The Oral–Gut–Joint Axis in Osteoarthritis: A Multiomics Case‒Control Study

Background: Osteoarthritis (OA) is a globally prevalent degenerative joint disorder that imposes significant socioeconomic burdens. While traditionally viewed as a localized “wear-and-tear” disease, emerging evidence supports a systemic pathogenesis involving the gut-joint axis. The oral-gut-joint pathway remains underexplored in OA pathophysiology. Objective: This study aimed to characterize oral and gut microbiota signatures in knee OA patients and elucidate their functional connections to cartilage degeneration through multiomics integration. Methods: We conducted a cross-sectional observational study involving 25 OA patients and 20 healthy controls. 16S rDNA gene amplicon sequencing region was performed on fecal and oropharyngeal swab samples. Cartilage tissues were subjected to transcriptomic and proteomic analyses. Results: We identified distinct dysbiosis patterns in both the gut and oral microbiomes of OA patients. The α-Diversity of the gut microbiota significantly increased (P < 0.05) with enrichment of Ruminococcaceae and Subdoligranulum. Concurrently, the oral microbiota showed increased α-Diversity and activation of the lipopolysaccharide biosynthesis pathway. We constructed two significant cross-omics correlation modules: one linking gut microbes (Lachnospiraceae and Muribaculaceae) to cartilage inflammatory genes (MAPK11, ITGB3, CD55 and ANGPT2) and extracellular matrix remodelling proteins and another connecting gut microbes (Helicobacter, Pseudomonas, and Phocea) with CXCL14 and GNGT2. Conclusion: Our study revealed the dysbiotic characteristics of the oral-gut microbiome and its complex functional connections with pathological changes in cartilage. These findings offer novel mechanistic insights and potential therapeutic targets for microbiota-based precision interventions in OA.