Multiomics Analyses Reveal an Essential Role of Tryptophan in Treatment of csDMARDs in Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a autoimmune disease characterized by heterogeneity in response to conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs). This study aims to elucidate molecular differences in response mechanisms of RA patients to csDMARDs through multiomics approach, with particular focus on the role of tryptophan (Trp) in treatment. Plasma, fecal, and peripheral blood mononuclear cells (PBMCs) were collected for metabolomics, microbiomics, transcriptomics, single‐cell transcriptomics, proteomics, and phosphoproteomics analyses. Additionally, in vitro/vivo experiments and controlled clinical trial were conducted to validate the findings. Comprehensive analysis revealed significant alterations in Trp‐related metabolic profiles, microbiota composition, and immune cells, indicating the role of Trp in modulating therapeutic response to csDMARDs. In vitro experiments demonstrated that Trp significantly inhibited the proliferation of MH7A and PBMCs while reducing the secretion of IL‐1β, IL‐6, and TNF‐α. Furthermore, in vivo studies showed that Trp treatment decreased arthritis scores and histological scores in mice. Clinical data further confirmed that dietary supplementation with Trp significantly improved disease activity scores and alleviated inflammatory in RA patients. This study highlights the crucial regulatory role of Trp in RA therapy, providing novel insights for optimizing clinical treatment strategies for RA.