IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote T _H 17-dependent inflammation

Abstract

Peripheral spondyloarthritis (SpA) is a common extra-intestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of non-axial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. Here, we evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of IgA-coated microbiota with 16S rRNA-based analysis (IgA-seq) revealed a selective enrichment in IgA-coated E. 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 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 IL-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 immune-reactive 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.

Single Delivery of High-Diversity Fecal Microbiota Preparation by Colonoscopy Is Safe and Effective in Increasing Microbial Diversity in Active Ulcerative Colitis

“…Alterations in the composition of the intestinal microbiome have been shown to impact mucosal T cell effector function in mouse models (15, 16). To evaluate the impact of two donor FMP on mucosal immunity in active UC, we profiled mucosal CD4+ T cell function in rectal biopsies performed at the time of FMT and 4 weeks post-FMT (Fig.…”

“…Although Crohn’s disease was initially characterized as a Th1- and UC as a Th2-driven inflammatory disease, additional T cell subsets have been identified to play a role in IBD mucosal barrier immunity including regulatory T cells and IL-23 responsive Th17 cells (15). In mouse models, human microbiota have been shown to play a critical role in regulating Th1 (19), regulatory T cells (20), and Th17 (16, 21). Immune cell analyses in FMT studies have been limited, but a recent analysis in Crohn’s disease revealed a borderline increase in CD25+ CD127 lo CD4+ T cells at 12 weeks post-FMT (17).…”

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…Viladomiu et al revealed that AIEC isolated from patients with CD with spondyloarthritis induce Th17 mucosal immunity in germ-free mice, as well as specific pathogen-free mice, compared with non-AIEC strains. This demonstrates that AIEC can induce Th17 polarisation, even in the presence of other commensal microbiota, which requires the virulence-associated metabolic enzyme propanediol dehydratase 135. Recently, it has been shown that infection with the LF82 strain could induce the release of exosomes, which activate NF-κB, mitogen-activated protein kinases p38 and c-Jun N-terminal kinase, as well as increase the secretion of proinflammatory cytokines in vitro and in vivo.…”

Regulation of inflammation by microbiota interactions with the host

“…Fecal IgA varies independently of bacterial phylogeny and can be perturbed during disease 30 . Enrichment of Enterobacteriaceae and Lachnospiraceae in IgA-coated and IgA-negative microbiota, respectively, in both Crohn’s disease–associated spondyloarthritis 31 and malnutrition 26 , suggest that a potential core IgA response may exist in various inflammatory conditions.…”