UCLA

The gut microbiota directly interacts with dietary components that their host consumes, generating metabolites that can affect host physiology and behavior. For example, gut bacteria digest complex carbohydrates, or fibers, that cannot be digested by the host and produce short chain fatty acids (SCFAs) via fermentation. SCFAs can stimulate gut motility, promote satiety, improve glucose homeostasis, and decrease inflammation. These diverse effects can be explained by many cell types expressing SCFA receptors, including neurons, gut epithelial cells, immune cells, and endothelial cells. However, the molecular mechanisms by which bacterial metabolism of dietary components affect host physiology remain incompletely understood. The work in this dissertation combines genetic engineering, in vitro assays, and mouse models to study these mechanisms in three distinct contexts: host food preference, methylmercury-induced toxicity, and placental development. In Chapter 2, we review evidence in the literature on whether and how the gut microbiota can influence host food preference. In Chapter 3, we show that gut bacterial metabolism of fructose-containing fibers called fructans influence host food preference. Specifically, colonization of germ-free mice with bacteria that selectively ferment fructans with different linkages increases host preference for the non-fermentable fructan. In Chapter 4, we focus on bacterial metabolism of an ingested environmental toxin—methylmercury in fish. We demonstrate that a gut bacterium engineered to demethylate methylmercury can reduce methylmercury levels in mice eating a high mercury fish diet. In Chapter 5, we show that the maternal gut microbiota is necessary to support placental development in mice, particularly vascularization. SCFAs stimulate angiogenesis in both in vitro assays of an umbilical cell line and microbiota-deficient mice. Together, the results of this work reveal novel mechanisms by which gut bacterial metabolism of diet can affect host health and behavior, which will contribute to development of microbiota-directed therapies for metabolic disorders, methylmercury toxicity, and intrauterine growth restriction.