Decoding Microbial Diversity in the Human Gut Microbiome

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PROJECT SUMMARY / ABSTRACT The ecological concept of diversity is deceptively simple: what organisms are present and how are they distributed. The advent of high-throughput sequencing enabled more than a decade of observational human microbiome studies; however, these studies frequently established correlation, but not causation, between microbial diversity and health. Through mechanistic research, I and others have shown the significance of strain variation, i.e. phenotypic and genotypic variation within a species, in host-microbiome interactions; however, most of our understanding comes from a limited range of model organisms which poorly represent the large diversity observed in the human gastrointestinal tract. Rather than view strain diversity as a limitation and caveat in microbiome research, my group takes a fundamentally different approach: we exploit it as a tool for mechanistic research. The mission of my research program is to understand how our microbial communities shape human health and physiology. We do this through leveraging computational biology and big data with wet lab experiments including gnotobiotic animal models to balance reductionism and biological relevance. The research themes in this proposal ask discrete questions about the interface of host and microbe but are unified in their approach of using naturally occurring strain variation coupled to comparative genomics as a tool for gene discovery in a reference panel of >300 genome sequenced bacterial isolates. Theme I will ask a fundamental question: can we leverage 10 years of publicly available data to rationally design functional synthetic communities? These consortia will act as both tools for understanding the assembly and function of complex communities, and will have translational applications as alternatives to human fecal transplant therapy. Theme II will focus on deconvoluting the shared host and microbial metabolism of bile acids (BAs), a family of compounds with broad relevance to infectious and autoimmune diseases, cancer, and metabolic health. Despite their importance, the microbial metabolic pathways of BA metabolism and their phylogenetic distribution are poorly characterized. Through comprehensive analysis of our strain library and synthetic communities derived thereof, we will determine the origins of biologically significant BAs. Understanding these trans-species pathways will address an important question: can we predict the metabolic output of a community based on the sum of its parts? Theme III addresses an urgent question in medicine: how does microbial strain-variation contribute to interpersonal variation in drug response? We are now working on a new class of important orally administered drugs which were not previously known to interact with the gut microbiome: antimalarials. Building on preliminary data demonstrating off-target strain-variable antibacterial effects, we will characterize how bacterial interactions with antimalarials affect therapeutic efficiency. These themes have a shared and unified goal: to generate both resources and fundamental understanding of host-microbe interactions leading to translational applications.