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.

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Background Over two million people worldwide suffer from ulcerative colitis (UC). Biologic therapy has significantly improved treatment, but nearly two-thirds of patients attenuate response. Fecal microbiota transplant (FMT) is an emerging therapy for the treatment of UC, but the microbial mechanism responsible for clinical response is poorly understood. Using samples from our pilot FMT study (Jacob V, et al 2017), we aim to define the core transferable microbiota (CTM) in UC patients responsive to FMT therapy and its therapeutic mechanism. Methods IBD disease activity scores were used to define clinical response. Metagenomic sequencing of donor, recipient, and 4 week post-FMT fecal samples was performed to define the CTM and strain level transferability. To define the transferable immune-reactive microbiota (TIM), IgA-seq was also performed on donor and recipient samples. Patient TIM strains were isolated and tested in gnotobiotic mouse models to evaluate their impact on mucosal immunity and colitis. Results We defined a CTM associated with clinical response to FMT. CTM strain tracking confirmed that clinical response correlated with strain transferability. We defined a core TIM by IgA-seq that correlated with clinical response. In humanized mouse models, TIM induced IgA in a T cell independent manner. Colonization of germ-free mice with a core TIM strain, Odoribacter splanchnicus, robustly induced mucosal Th17 and RORgt+/Foxp3+ iTreg cells and reduced the severity of transfer T cell colitis. Our data highlights a core TIM in UC responders to FMT and the mechanistic impact of it in shaping mucosal immunity and guiding the response to UC. This provides a framework for rational selection of TIM for microbial-therapy in IBD.

Spondyloarthritis (SpA) is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD). Sulfasalazine (SAS) is one of the earliest medications used in IBD and its efficacy in spondyloarthritis is thought to depend on its antibacterial properties. Therefore, our study aims to diagnostically evaluate the role for the fecal microbiome in clinical response to SAS and identify microbial and immunologic therapeutic targets associated with clinical response. We have longitudinally followed IBD-SpA patients subjected to SAS therapy. Clinical data, including validated IBD and joint disease activity scores, and fecal samples from 19 patients were collected at baseline and at week 2 and 12 after SAS initiation. Metagenomic sequencing was used to define the effect of SAS on the IBD-SpA fecal microbiome and to evaluate its relationship with joint symptoms improvement. Gnotobiotic mouse models were used to test the sufficiency of the SAS effect observed in patients. Fecal microbiome of SAS-responders was distinct from that of non-responders and 6 pre-treatment microbial markers (including Faecalibacterium prausnitzii) predicted SAS-response (AUC: 0.9). SPF mice and germ-free mice colonized with patient microbiota revealed that SAS selectively reduced mucosal-associated bacteria. Gnotobiotic mouse models revealed a critical role for A. muciniphila in modulating mucosal inflammation. Our study reveals the ability of SAS to selectively target mucosal-associated bacteria and modulate the inflammatory impact of IBD-SpA associated pathobionts. This study highlights the potential use of microbial-based diagnostic tools to improve drug efficacy and therapeutic strategies for IBD-SpA.

Joint inflammation (spondyloarthritis, SpA), is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD), but the specific role for therapies targeting SpA is not well defined. Sulfasalazine (SAS) is a prodrug composed of two chemical moieties, 5-aminosalicylate and the anti-folate antibiotic sulfapyridine, with efficacy in peripheral arthritis. Our study aims to evaluate the role for the gut microbiome in clinical response of SpA to SAS and to define microbial mechanisms targeted by SAS. We longitudinally follow IBD patients with SpA who have a medical indication for SAS therapy. Clinical data and fecal samples from 22 patients were collected before initiation of SAS and at week 12 after initiation of SAS. The fecal microbiome of SAS-responders was distinct from that observed in non-responders and 6 pre-treatment microbial markers (including the short chain fatty acid (SCFA) producer Faecalibacterium prausnitzii) predicted SAS-response (AUC=0.9). Fecal metabolome of SAS responders had lower thymine and higher deoxyuridine compared to non-responders consistent with evidence of a folate trap in response to SAS treatment. SAS therapy in SPF mouse-model of chemically-induced colitis alleviated colitis in GPR 109a- and 43-dependent fashion consistent with a synergistic role for SCFA. In vitro and in vivo models revealed SAS direct regulation of F. prausnitzii transcription and metabolic function and its impact on host immune response. Collectively, these findings highlight the potential role for microbial diagnostics to improve SAS efficacy, and drug modulation of microbial markers to potentiate therapy for IBD patients with SpA. Supported by New York Crohn's Foundation

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