Microbial mechanisms underlying prebiotic-linked improvements in physical function and metabolism in knee osteoarthritis and obesity

BackgroundKnee osteoarthritis (OA) is a prevalent painful degenerative disease without effective disease-modifying drugs. The rising prevalence of comorbid obesity and knee OA underscores the urgent need for effective management to delay or prevent disease progression. In a recently completed randomized, placebo-controlled trial in adults with comorbid obesity (BMI >30 kg/m{superscript 2}) and unilateral or bilateral knee OA (Kellgren-Lawrence grade II-III), we were the first to demonstrate that a 6-month prebiotic intervention (16 g/day oligofructose-enriched inulin) significantly improved physical function and metabolic health. MethodsTo elucidate the underlying mechanisms, we incorporated metagenomics, metabolomics, and machine-learning-based multi-omics integration in 30 participants who completed baseline and at least one follow-up assessment and sample collection at months 3 and 6. ResultsPrebiotic supplementation reshaped gut microbial composition and function, increasing diet-derived carbohydrate availability, mitigating excessive host-glycan degradation and mucosal barrier disruption, reducing systemic inflammation and metabolic dysregulation, and ultimately improved physical performance and metabolic health. In a diet-induced obese rat model, prebiotic treatment reduced tibial cartilage degeneration and synovial membrane thickening, providing protection against OA onset and progression through a shared inflammatory pathway. ConclusionsOur findings provide mechanistic evidence supporting the therapeutic potential of prebiotic supplementation as a conservative management in humans and as a preventive approach for obesity-related knee OA in a preclinical rat model, mediated through the gut-joint axis. Trial registrationClinicaltrials.govNCT04172688