Potential role of bile acids as a microbiome-derived mechanism in synovitis of knee osteoarthritis synovitis

OBJECTIVE: To evaluate the relationship between bile acids (BAs) and synovitis in knee osteoarthritis (KOA). METHODS: Radiographic KOA patients with complete datasets were included. WOMAC total and subscores were calculated. Synovitis was assessed by ultrasound or Krenn score. BAs were profiled in plasma (N=28) or synovial fluid (SF, N=29) using liquid chromatography-tandem mass spectrometry. OA synovial explants, OA fibroblast-like synoviocytes (FLS), and bone marrow-derived macrophages (BMDM) were used for in vitro experiments. Data analysis was performed using R and MetaboAnalyst. RESULTS: Sixteen KOA participants had low-grade (0-1) and twelve had high-grade synovitis (2-3). Glycohyodeoxycholic acid (1.198 ± 0.983 vs. 1.954 ± 0.686, 0.76[95% CI: 0.04-1.89]) and lithocholic acid (0.19 ± 0.53 vs. 0.825 ± 0.866, 0.63[95% CI: 0.00-1.58]) were elevated in subjects with high-grade synovitis. LPS-binding protein (LBP) (rho = 0.58, p = 0.037, [95% CI: -0.807-0.46]) correlated with synovitis but only in obese participants (BMI ≥ 30). LBP, lithocholic acid, and glycohyodeoxycholic acid predicted high synovitis (92% sensitivity, 75% specificity, AUC = 0.875[95% CI: 0.99-1.05], p < 0.001). In SF, taurodeoxycholic and glycohyodeoxycholic acids correlated positively with WOMAC pain and stiffness subscores and the total WOMAC score. The BA receptors, TGR5 and LXR, were present in synovial tissue. In vitro, BAs reduced cytokine secretion in FLS and BMDM. CONCLUSION: Detection of BAs and their receptors in synovial tissue, together with their modulatory effects on synovial cells, supports a potential biological role for BAs in KOA.