Abstract
Although emerging evidence implicates gut microbiome-cartilage cross-talk in the pathogenesis of osteoarthritis (OA), the most common joint disease, studying this microbe-gut-joint axis remains challenging due to limitations of animal models and conventional in vitro systems. Here, we report a microbe-gut-cartilage axis-on-a-chip (MGCAoC) that recreates tissue-specific microenvironments with oxygen gradients and physiological fluid shear. The computer simulation–optimized chip design generates an anoxic-oxic interface for the gut module and enables perfusion of probiotic metabolites to human cartilage organoids without cross-contamination. Multiomics profiling suggested that probiotic metabolites may promote cartilage anabolism, potentially involving PI3K and MAPK pathway, and this effect was associated with up-regulated collagen type II and aggrecan expression while suppressing metalloproteinases. In inflamed cartilage organoids, these metabolites were associated with reduced proinflammatory signaling while preserving matrix integrity. The chondroprotective effects were confirmed using cartilage organoids derived from patients with OA treated with identified metabolites. This MGCAoC enables mechanistic investigation of gut-joint axis physiology and provides a versatile preclinical tool for screening probiotic-based OA therapeutics.