Chlorogenic acid attenuates rheumatoid arthritis by modulating immunity via the gut microbiota-derived metabolite indolelactic acid.

The pathogenesis of rheumatoid arthritis (RA) is closely associated with gut microbiota dysbiosis. Chlorogenic acid (CGA), a plant-derived polyphenol, exhibits well-documented anti-inflammatory and immunomodulatory activities; however, whether it alleviates RA through gut microbiota modulation remains unclear. In this study, a collagen-induced arthritis (CIA) mouse model was established, and we found that CGA significantly ameliorated arthritic symptoms and modulated systemic immune responses. 16S rRNA sequencing combined with antibiotic-mediated microbiota depletion confirmed that the anti-RA effect of CGA depended on an intact gut microbiota. Untargeted metabolomics further revealed that CGA treatment markedly enriched the gut microbiota-derived tryptophan metabolite indolelactic acid (ILA), whose levels correlated positively with the abundance of Lactobacillus. In vitro experiments demonstrated that ILA suppressed LPS-induced M1 polarization of RAW264.7 macrophages, downregulated the expression of pro-inflammatory cytokines such as IL-6 and TNF-α, and inhibited phosphorylation of NF-κB p65. Collectively, this study systematically elucidates the mechanism by which CGA alleviates RA via remodeling the gut microbiota, promoting ILA production, and subsequently inhibiting macrophage inflammatory polarization and modulating T-cell balance through the AhR/NF-κB signaling axis. These findings provide novel insights and potential therapeutic targets for RA treatment based on the "gut microbiota-metabolite-immune" axis.