Altered gut microbiota and host pathways in obesity-related knee osteoarthritis

OBJECTIVES: To investigate gut microbial alteration and their functional consequences in obesity (OB)-related knee osteoarthritis (OA) by integrating microbiome with metabolomic, proteomic, and dietary data. METHODS: Fecal and fasting plasma samples were collected from 91 knee OA patients and 12 OA-free controls, classified into four subgroups based on OB and OA status: 66 OB+OA+, 25 OB-OA+, 5 OB+OA-, and 7 OB-OA-. 16S rRNA gene sequencing was performed to profile gut microbiota. MaAsLin2 modelling was applied, and dietary intake was incorporated into the models. Plasma metabolomics (n=630 metabolites) and proteomics (n=5,416 proteins) were integrated with microbial signatures to assess functional associations. RESULTS: OB+OA+ patients exhibited significantly lower a- and β-diversity than OB-OA+ (p<0.05). Seventeen microbial taxa were identified to be significantly associated with OB+OA+ (all p<7.65×10-5 after correcting tests for 654 ASVs), and 16 of them remained significant after adjustment for age, sex, antibiotic use, and dietary intake. PICRUSt2-based predictive analysis on these taxa suggested that bile acid biosynthesis was upregulated in OB+OA+ group. These taxa were correlated with 376 metabolites (p<0.05) with enrichment in fatty acid biosynthesis, linoleic/arachidonic acid metabolism, and propanoate metabolism pathways. They were also associated with 146 proteins (p<0.001) with enrichment in PI3K-Akt signalling, ECM-receptor interaction, and lipid/atherosclerosis pathways. CONCLUSIONS: OB+OA+ patients exhibited significant gut microbial dysbiosis associated with systemic metabolic and proteomic alterations relevant to OA pathophysiology. The microbiome-metabolome-proteome axis may provide mechanistic insights into worsened OA outcomes in OB individuals and could inform microbiome-targeted interventions.