Gut microbiome dysbiosis accelerates osteoarthritis progression by inducing IFP-SM inflammation in “double-hit” mice

Abstract

Abstract Background This study investigates the complex interplay between gut microbiome dysbiosis and systemic inflammation as a critical risk factor in the pathogenesis of osteoarthritis (OA). Furthermore, it elucidates the role of gut microbiota (GMB) dysbiosis in driving OA progression. Methods A refined “double-hit” murine model was developed to explore this relationship. The first intervention involved inducing gut microbiota dysbiosis through the administration of colistin and Escherichia coli, followed by surgical destabilization of the medial meniscus (DMM) to induce joint instability. The composition of the gut microbiota was analyzed using 16 S rRNA sequencing. Gut permeability was assessed via RT-PCR and immunofluorescence (IF), while mRNA sequencing was employed to examine alterations in gene expression. Results Treatment with colistin and E. coli significantly altered the gut microbiota composition, characterized by a marked increase in the absolute abundance of Firmicutes and a concomitant reduction in Bacteroidota and the Bacteroidota/Firmicutes (B/F) ratio. At the genus level, the absolute abundances of Muribaculaceae, Rikenellaceae_RC9_gut_group, and Roseburia were significantly diminished. GMB dysbiosis led to the downregulation of intestinal tight junction proteins, including ZO-1 and Occludin, resulting in increased intestinal permeability. Consequently, serum levels of lipopolysaccharide (LPS) were significantly elevated, indicating LPS translocation from the gut into systemic circulation. Notably, GMB dysbiosis markedly exacerbated OA progression, as evidenced by accelerated cartilage degeneration, increased osteophyte formation, and reduced bone mineral density (BMD). The OARSI scoring system revealed that OA severity in both colistin and E. coli treatment groups was significantly higher than in the control group. Additionally, GMB dysbiosis promoted the expression of inflammation-related genes in the synovium and induced M1 polarization of macrophages, demonstrated by the upregulation of CD86 and an elevated CD86/CD206 ratio. Correlation analyses indicated that Bacteroidota and the B/F ratio were positively associated with intestinal barrier integrity and negatively correlated with OA progression. In contrast, Firmicutes exhibited a positive correlation with inflammation and OA deterioration. Conclusions These findings collectively underscore the critical role of GMB dysbiosis in modulating intestinal permeability, systemic inflammation, and OA pathogenesis. The protective effects of Bacteroidota and the B/F ratio, as well as the detrimental impact of Firmicutes, highlight potential therapeutic targets for mitigating OA progression through GMB modulation.

Keywords

• Gut Microbiome
• Osteoarthritis
• Lipopolysaccharide
• Synovitis