DEFINING THE ROLE FOR THE GUT MICROBIOME IN THE CLINICAL EFFICACY OF SULFASALAZINE THERAPY FOR IBD ASSOCIATED SPONDYLOARTHRITIS

Autor: Svetlana Ferreira Lima, Amanda Rupert, Monica Viladomiu, Andrew Marderstein, Silvia Pires, Gregory Putzel, Viola Woo, Gabriela Funez-dePagnier, Wen-Bing Jin, Chun-Jun Guo, Ellen Scherl, Randy S. Longman
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:174.01-174.01
ISSN: 1550-6606
0022-1767
Popis: 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
Databáze: OpenAIRE
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