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Pathosymbiont perturbation of immune homeostasis
The influence of the gut microbiome extends beyond the intestines and can modulate many host systems. A subset of Crohn’s disease patients also experience painful spondyloarthritis, and Viladomiu et al. discovered that the immune systems of these patients are more likely to recognize a certain kind of Escherichia coli. As colonization with this bacterium induced systemic TH17 immunity and worsened development of colitis and arthritis in mouse models, this pathosymbiont may be causing a systemic TH17-driven inflammation that leads to extraintestinal complications in Crohn’s disease patients, such as stiffness and spinal pain. Precise targeting of these types of bacteria or reversing the TH17 phenotype they induce could bring relief to patients.
Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)–coated microbiota with 16S ribosomal RNA–based analysis (IgA-seq) revealed a selective enrichment in IgA-coated Escherichia coli in patients with Crohn’s disease–associated SpA (CD-SpA) compared to CD alone. E. coli isolates from CD-SpA–derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype. In comparison to non-AIEC E. coli, colonization of germ-free mice with CD-SpA E. coli isolates induced T helper 17 cell (TH17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (pduC). Modeling the increase in mucosal and systemic TH17 immunity we observed in CD-SpA patients, colonization of interleukin-10–deficient or K/BxN mice with CD-SpA–derived E. coli lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic TH17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.
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