Tryptophan Metabolism Linked to csDMARD Response in Rheumatoid Arthritis

A comprehensive, multi-phase investigation published in Advanced Science suggests that the amino acid tryptophan (Trp) may be a key determinant of therapeutic response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA).1

Using an integrated “multiomics” framework spanning blood, stool, and immune cell analyses, investigators from Sichuan University and Dazhou Central Hospital found that patients who responded well to csDMARDs exhibited stronger tryptophan-related activity across multiple biological systems. Elevated Trp metabolism correlated with improved treatment response, lower inflammatory activity, and better overall clinical outcomes.

Metabolomic profiling of 244 patients with rheumatoid arthritis and 69 controls identified 111 differential metabolites, including 33 upregulated and 78 downregulated compounds. | Image credit: Oporty786 - stock.adobe.com

The study included 566 participants, comprising 371 individuals with rheumatoid arthritis (RA) and 195 healthy controls, and employed an integrated multiomics approach that combined metabolomic, microbiomic, transcriptomic, proteomic, and single-cell analyses. Of the RA group, 90 patients were prospectively followed for 6 months during csDMARD therapy—primarily methotrexate, leflunomide, or hydroxychloroquine, with or without glucocorticoids or NSAIDs. Based on disease activity score (DAS28) improvement, 55 patients were classified as responders and 35 as nonresponders (ΔDAS28 > 1.2 and final DAS28 ≤ 3.2).

Blood plasma of sample sets was analyzed for metabolic and proteomic changes, stool samples were examined for shifts in the gut microbiome, and peripheral blood mononuclear cells (PBMCs) were analyzed for gene and protein expression. Data from these layers were then integrated to identify molecular networks associated with csDMARD response.

Metabolomic profiling of 244 patients with RA and 69 controls identified 111 differential metabolites, including 33 upregulated and 78 downregulated compounds (P < .05). Compared with controls, patients with RA showed reductions in lipid and amino acid metabolites such as glycerophosphocholine, linoleic acid, ornithine, and Trp. Subgroup analysis between responders and nonresponders revealed 27 differential metabolites (6 upregulated, 21 downregulated), with the Trp metabolism pathway significantly enriched (P < .001). Responders had higher Trp and 2-oxoadipic acid levels, while C-reactive protein (CRP) correlated negatively with Trp (r = -0.45; P = .002) and alanine (r = -0.39; P = .005). These findings suggest that higher systemic Trp availability and more efficient Trp metabolism may support improved inflammatory control under csDMARD therapy.

Fecal microbiome analysis from 246 RA patients and 124 controls revealed broad compositional differences: RA patients had lower levels of Faecalibacterium and Bacteroides and higher abundance of Escherichia-Shigella and Enterococcus (P < .01). Functional predictions using PICRUSt2 revealed that Trp metabolism was among the most activated pathways in RA (P < .001), alongside MAPK and mTOR signaling pathways. In responders, the Trp pathway remained significantly upregulated (P = .006). Holdemanella and Megasphaera, bacteria associated with Trp metabolism, were more abundant (P = .03 and P = .04), whereas Clostridium innocuum group and Atopobium correlated with higher CRP and DAS28 values (r > 0.4; P < .05), pointing to a potential gut-metabolism-inflammation axis influencing csDMARD efficacy.

Transcriptomic and proteomic analyses of PBMCs from 35 RA patients identified 196 differentially expressed genes (P < .05). Enrichment analysis linked gene dysregulation to Trp metabolism and immune-related signaling pathways, including Wnt, MAPK, PI3K–Akt, and cytokine-receptor interactions. Notably, IDO1, the enzyme that converts Trp to kynurenine, emerged as a strong predictive biomarker.

"Our findings of significantly reduced expression levels of IDO1 and IDO2 in responders suggest that alterations in Trp metabolism may impact therapeutic outcomes, underscoring Trp’s crucial role in regulating inflammatory responses and immune reactions," the researchers explained.

In vitro, Trp supplementation significantly inhibited the proliferation of MH7A synovial fibroblasts and PBMCs and reduced IL-1β, IL-6, and TNF-α secretion (all P < .01). In collagen-induced arthritis (CIA) mice, Trp administration (200 mg/kg) reduced arthritis scores and histopathologic damage (P < .01) and lowered cytokines, including IL-1, IL-17A, IL-6, and TNF-α, though not all reached statistical significance.

A controlled clinical trial further evaluated dietary Trp supplementation among patients with a suboptimal response to treatment with csDMARDs. Thirty-three patients were randomized to receive csDMARD therapy alone (n = 17) or csDMARDs plus 2 g of Trp per day for 6 weeks (n = 16). The Trp-supplemented group achieved significant improvements in DAS28 (P = .008), CRP (P = .012), and ESR (P = .021), with no differences in liver or renal parameters (ALT, AST, BUN, Scr) and no serious adverse events, supporting a favorable short-term safety profile.

“Omics features play a crucial role in predicting therapeutic responses, with previous studies indicating that metabolites and gut microbiota can serve as effective biomarkers,” the authors note,2,3 further explaining, "At present, integrative multiomics approaches provide valuable insights into the pathogenesis and therapeutic responses in RA.” Although these findings do not yet justify routine Trp supplementation, they highlight a biologic pathway that could inform future approaches to optimize csDMARD efficacy and individualize RA treatment.

References

1. Jian C, Zhu J, Wu J, et al. Multiomics analyses reveal an essential role of tryptophan in treatment of csDMARDs in rheumatoid arthritis. Adv Sci. Published September 23, 2025. doi:10.1002/advs.202413170
2. Onuora S. Gut microbiome could predict drug response in RA. Nat Rev Rheumatol. 2021;17(3):129. doi:10.1038/s41584-021-00582-6
3. Takahashi S, Saegusa J, Onishi A, Morinobu A. Biomarkers identified by serum metabolomic analysis to predict biologic treatment response in rheumatoid arthritis patients. Rheumatology. 2019;58(12):2153-2161. doi:10.1093/rheumatology/kez199.