Muehlbauer, Amanda2022-11-142022-11-142022-07https://hdl.handle.net/11299/243138University of Minnesota Ph.D. dissertation. July 2022. Major: Ecology, Evolution and Behavior. Advisor: Ran Blekhman. 1 computer file (PDF); ix, 193 pages.The gut microbiome performs numerous important functions for the host and has been closely linked to the development of certain diseases. Extreme variation in gut microbiome composition has been observed between different primate species, between individuals within the same species, and in individuals in various disease states. It is unclear how the gut microbiome can impact host physiology, and the effect that the gut microbiome has on host gene expression remains poorly understood. One hypothesis is that the gut microbiome regulates gene expression in host cells, which can affect host physiology and contribute to the development of various chronic diseases and cancers. However, due to the complexity of the gut microbiome and the various confounding factors that shape its composition, establishing causal relationships between variation in the microbiome and the host is inherently difficult to do in vivo. Here, we have used a novel in vitro co-culture system to characterize the impact of variation in the gut microbiome on host gene regulation. First, we tested how variation in gut microbiome composition between five healthy human individuals drives changes in gene expression in colonic epithelial cells. We found that specific microbes in the microbiome may be regulating host gene expression in the gut, and that these genes are related to complex traits. Next, we expanded this system to test how microbiomes from four different primate species - chimpanzees, gorillas, humans and orangutans - change gene regulation in colonic epithelial cells. We found that most host genes respond to microbiomes from different primate species in the same way, but that there are some host genes that have a highly divergent response across different primates, and that these genes are enriched for functional categories related to complex diseases. Finally, we artificially manipulated microbiome communities with a pathogenic strain of Bacteroides fragilis and cultured these communities with colonocytes and colon cancer cell lines in order to explore the link between the gut microbiome and colorectal cancer. We find that specific microbes exert a powerful effect on host gene regulation, but that the strain of B. fragilis had a minor impact on host gene expression in the context of the rest of the gut microbiota. Taken together, this work sheds light on the interaction between gut microbiome composition and host gene regulation and expands our understanding of how the gut microbiome affects host health.encolon cancergut microbiomeprimatesThesis or Dissertation