ERIN CRC: Host-microbiota-pathogen interactions govern enteric health and disease

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DESCRIPTION (provided by applicant): The Michigan State University Enterics Research Investigational Network, Cooperative Research Center (MSU ERIN CRC) is a multidisciplinary Research Center proposal to study the enteric microbiome in health and disease with the overarching objective to elucidate its relationship to one of the most important global health problems, diarrheal illness. MSU ERIN CRC is a synergistic group of scientists from multiple disciplines, including microbial ecology, microbiology, immunology, epidemiology, and engineering, with cooperation from physicians working in infectious diseases, surgery, and pediatrics. Our long term goal is to determine the role of the microbiome in enhancing susceptibility or providing resistance to enteric diseases. We will focus on relationships between factors mediating diarrheal disease: enteric bacterial pathogens, the enteric microbiome, and host responses controlling susceptibility, resistance, or autoimmunity. Our overarching hypotheses are: (1) the enteric microbiome protects the host from luminal, epithelial and invasive pathogens, (2) diversity of the microbiome controls resiliency after perturbations, (3) the community metabolome contributes to lesions during pathogen invasion, and (4) resident microbiota intensify autoimmune responses by bacterial motifs exhibiting molecular mimicry. We will address these hypotheses using (1) bioreactors and mice colonized with human microbiota in Areas 1 and 2, and (2) samples from an epidemiological study of laboratory-confirmed cases of diarrhea in Area 3. In Area 1, Microbial Ecology and Pathogenesis, our overall objectives are to determine if (1) reduced diversity of the intestinal microbial community allows enteric pathogens with different lifestyles (luminal, epithelium-associated, and invasive) to become established in human fecal microbial communities in bioreactors and humanized mice, and (2) if the general ecological principle of competitive exclusion governs this process. In Area 2, Host Response, our overall objectives are to determine if murine model(s) with a "humanized" microbiome will develop spontaneous autoimmune sequelae secondary to C. jejuni infection with class A LOS; these models will then be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS/MFS patients. In Area 3, Clinical Research, our overall objectives are to determine if shifts in the intestinal microbiome that increase host susceptibility to enteric disease are associated with (1) loss or inhibition of community members that negatively impact activities of an enteric pathogen, or (2) loss or inhibition of community members that interact with the host to promote resistance to enteric pathogens.