Project Summary – NIH F32 Fellowship – Andrew Brooks – P.I. Mike Snyder Application Title: Gut Bacteriophage Correspondence with Inflammation and Clinical Dietary Interventions Recurring gastrointestinal inflammation contributes to chronic non-transmissible diseases like diabetes, inflammatory bowel disease, and colorectal cancer that afflict millions of Americans. A primary culprit is the gut microbiome, which is filled with trillions of bacteria and roughly as many predatory bacteriophages. Many gut phages are temperate, meaning they can cycle between dormant lysogenic prophages and active lytic phage particles that attack bacterial hosts. There are many direct and indirect mechanisms through which lytic phages trigger human immunity, yet whether those result in significant inflammatory responses is unknown. Therefore, it is critical to investigate the hypothesis that phages periodically contribute to gut inflammation during peaks in active lytic growth. Knowing whether phages significantly impact gut inflammation will be important as new evidence suggests phages are transmitted from mother to child, passed through fecal microbiome transplants, and persist within individuals for long periods. Phage persistence and growth are closely tied to availability of nutrients and bacterial hosts, and human diet shapes gut metabolites which in-turn affect bacteria in the microbiome. This suggests the second hypothesis, that dietary metabolites and their effects on gut bacteria can predict and shape phage activity. This project is well positioned to comprehensively address both aims by leveraging three temporal human studies within the Snyder lab and Stanford University which have proven research records instilling the foundations for productive academic careers. Participant samples are undergoing extensive multi’omic profiling (immunity, metabolism, genomics…), which will be related to gut phage and microbiome profiles generated using high throughput metagenomic sequencing. Immune profiles from blood and stool will quantify gut inflammation alongside metagenomic measures of gut phage activity. The expectation of the first hypothesis is that peaks in phage lytic activity will associate with increased inflammatory biomarkers. Two of the studies also involve clinical dietary interventions, providing controlled perturbation to address the second hypothesis that diet predicts and shapes phage activity. The expectation is that profiles of gut metabolites and bacteria are predictive of phage activity, and therefore clinical dietary effects on gut metabolites and microbiomes can shape phage growth. Aims will be addressed in three multi’omic studies examining diverse aspects of human health. This facilitates comprehensive scientific validation in an expert collaborative environment supported by a robust mentorship team. Pursuit will provide a population scale examination of human gut phages in an unprecedented multi’omic context, while the first aim examines pha...