Effect of the gut microbiota on frozen shoulder and potential mediating role of inflammatory cytokines: A Mendelian randomization study and mediation analysis

Frozen shoulder (FS), characterized by chronic inflammation and joint fibrosis, remains etiologically unclear. Emerging evidence suggests that gut microbiota may modulate systemic inflammation via the "gut-joint axis," yet causal links to FS are unverified. This study aimed to investigate GM-FS causality using Mendelian randomization and explore inflammatory cytokines as potential mediators. This study was conducted using genome-wide association study data from MiBioGen and IEU. Six cytokines were included in the mediation analysis. Inverse variance weighted served as the primary method, supplemented by weighted median and MR-Egger, with sensitivity analyses to ensure robustness. Among 119 bacterial genera, Butyrivibrio (OR = 0.922), Lachnospiraceae UCG004 (OR = 0.897), Lactobacillus (OR = 0.843), Parabacteroides (OR = 0.790), and Ruminococcaceae UCG003 (OR = 0.836) are protective against FS, while Eubacterium coprostanoligenes (OR = 1.172) is a risk factor (all P < .05). Mediation analysis revealed interferon -γ partially mediated the protective effect of Lactobacillus on FS (β = 0.170, P = .011). These findings advance the "gut-joint axis" theory and suggest novel therapeutic targets for FS, deserving further experimental validation.