Bacteriophage pathobiology of inflammatory bowel disease Ulcerative colitis and Crohn’s disease are types of inflammatory bowels diseases (IBD) that affect millions of people around the world. IBD is characterized by chronic progressive intestinal inflammation which is driven in large part by disruption of the gut microbiome in susceptible individuals. Infection by pathogens such as adherent invasive Escherichia coli (AIEC) in particular exacerbates IBD pathogenesis. Treatment strategies that restore gut microbiota homeostasis such as probiotics and fecal microbiota transplantation show promise in treating IBD. These treatment strategies, however, focus primarily on the bacterial component of the microbiota. The most abundant entities in the gut are the bacteriophages (phages) that infect these bacteria. Even though it is recognized that phage populations expand during IBD exacerbations, we know surprisingly little about how phages contribute to IBD pathogenesis. Our recent work demonstrates that diverse species of phages are recognized by pattern recognition receptors on human and murine immune cells. We find filamentous phages trigger TLR3-dependent inflammatory responses that promote bacterial infection in a wound infection model. Vaccinating against these phages was an effective strategy at preventing wound infection. We also find that tailed Caudovirales phages stimulate TLR9-dependent inflammation in the gut. Based on these observations, we hypothesize that phages produced by adherent invasive E. coli modulate immune responses in ways that exacerbate IBD. To test this hypothesis, we have established a team of microbiologists, immunologists, and vaccine scientists. In Aim 1, we will characterize how inflammatory conditions stimulate bacteriophage replication in the gut. In Aim 2, we will determine how broadly bacteriophages are recognized by innate pattern recognition receptors. In Aim 3, we will develop and optimize an anti-bacteriophage vaccine strategy to treat IBD. Together, these aims represent a novel and timely approach in understanding not only how phages affect IBD pathogenesis, but for evaluating the safety and efficacy of phage therapy to treat multidrug-resistant bacterial infections.