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  • The American Association of Immunologists  (4)
  • 1
    Online Resource
    Online Resource
    Transferable Immune Reactive Microbiota Determine Clinical and Immunologic Outcome of FMT in UC
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 237.14-237.14
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 237.14-237.14
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.237.14
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Metabolic utilization of propanediol by adherent-invasive E. coli regulates intestinal tissue immunity
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 232.7-232.7
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 232.7-232.7
    Abstract: Crohn’s Disease (CD) has been associated with alterations in the intestinal microbiota, but the microbial mechanisms that regulate host immunity are largely unknown. We have recently shown that Adherent-Invasive E. coli (AIEC), which are enriched in CD patients, are sufficient to induce intestinal Th17 cells. Although AIEC lack pathogenic factors including type III secretion systems, many CD-derived isolates express virulence-associated metabolic enzymes including propanediol dehydratase (PduC), which enables AIEC to use fucose-derived propanediol as an alternate carbon source. We found that pduC is enriched in the microbiome and among E. coli genomes in CD patients compared to healthy controls. To evaluate the physiologic contribution of propanediol utilization to AIEC Th17 induction, we generated a pduC-deficient mutant of a CD-derived, AIEC isolate. Deletion of pduC resulted in reduced, inflammatory Th17 cells and attenuated weight loss following T cell transfer colitis. Using genetic mouse models, we found that CX3CR1+ mononuclear phagocytes are required for AIEC-mediated Th17 induction and IL-10 is required to restrain pduC-dependent colitis. Using a catalytically-inactive mutant, we determined that PduC metabolic activity was required for this immune phenotype. Cell-free supernatants from WT AIEC (but not the isogenic, pduC-deficient clone) promoted ex vivo Th17 cell polarization and metabolomics analysis (LC-MS) of these supernatants defined PduC-dependent metabolites capable of promoting Th17 polarization. These studies reveal a link between AIEC metabolism and inflammatory Th17 cells with the potential to serve as a therapeutic target in the treatment of CD.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.232.7
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    DEFINING THE ROLE FOR THE GUT MICROBIOME IN THE CLINICAL EFFICACY OF SULFASALAZINE THERAPY FOR IBD ASSOCIATED SPONDYLOARTHRITIS
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 174.01-174.01
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 174.01-174.01
    Abstract: 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
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.174.01
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Defining the role for the gut microbiome in the clinical efficacy of sulfasalazine therapy for IBD associated spondyloarthritis
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 237.8-237.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 237.8-237.8
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.237.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
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