Exploring therapeutic targets of curcumin for knee osteoarthritis via the gene–gut microbiota–plasma metabolite axis: An observational study

Osteoarthritis (OA) is a prevalent, chronic, degenerative joint disorder characterized by a multifaceted pathogenesis. Conventional risk variables inadequately account for its evolution, leading to heightened focus on systemic causes. Dysbiosis of gut microbiota associated with immunological, metabolic, and inflammatory abnormalities, can influence joint health through the "gut-joint axis." This study investigated the correlation between OA and gut microbiota dysbiosis to identify novel therapeutic targets. This study utilized 211 gut microbiota characteristics as exposures, 1400 plasma metabolite concentrations as mediators, and Genome-Wide Association Study (GWAS) data for patients with knee osteoarthritis (KOA) as outcomes. Mendelian randomization (MR) analyses were performed via inverse variance weighting, with robustness verified using pleiotropy and heterogeneity assessments. We identified the intersection of differentially expressed genes from the transcriptome analysis of OA patients with genes exhibiting significant causal associations derived from MR analysis. The intersecting genes were then analyzed through Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology enrichment analysis, as well as molecular docking and molecular dynamics simulations. Our analyses indicated that the Lachnospiraceae family, genus UCG001, exhibited a negative correlation with KOA, potentially mitigating the condition by reducing the glycine-to-serine ratio. Sensitivity analyses validated the robustness of these associations. Reverse Mendelian randomization analyses (rMRa) provided no evidence of reverse causality. The integration of GWAS and Gene Expression Omnibus (GEO) data revealed that 1 gene had a substantial association with KOA, suggesting it as a potential therapeutic target for KOA. Molecular docking analysis and molecular dynamics simulations were employed to forecast potential drug-target interactions, therefore substantiating the therapeutic potential of curcumin. Our study provides insights into the development of personalized therapeutic strategies for KOA and identifies preliminary possible targets for curcumin.