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.

SUMMARY Inflammatory bowel disease (IBD) results from a dysregulated interaction between the microbiota and a genetically susceptible host. Genetic studies have linked TNFSF15 polymorphisms and its protein TNF-like ligand 1A (TL1A) with IBD, but the functional role of TL1A is not known. Here, we found that adherent IBD-associated microbiota induced TL1A release from CX3CR1+ mononuclear phagocytes (MNPs). Using cell- specific genetic deletion models, we identified an essential role for CX3CR1+MNP- derived TL1A in driving group 3 innate lymphoid cell (ILC3) production of interleukin 22 and mucosal healing during acute colitis. In contrast to this protective role in acute colitis, TL1A-dependent expression of co-stimulatory molecule OX40L in MHCII+ ILC3s during colitis led to co-stimulation of antigen-specific T cells that was required for chronic T cell colitis. These results identify a role for ILC3s in activating intestinal T cells and reveal a central role for TL1A in promoting ILC3 barrier immunity during colitis.

Background: Recent trials suggest fecal microbiota transplantation (FMT) with repeated enemas and high diversity FMT donors is a promising treatment to induce remission in ulcerative colitis (UC). Methods: We designed a prospective, open-label pilot study to assess the safety, clinical efficacy, and microbial engraftment of single FMT delivery by colonoscopy for active UC using a two donor fecal microbiota preparation (FMP). Safety and clinical endpoints of response, remission, and mucosal healing at week 4 were assessed. Fecal DNA and rectal biopsies were used to characterize the microbiome and mucosal CD4+ T cells, respectively, before and after FMT. Results: Seven patients (35%) achieved a clinical response by week 4. Three patients (15%) were in remission at week 4 and two of these patients (10%) achieved mucosal healing. Three patients (15%) required escalation of care. No serious adverse events were observed. Microbiome analysis revealed that restricted diversity of recipients pre-FMT was significantly increased by high diversity two donor FMP. The microbiome of recipients post-transplant was more similar to the donor FMP than the pre-transplant recipient sample in both responders and non-responders. Notably, donor composition correlated with clinical response. Mucosal CD4+ T cell analysis revealed a reduction in both Th1 and regulatory T cells post-FMT. Conclusions: High-diversity, two donor FMP delivery by colonoscopy is safe and effective in increasing fecal microbial diversity in patients with active UC. Donor composition correlated with clinical response and further characterization of immunological parameters may provide insight into factors influencing clinical outcome.

Contact mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate Junctional Adhesion Molecule-A (JAM-A), an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic JAM-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that JAM-A mediated signaling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, proinflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces, and a milder histopathological and clinical course of disease compared to wild-type controls (JAM-Afl/fl). Treatment of wild-type mice with intraperitoneal injection of soluble JAM-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact mediated astrocyte-immune cell signaling as a novel translational target against neuroinflammatory disease.

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