Causal role of serum metabolites in chronic periodontitis: A bidirectional Mendelian randomization and multi-omics integration study.

Chronic periodontitis (CP) is a multifactorial inflammatory disease. Growing evidence links dysregulated serum metabolites to CP pathogenesis, yet their causal roles in disease progression remain poorly defined. We performed bidirectional Mendelian randomization (MR) analysis to evaluate causal relationships between 486 serum metabolites and CP. Inverse-variance weighted, MR-Egger, and weighted median methods were employed to mitigate research bias. Sensitivity was evaluated via the Cochran Q test, MR-Egger, and leave-one-out analysis. Metabolic pathway analysis (based on metabolomics data) was carried out via the MetaboAnalyst 6.0. We analyzed RNA-seq data to identify genes and mechanisms involved in serum metabolite regulation of CP development. Bidirectional MR identified 22 metabolites associated with CP risk, with 6 metabolites exhibiting protective effects and 16 linked to risk-increasing associations. Sensitivity analyses confirmed robustness across multiple MR methods, and reverse MR excluded reverse causality. Caffeine metabolism and lysine degradation emerged as the core pathways. Nineteen overlapping genes were identified via transcriptomic integration as key mediators. Enrichment analysis highlighted FoxO signaling and p53-mediated signaling. This study deepens the understanding of metabolic crosstalk and its role in CP pathogenesis, revealing novel biomarkers and therapeutic targets that inform diagnostic precision and therapeutic innovation. However, limitations such as sample size constraints should be noted. Future research could validate these findings in larger populations and explore the underlying biological mechanisms linking these metabolites to CP.