbiota composition (dysbiosis) is associated with a number of inflammatory (IBD, NASH, atherosclerosis), metabolic (diabetes, metabolic syndrome), neoplastic (colon cancer) and even behavioral (depression, autism) disorders. However the functional consequences of these compositional changes and the role of individual bacterial species remain unknown. Selective colonization of gnotobiotic mice with native or genetically engineered bacterial species or defined consortia can determine bacterial function, host/microbial and microbial/microbial interactions.