Multi-omics Analysis Reveals the Anti-Osteoarthritic effect of Dietary Carnosic Acid through Modulation of Gut Microbiota and Metabolic Profile

Osteoarthritis (OA), the most prevalent degenerative joint disease, currently lacks effective disease-modifying therapeutic agents. Accumulating evidence has highlighted the involvement of gut microbiota in OA via gut-joint axis. This study demonstrated that dietary carnosic acid (CAD) supplementation significantly modulated the gut microbiota composition and metabolites to improve the intestinal barrier integrity and mitigate joint damage in the anterior cruciate ligament transection (ACLT)-induced OA mice. Integrated analyses of 16S rRNA sequencing and untargeted metabolomics revealed that specific gut microbial families (Lachnospiraceae and Akkermansiaceae) and the plasma metabolite carnosol are key contributors to the protective effects of CAD intervention. Mechanistically, RNA-sequencing and experimental validation showed that CAD suppressed the inflammatory response in IL-1β-induced chondrocytes via the inhibition of the CCAAT/enhancer binding protein β (CEBPβ)/nuclear factor-κB (NF-κB) signaling pathway. Collectively, these findings provide a potential dietary intervention strategy for the management of OA.