Multi-Omics Reveal the Dysregulated Gut-Joint Axis in Knee Synovitis: Data from Two Osteoarthritis Studies in China

Gut microbiota dysbiosis and associated host immuno-metabolic disorders may play a role in knee synovitis. Herein, integrated multi-omics analyses of stool and blood samples from subjects from Pearl River Osteoarthritis Cohort (PROC, N = 207) are conducted to explore the potential gut-joint axis. Specifically, gut metagenomics, serum metabolomics and plasma proteomics are carried out. Knee synovitis is identified by magnetic resonance imaging. A total of 87 synovitis cases are identified in PROC, which are characterized by increased Firmicutes/Bacteroidetes (F/B) ratio. Alterations in microbial functions of both leucine and geraniol degradation are closely associated with increased serum 3-hydroxyisovaleric acid and decreased geranic acid. These perturbations are significantly correlated with F/B ratio and down-regulated plasma TWEAK. Building upon these, the potential synovial targets are explored using a synovial single-cell dataset and the Nanjing Osteoarthritis Cohort (NOC, N = 22). Synovial fluid proteomics, histological analysis, and in vitro experiments with human fibroblast-like synoviocytes (FLS) are conducted for NOC subjects with different synovitis grades. An upregulated TWEAK receptor is found in higher grade of synovitis. In vitro, higher TWEAK induced down-regulated TWEAK receptor in FLS. The study for the first time revealed the gut-joint axis in knee synovitis, providing new insight into potential targets for synovitis treatment.