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

Abstract 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.