Genetically predicted plasma metabolites mediate the relation between inflammatory factors and Meniere's disease

• MR Revealed IF→MD unidirectional causality, and PMs mediated 14.6% risk reduction. • CCL23 is associated with the inflammatory/repair/stress mechanisms of MD. • X-23639 is positively correlated with CCL23, or it may be a new marker. Emerging evidence suggests inflammation contributes to Meniere’s Disease (MD), a chronic vestibular disorder characterized by vertigo, hearing loss, and tinnitus. However, the causal role of Inflammatory Factors (IFs) and the mediating effects of Plasma Metabolites (PMs) in MD remain unclear. This study investigated bidirectional causality between IFs and MD and evaluated PMs as potential mediators. Using Genome-Wide Association Study (GWAS) summary data, we performed bidirectional Mendelian Randomization (MR) analyses to assess causal links between 91 IFs, 1,400 PMs, and MD. Single Nucleotide Polymorphisms (SNPs) genome-wide significant for IFs, PMs, and MD served as instrumental variables. Inverse Variance Weighting (IVW), MR-Egger, and weighted median methods were applied. Mediation analysis quantified PMs’ role in IF-MD associations. Sensitivity analyses (MR-PRESSO, leave-one-out) tested robustness. Genetically predicted higher CCL23 levels reduced MD risk (IVW OR = 0.5757 per SD decrease; 95% CI 0.3679–0.9007; p = 0.0156). No reverse causality from MD to IFs was observed (IVW OR = 0.9919; 95% CI 0.9812–1.0028; p = 0.1448). Mediation analysis revealed PMs accounted for 14.6% of the protective effect of IFs on MD. Elevated IF levels correlated with increased PMs (IVW OR = 1.0788; 95% CI 1.0125–1.1494; p = 0.0192), while higher PMs reduced MD risk (IVW OR = 0.5444; 95% CI 0.3006–0.9859; p = 0.0448). Sensitivity analyses confirmed result consistency, with no significant pleiotropy. This study identifies CCL23 as a protective factor against MD, partially mediated by PMs. Findings underscore inflammation and metabolic pathways as potential therapeutic targets. Further validation in diverse populations and exploration of biological mechanisms are needed to advance MD treatment strategies. 5.