Changes in the Gut Metabolic Landscape Drive Inflammation-Associated Dysbiosis and Host Responses




Hughes, Elizabeth Rose

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Intestinal inflammation is frequently associated with alterations in composition of gut microbial communities, termed dysbiosis. Inflammation-associated dysbiosis is characterized by an expansion of facultative anaerobic bacteria in the Proteobacteria phylum, such as Escherichia coli. A dysbiotic microbiota has been linked to increased disease severity in the context of inflammatory bowel disease. However, the mechanisms responsible for inflammation-associated dysbiosis and its impact on disease are incompletely understood. Utilizing bioinformatic analyses of gut microbiota composition and mechanistic studies with Escherichia coli as a model organism in murine models, we uncovered two metabolic pathways that are unique to intestinal inflammation and responsible for changes in microbiota composition. Aerobic respiration coupled with formate oxidation, and utilization of molecular hydrogen fuel expansion of Escherichia coli populations during intestinal inflammation. The impact of oxygen leakage into the gut lumen on obligate anaerobic bacterial metabolism was additionally investigated. In vitro metabolite measurements and use of bacterial genetics indicated formate production increased in Bacteroides exposed to low oxygen levels. Formate measurements and exogenous delivery of formate in mice suggested that intestinal formate levels increase during inflammation and may exacerbate disease. However, further study is required. In conclusion, we identified key changes that occur during non-infectious inflammation in the gut metabolic landscape, illustrating the importance of understanding bacterial metabolism in order to understand host-microbiota interactions.

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The file named "HUGHES-PRIMARY-2022-1.pdf" is the primary dissertation file. Three (3) supplemental files are also available and are referenced in the dissertation file as appendices; the files are Microsoft Excel documents and may be viewed individually.

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