Gut microbiota-derived indoleacrylic acid ameliorates rheumatoid arthritis by preventing necroptosis of fibroblast-like synoviocytes and regulating macrophage polarization

Abstract

Rheumatoid arthritis (RA) is associated with gut metabolite dysfunction, but the contribution of tryptophan-derived metabolites to RA remains fully uncharacterized. Here, we investigated the role of the gut microbiota-derived tryptophan metabolite indoleacrylic acid (IA) in experimental arthritis. Targeted metabolomics showed that fecal IA was markedly depleted in interleukin-1 receptor antagonist (IL1RA)-deficient and collagen-induced arthritis (CIA) mice. Oral administration of IA alleviated paw swelling, synovial hyperplasia, and cartilage destruction in both arthritis models. IA preserved intestinal barrier integrity by restoring ZO-1 and Occludin expression. In CIA mice, IA also reshaped the gut microbial community. In vitro, IA inhibited the proliferation and migration, promoted apoptosis, and suppressed inflammatory mediator production of fibroblast-like synoviocytes (FLSs). IA also inhibited M1 polarization and promoted M2 polarization of macrophages. Mechanistically, IA increased aryl hydrocarbon receptor (AhR) expression, and AhR silencing largely abolished its regulatory effects on FLS behavior and macrophage polarization. Transcriptomic analyses showed that IA suppressed necroptosis in FLSs by inhibiting RIPK1/RIPK3/MLKL signaling in an AhR-dependent manner. Collectively, these findings identify IA as a gut microbiota-derived metabolite with therapeutic potential in RA. The anti-RA effects of IA might involve coordinated regulation of the gut–joint axis, immune responses, and necroptotic signaling.