Application of gut microbiota metabolites in the treatment of knee osteoarthritis: a network pharmacology study

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent degenerative joint disease affecting approximately 654 million people worldwide. The gut-joint axis theory suggests a intrinsic link between gut microbiota(GM) metabolites and KOA pathogenesis. This study employs network pharmacology to investigate the protective effects of GM metabolites against KOA and elucidate their underlying molecular mechanisms. METHODS: KOA-related targets and GM metabolite targets were retrieved from public databases. After deduplication, intersecting targets were identified and subjected to protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to identify core targets and pathways. Functional association analysis was performed on core targets, followed by GO, KEGG, and functional clustering analyses. Results from both analytical rounds were compared. A "Gut Microbiota-Target-Metabolite" network was constructed to screen key metabolites and targets, which were subsequently validated using molecular docking, drug-like property assessment, and toxicity analysis. RESULTS: By integrating multi-source target prediction, network analysis, and molecular docking validation, this study first identified IL6, IL1B, and NFKB1 as core targets regulating KOA processes via GM metabolites. GO analysis revealed their functions primarily concentrate on immune response and inflammatory regulation. KEGG analysis highlighted the lipid and atherosclerosis pathway and TNF signaling pathway as key mechanisms. Butyrate, acetate, propionate, and trimethylamine oxide emerged as core metabolites. Molecular docking confirmed strong binding affinities with core targets. All four metabolites exhibited favorable bioavailability, acceptable Lipinski's rule violations, and no hepatotoxicity or carcinogenicity. CONCLUSION: This study provides novel network pharmacology evidence supporting the gut-joint axis theory, revealing a potential mechanism whereby GM metabolites may synergistically intervene in KOA through multiple targets and pathways. It also identifies candidate targets and metabolites for gut microbiome-based prevention and treatment strategies for KOA.