Siweixizangmaoru decoction attenuates collagen-induced arthritis via gut microbiota-dependent SCFA restoration and immunomodulation.

BACKGROUND

Rheumatoid arthritis (RA) arises from immune imbalance that may be affected by gut microbiota dysbiosis and dysregulation of their metabolites. Siweixizangmaoru decoction (SXD), a classical formula in Traditional Tibetan Medicine (TTM), alleviates RA symptoms, yet its mechanisms remain unclear.

PURPOSE: The aim of this research is to elucidate the mechanism by which the SXD alleviates RA through the gut microbiota-metabolite-immune axis.

METHODS

A collagen-induced arthritis rat model was established. The effects of SXD on gut microbiota and short-chain fatty acid (SCFA) metabolism were assessed using 16S rRNA sequencing and metabolomics. Flow cytometry performed to quantify the proportions of immune cell in blood and spleen. Moreover, Caco-2 cells was utilized to assess the effects of SXD and butyrate on AMP-activated protein kinase (AMPK) signaling activation.

RESULTS

SXD significantly alleviated arthritis symptoms and decreased serum TNF-α and IL-17 levels. SXD reversed the Firmicutes/Bacteroidetes ratio, suppressing the pathogenic genus Desulfovibrio and enriching SCFA-producing Butyricicoccus. SXD significantly upregulated ZO-1, occludin and downregulated zonulin, while enhancing biosynthesis of SCFAs like butyrate. SXD and butyrate enhance tight junction protein expression in Caco-2 cells via AMPK pathway. Correlation analysis revealed strong positive correlations between SCFA levels and tight junction proteins/anti-inflammatory factors, while negative correlations were observed with pro-inflammatory cytokines, intestinal permeability markers and the Th1/Th2 and Th17/Treg ratio.

CONCLUSION

This study demonstrates that SXD alleviates RA by synergistically regulating the gut microbiota-SCFA metabolism-immune homeostasis axis, providing a promising approach for Tibetan medicine targeting the "gut-joint axis" in RA therapy.