Project Details
Description
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.
Status | Active |
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Effective start/end date | 8/1/23 → 5/31/25 |
Funding
- National Institute of General Medical Sciences: $377,983.00
- National Institute of General Medical Sciences: $383,000.00
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