From cells to communities: The multi-scale impacts of bacteriophages in the gut microbiome

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PROJECT SUMMARY/ABSTRACT Bacteriophages (phages) are the most abundant but least understood constituents of microbial communities. This is especially evident in the mammalian gastrointestinal tract, where a diverse community of up to 1012 phages are present per gram of stool. Though mounting evidence suggests the importance of phages in human microbiomes, methods of data generation and analysis routinely used in microbiome science neglect important aspects of phage biology. Furthermore, there is a lack of foundational knowledge and experimental tools for understanding phages and the roles they play in microbiomes. This lack of understanding is especially salient when the burgeoning antibiotic resistance crisis is considered: many important human pathogens are becoming increasingly resistant to our antibiotic arsenal. While a growing number of clinicians and scientists believe that “phage therapy” (the therapeutic application of phages to remove specific bacteria from host- associated microbiomes) will be important in our recovery from the antibiotic resistance crisis, phage therapy is inconsistently effective. This is largely due to an incomplete understanding of how phages impact their target bacteria, their off-target effects on other microbiome members, and their interactions with the mammalian host. Without such knowledge, important facets of phage-centric microbiome community dynamics will remain obscure and hinder robust and reproducible phage therapy applications. The goal of the proposed research program is to build a deep understanding of the roles that phages play in host-associated microbiomes and to eventually exploit this understanding to inform phage-based therapeutic strategies. We will work towards this goal using phage isolates, bacterial culture, bacterial genetics, gnotobiotic mice, and systems biology approaches. Using these tools, the proposed research program will build on my previous work with Bacteroides thetaiotaomicron-infecting phages and will focus on an isolate of the prominent crAss-like phage family, DAC15. We will determine how phenotypic heterogeneity in B. thetaiotaomicron influences resistance to DAC15, the specific interactions between DAC15 and B. thetaiotaomicron that lead to productive infection, and how DAC15 influences microbiome-host interactions. We will additionally build a collection of phages that infect other members of a model human gut microbiome to facilitate similar work with diverse bacteria and phages. Together, this work will be a much-needed foundation to understand the roles and identities of gut- resident phages, will build tools for sustained and powerful phage-centric study of the gut microbiome, and will inform the development of robust and reproducible phage therapy.