Effect of W-3 supplementation on IBD via alterations in the enteric microbiome

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DESCRIPTION (provided by applicant): It is accepted that we live in symbiotic homeostasis with our intestinal microbiota and perturbations that alter the quantity or makeup of this microbiota can cause gastrointestinal distress. Recently, altered homeostasis with our microbiota has been linked to diseases including obesity, diabetes, and inflammatory bowel diseases (IBD). In the case of IBD, clinical evidence suggests the chronic inflammation results from a combination of environmental/microbial factors on a patient background of genetic susceptibility. The mechanisms that underlie this relationship are unknown, however two possibilities exist which we seek to examine: 1) There is a genetically-defined, abnormal host response to the normal enteric flora that promotes sustained mucosal inflammation and injury (host triggering), or 2) alterations in the composition of gut microbiota trigger a pathologic response from genetically susceptible individuals (microbiota triggering). Which one plays the major role in causing IBD is not known because virtually all studies have been performed after the onset of disease. Even less is known about the effect of various dietary compositions on the species of bacteria in our gut and how changes in these species may predispose individuals to IBD or worsen the condition. My preliminary data in normal mice show that a diet high in saturated fat induce a bloom of a bacterial strain implicated in an array of inflammatory disorders. Data from our lab also show that a high saturated fat diet dramatically increases incidence of colitis in genetically susceptible mouse model. Conversely, fish oil supplementation has been shown to relieve symptoms of IBD in numerous studies, however these results remain circumstantial as no mechanistic studies exist to explain the correlation. Thus, the objective of this project is to provide new insight into the impact of I-3 fish oil supplementation on IBD via alterations in the intestinal microbial environment. This objective will be achieved by using an established mouse model of genetically susceptible colitis (IL10-/-) and the novel IL10-/- germ-free (GF) mouse completely devoid of enteric microbiota which will elucidate a direct cause-effect role of the microbiota. Analyses will include high-throughput pyrosequencing and metabolomic analysis of altered microbial species and subsequent host inflammatory responses. The project objective will be examined in the following specific aims: Aim 1: Define the effects of dietary I-3 and I-6 supplementation on the enteric microbiota and microbial production of inflammatory markers in an established mouse model of colitis. Aim 2: Define the effects of dietary I-3 and I-6 supplementation on the host inflammatory response to altered microbiota in conventional and germ-free IL10-/- mouse models. PUBLIC HEALTH RELEVANCE: The insights gained through these studies will provide clues to the fundamental nature of inflammatory bowel diseases pathogenesis. Accordingly, this information will help define complementary or alternative strategies to restore intestinal microbiota or host immune responses to non-inflammatory state, thereby preventing or treating inflammatory bowel diseases.