Triptolide alleviates rheumatoid arthritis via modulating gut microbiota - intestinal barrier - TLR4/NF-κB axis

Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by dysregulated inflammation and intestinal microbiota-gut-joint axis dysfunction. While triptolide, a natural immunosuppressive compound, exhibits anti-RA activity, its mechanism linking gut microbiota modulation, intestinal barrier repair, and inflammatory signaling remains unclear. This study aimed to investigate whether triptolide alleviates adjuvant-induced arthritis (AIA) in mice by regulating the gut microbiota-intestinal barrier-toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) axis. The anti-inflammatory effect of triptolide was assessed using lipopolysaccharide (LPS)-induced RAW 264.7 cells and primary peritoneal macrophages. The anti-RA efficacy was investigated in AIA mice through detecting inflammatory factors, intestinal barrier integrity and gut microbiota. The results showed that triptolide decreased inflammatory factors in both RAW 264.7 cells and primary peritoneal macrophages. Meanwhile, triptolide dose-dependently reduced AI scores and paw swelling in AIA mice (p < 0.05 vs. AIA group), along with restored intestinal barrier integrity by upregulating ZO-1 and Occludin (p < 0.05 vs. AIA group) and modulated gut microbiota. Mechanistically, triptolide inhibited TLR4/NF-κB activation, reducing downstream pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor α (TNF-α)). In sum, these findings reveal that triptolide alleviates AIA by modulating the gut microbiota, repairing the intestinal barrier, and suppressing TLR4/NF-κB signaling. This highlights a novel "microbiota-gut-joint" regulatory mechanism of triptolide, supporting its potential as a therapeutic agent targeting RA's multifactorial pathogenesis.