ABSTRACT Bacteroides vulgatus (Bvu) is one of the most common members of the gut microbiota across diverse human populations and has been strongly associated with multiple human diseases including the inflammatory bowel diseases (IBD). However, there exist fundamental gaps in our understanding of the genetic and phenotypic diversity within the Bvu species complex, as well as how Bvu strains mechanistically contribute to host inflammatory phenotypes. Our long-term goal is to understand how gut microbes impact human health and disease. Our preliminary studies in the human-derived Bvu strain CL09T03C04 identified putative genetic determinants for Bvu fitness and competition in the mouse gut and also associated these genes with metabolites identified by mass spectrometry. Using gnotobiotic mice, we have also established that different Bvu strains have variable impacts on intestinal inflammation and immunity. These results and other diverse associations between Bvu and gut inflammation in humans and animal models could be explained in part by genetic diversity among Bvu strains. Yet, there remains a paucity of well-annotated genetic information associated with this species, and strain-level variation across the Bvu species complex is almost completely unexplored. The objective of the proposed research is to define the relationships between Bvu genetic variation with host inflammation and gut microbial ecology. We will test the central hypothesis that Bvu uses distinct genetic and metabolic traits to colonize the gut and modify host inflammation, and that the variable presence of those traits in Bvu strains explains their divergent host responses. In Specific Aim 1, we will test the working hypothesis that regulation of distinct lipid metabolites is required for in vivo survival and competition in Bvu strain CL09T03C04. In Specific Aim 2, we will test the working hypotheses that the ability of different Bvu strains to promote or restrict gut inflammation is mediated by distinct genetic traits, and that gut inflammation alters Bvu fitness. The expected outcomes will vertically advance the field in several ways. First, they will provide the first in-depth understanding of genetic and phenotypic diversity in the Bvu species complex, including identification of genes, pathways, and metabolites responsible for Bvu’s ability to colonize the gut and to impact and adapt to gut inflammation. Second, they will identify pro- and anti-inflammatory Bvu strains and affiliated mechanisms that may explain prior association of the Bvu species complex with both exacerbation of and protection against IBD-associated inflammation. These results are expected to have a positive impact because they could lead to the development of new Bvu-directed prognostic markers and therapeutic approaches to modify gut microbial ecology and inflammation, potentially improving diagnostic and therapeutic management of IBD and other human diseases.