DESCRIPTION (provided by applicant): The mammalian intestine is home to a dense community of bacteria that are integral to host health. Alterations in this bacterial population ca cause intestinal distress and even in some cases inflammatory disease. Aside from bacteria, viruses are also abundant in the intestinal tract. Both eukaryotic and prokaryotic viruses make up the intestinal "virome", however, viruses that infect bacteria, known as bacteriophages (phages), dominate. The majority of intestinal phages exist as lysogenic prophages that are stably integrated into bacterial chromosomes. Prophages typically undergo lytic induction to produce infectious phage particles when bacterial cells are stressed or when they are stimulated by nutrients. Preliminary studies have revealed that the commensal bacterium Enterococcus faecalis V583 induces the prophages when growing in the mouse intestine. In vitro, prophage induction depends on elevated amino acid concentrations; however, the exact mechanisms underlying nutrient-mediated induction of prophages are unknown. Further, in vivo studies indicate that the release of lytic phage particles allows E. faecalis to compete with genetically related enterococci vying for similar intestinal resources. Together, these initial findings indicae that phages can impact the dynamics of bacterial colonization in the mammalian intestinal ecosystem and have established E. faecalis prophages as model intestinal phages for the study of phage-host interactions. The long-term goal of this research is to understand how intestinal bacteriophages impact human physiology and health. The specific research proposed under this K01 award mechanism will advance this goal by defining the mechanisms that elicit phage production in the intestine, by determining how bacteriophage impact host immunity, and by exploring how phage predation impacts bacterial interactions with the host. These studies will provide novel insights into how intestinal phages influence host health and physiology, and will set the stage for future exploration of phage as therapeutic tools for manipulating the microbiota to improve health.

PUBLIC HEALTH RELEVANCE: The mammalian intestine contains a diverse array of microbes including intestinal viruses that infect bacteria called bacteriophages (phages). Virtually nothing is known about how phages contribute to the microbial functionality of the intestine and whether they have any influence on human physiology. For this proposal, I will use Enterococcus faecalis phages as a model system to discover the mechanisms that elicit phage production in the intestine, to determine how phages impact host immunity, and to explore whether phage predation impacts bacterial interactions within the host, which will set the stage for understanding the roles of phages during intestinal health and disease.