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.