Interrogating function, regulation, and interactions in a clade of prevalent human gut microbes

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PROJECT SUMMARY/ABSTRACT Human-associated microbes are causally linked to processes as diverse as immunomodulation, protection against pathogens, and atherosclerosis. Many of these links are mediated through biochemical transformations of dietary, drug, or host compounds. This makes the microbiome a promising therapeutic target, especially as we could potentially affect downstream processes by controlling metabolic inputs. However, in order to effectively intervene, we must first understand how exactly changes in these inputs lead to differential regulation of growth, gene expression, and metabolism. This is challenging because our microbiomes are not only genetically and physiologically diverse, but are also highly diverged from the most common model organisms, with many genes of unknown function. Over the next five years, my research group will use a combined computational and experimental strategy to characterize gene function, metabolic regulation, and microbial interactions in one of the most prevalent and abundant clades of gut bacteria, the Bacteroidales. Specifically, we seek to determine 1) which Bacteroidales genes are involved in growth on different nutrients and stressors; 2) how Bacteroidales genes are regulated, and how this affects their metabolic outputs; and 3) how Bacteroidales interact with the other microbial inhabitants of the gut. We will accomplish this by gathering high-throughput in vitro data from diverse sets of microbiome isolates and synthetic communities, developing more powerful and specific statistical tools to analyze these data, and using these new data and tools to re-analyze metagenomics data gathered from in vivo case-control studies. I envision that this line of inquiry will provide missing fundamental knowledge about this clade of microbes, which will ultimately help us interpret case-control studies of the microbiome and support the development of more precise interventions.