ABSTRACT The gut microbiome (GM) strongly influences human health, playing critical roles in immune priming, nutrient metabolism, and pathogen exclusion. During infant and child development, the GM undergoes a systematic turnover of species until reaching an adult-like state. The equilibrium of the gut ecosystem can be disrupted by perturbations, such as antibiotic usage and inflammatory exposures, causing significant decreases in microbial diversity and aberrant physiological processes, sometimes with lifelong implications. However, the mechanisms underlying the resilience of the GM to shifts or perturbations are not well understood. The gut virome is dominated by bacteriophages (phages), which play crucial roles in shaping bacterial communities through predation and horizontal gene transfer. Viruses can also directly interact with human cells to influence gut physiology. Herein, we hypothesize that altered viral communities are both symptoms of and contributors to human disease, as gastrointestinal perturbations drive phage induction and subsequent virus-bacteria and virus-human interactions which impact human health. Accordingly, we propose to study virus-bacteria-human dynamics during antibiotic exposure and inflammatory diseases, leveraging over 70,000 banked patient stools from four cohorts with well- curated clinical metadata. The rationale implicating a functional role for viruses in human gut health is that changes in the abundance of specific viruses targeting certain bacterial populations are frequently observed in perturbed GM states. These include antibiotic exposure and intestinal inflammatory conditions for which there is no clear bacterial etiological agent, such as inflammatory bowel disease in adults and necrotizing enterocolitis in preterm infants. Our central motivation is to provide a comprehensive analysis of human gut ecology during dramatic GM shift events that are consistently correlated with virome alterations. Understanding these alterations is critical for the design of virus-related diagnostic or therapeutic strategies to improve inflammatory disease outcomes and antibiotic-triggered GM imbalance. This will be achieved through two aims to: I) Define the interactions between viruses, bacteria, and human cells contributing to perturbation-associated shift events, and II) Determine the effects of host-associated perturbations on gut viruses and their contributions to the inflammatory responses in mammalian cells and GM-humanized mouse models. Our analyses are significant as they provide a systematic investigation of the relationship between GM perturbations and virome alterations in adult and pediatric populations. Our proposal is innovative in leveraging novel complementary technologies including high-resolution genomics, viral tagging of bacterial and human cells, and GM-humanized gnotobiotic mouse models to identify viral drivers of clinical outcomes. Our proposal is impactful in its goal to address basic, translation...