Crohn's disease (CD)-associated spondyloarthritis (SpA) is the most common extra-intestinal manifestation of IBD. Genetic analysis independently identified shared genetic variants in the IL23R and TNFSF15 loci in both IBD and SpA, highlighting the potential role for these pathways in the pathogenesis of CD-SpA. Although clinical evidence linking intestinal inflammation with SpA has implicated the intestinal microbiota as the source of aberrant systemic joint inflammation, a mechanistic understanding of the link between the microbiome and CD-SpA has yet to emerge. To address this unmet clinical need, the long-term goal of this research is to define the biologic mechanisms of CD-SpA and enable the more precise use of medical and biologic therapy. The objective of this proposal is to identify immune-relevant microbiota and cellular pathways associated with CD-SpA. The central hypothesis is that IgA-coated microbiota in CD-SpA are enriched with pduC+ Adherent-invasive E. coli (AIEC) and these isolates act as pathosymbionts that drive mucosal and systemic IL-23- and TL1A-dependent inflammatory disease via CX3CR1+ mononuclear phagocytes. To test this hypothesis, the following three aims are proposed. First, using an innovative approach to sort, sequence and culture IgA-coated microbiota, the enrichment of unique pduC+ AIEC strains in the IgA-coated microbiota of CD patients with SpA will be evaluated. Second, using gnotobiotic and genetically modified mouse models of colitis and arthritis, the contribution of pduC+ AIEC to mucosal and systemic IL-23-dependent inflammatory disease will be tested. Third, the contribution of intestinal CX3CR1+ mononuclear phagocytes (MNPs) and their production of TNFSF15 (also called TL1A) in AIEC-induced Th17 immunity will be tested using novel genetic mouse models. These experiments will fundamentally advance our understanding of the immunological impact of pduC+ AIEC in CD-SpA and test the role for both IL-23 and CX3CR1+ MNP-derived TL1A in mediating Th17 cell induction. This mechanistic understanding of the link between the microbiome and spondyloarthritis will help drive earlier diagnosis and more precise therapy for patients with CD-SpA.