While the contribution of the gut microbiome to intestinal and extra-intestinal inflammation has been well described, the direct molecular mechanisms by which the host and microbes interact to promote local and systemic inflammation remain to be elucidated. Adherent invasive E. coli are expanded in Crohn’s disease patients and have been shown to drive inflammation in the intestine and extra-intestinal sites like the joints. This work identifies microbial metabolism as a novel and potentially targetable mechanism of inflammation that is driven by CD-associated pathobionts. By endowing AIEC with the ability to utilize fucose, the pdu pathway links microbial fitness in the gut to modulation of mucosal immunity and inflammation. Sensing of AIEC metabolism by sentinel phagocytes in the intestinal lamina propria initiates intestinal inflammation that is driven by inflammatory T cells. To evaluate systemic immune responses to AIEC and other gut microbes by an unbiased, high throughput approach, a novel platform, Human Antibody assisted Bacterial Isolation Technique (HABIT), was developed to assess IgG-reactivity to the gut microbiome in humans and mice. Analysis of IgG-coating of microbiomes from healthy and Crohn’s disease patients with a form of arthritis called peripheral spondyloarthritis shows enriched coating of specific bacterial taxa that correlates with joint disease activity. Further analysis demonstrates AIEC triggers T cell-dependent IgG responses that correlate with joint disease in Crohn’s disease-spondyloarthritis patients. This work provides mechanistic insights into how the gut microbiome contributes to intestinal and extra-intestinal disease and identifies novel therapeutic targets and biomarkers for Crohn’s disease and Crohn’s associated spondyloarthritis.