Abstract
PURPOSE: This study investigates the causal relationship between gut microbiota (GM) and Graves' ophthalmopathy (GO) and explores the mediating role of circulating inflammatory proteins (IPs) in this association. METHODS: A two-step, two-sample Mendelian randomization (MR) analysis was performed using GM data from MiBioGen (N = 18,340), GO data from the FinnGen Research Project (691 cases, 411,490 controls), and IP data from a genome-wide association study (N = 14,824). The primary MR analysis utilized the inverse variance-weighted approach, supplemented by MR Egger, weighted median, maximum likelihood, and MR robust adjusted profile score methods. Mediation MR was used to assess the mediating role of IPs. RESULTS: We identified 26 GM taxa causally associated with GO. Notably, the genus Parabacteroides exhibited a protective effect on GO (odds ratio = 0.29; 95% confidence interval, 0.16-0.51; P < 0.001). Additionally, five circulating IPs demonstrated protective effects, while three IPs (CXCL10, CXCL11, EN-RAGE) were associated with increased GO risk. Mediation MR showed that CXCL10 mediated the pathway from Parabacteroides to GO (mediation effect = -0.07), accounting for 5.27% of the total effect. CONCLUSIONS: This study supports a causal link between GM and GO, mediated by circulating IPs. These findings offer new insights into GO pathogenesis and potential targets for clinical intervention. TRANSLATIONAL RELEVANCE: Our findings reveal how gut microbiota influences Graves' ophthalmopathy through inflammatory proteins, providing potential therapeutic targets for disease prevention and treatment.