HDAC/NF-κB signaling pathway mediates gut microbiota dysbiosis in rheumatoid arthritis: Intervention mechanisms of Fengshining decoction

Abstract

Background: Gut microbiota dysbiosis has been associated with the development of rheumatoid arthritis (RA). Fengshining (FSN) is a traditional Chinese medicine decoction that can effectively alleviate RA. However, how FSN modulates the gut microbiota to mitigate RA has not been comprehensively studied. This study evaluated the gut microecological mechanisms underlying FSN's effects on RA, focusing on the impact of gut-derived short-chain fatty acids (SCFAs), specifically butyrate, in RA treatment.

Methods: The pharmacological effects of FSN on type II collagen-induced arthritis (CIA) in mice were assessed via pathological indicators, metagenomics, and metabolomics analyses. Furthermore, the impact of FSN on gut microbiota and metabolic profiles was also evaluated. Moreover, a pseudo-germ-free CIA model was established to validate whether exogenous butyrate alleviates RA. This study also elucidated whether fecal microbiota transplantation (FMT) from FSN-treated mice could mitigate RA symptoms.

Results: The data showed that FSN markedly alleviated CIA symptoms and reduced serum inflammatory cytokine levels. Metagenomic and metabolomic analyses revealed that FSN-enriched SCFA-producing bacteria, including Butyrivibrio, Faecalicatena, and Lacrimispora. Furthermore, FSN increased the activity of carbohydrate metabolism-related enzymes and upregulated the expression patterns of homologous protein families. Moreover, exogenous butyrate supplementation suppressed pro-inflammatory factors, modulating immune responses, and enhanced intestinal barrier function. Further, Western blot analysis validated that FSN inhibited the HDAC/NF-κB pathway.

Conclusion: This study indicated that the gut microecological mechanism of FSN might be associated with its herbal components, which regulate gut microbiota diversity, restore the intestinal barrier, and boost microbial metabolite production. Furthermore, butyrate was observed to modulate intestinal mucosa, inhibit inflammatory responses, repair the intestinal barrier, and mitigate joint damage, thus alleviating RA symptoms.

Keywords: Fecal microbiota transplantation; Fengshi ning decoction; Gut microbiota; HDAC/NF-κB pathway; Rheumatoid arthritis.