Tripterygium wilfordii ameliorates complete freund adjuvant-induced rheumatoid arthritis through modulating the gut-joint axis

Introduction Although Tripterygium wilfordii (TW) is a classical Chinese herbal medicine for the treatment of rheumatoid arthritis (RA), the mechanism by which it alleviates inflammation through modulation of the gut microbiota remains unclear. Methods To elucidate the mechanism underlying the therapeutic effects of TW on RA, we first employed network pharmacology to predict the relevant pathways and core targets. Subsequently, an integrative multi-omics approach was applied, including gut metagenomics, gut metabolomics, serum metabolomics, and synovial transcriptomics, to investigate the alterations in gut microbiota, intestinal and serum metabolites, and synovial gene expression in a rat model of RA. Results Our findings revealed that TW supplementation lowered serum concentrations of IL-6, IL-1β, TNF-α, and IL-10 and modulated the Th17/Treg balance in intestinal tissue. TW treatment altered gut microbiota (GM) composition, marked by increased abundance of Prevotella sp PCJ2 and Psychrobacter pasteurii , and decreased Adlercreutzia equolifaciens and Schaedlerella arabinosiphila , synergizing with keystone species ( Bifidobacterium animalis, Phocaeicola sartorii, Blautia faecis ) to promote gut health. Concurrently, TW elevated tryptophan metabolites (tryptophol, tryptamine, 5-hydroxykynurenamine) while reducing 4-(2-aminophenyl)-2,4-dioxobutanoic acid, restoring tryptophan metabolism. This regulation coincided with upregulated Inmt mRNA in synovium, activating the tryptophan pathway. Correlation and mediation analyses indicated that gut-derived circulating metabolites such as N-myristoyl arginine and lauramidoxide were positively correlated with synovial Jun expression, potentially participating in the modulation of the IL-17-NF-κB cascade. Consistently, upregulated synovial Socs3 may exert negative feedback suppression on JAK-STAT signaling to alleviate inflammatory responses. Discussion These findings point to the gut microbiome and tryptophan pathway as a new therapeutic avenue for RA.