Causal analysis of metabolites in periodontitis: a Mendelian randomization and validation study.

OBJECTIVE: This study aimed to investigate the causal relationship between metabolites and periodontitis using Mendelian randomization (MR), and validate findings through gingival crevicular fluid metabolomic profiling. METHOD AND MATERIALS: A two-sample MR analysis used genetic data from 486 metabolite Genome-Wide Association Study (GWAS) and periodontitis statistics, with inverse-variance weighting as the primary method, supported by MR-Egger, weighted median, and weighted mode. Sensitivity analyses included Cochran Q, MR-Egger, and MR-PRESSO tests. Gingival crevicular fluid metabolomics compared five periodontitis patients and five controls, identifying differential metabolites via t tests and partial least squares-discriminant analysis (PLS-DA), with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. RESULTS: Mendelian randomization analysis identified 17 metabolites causally linked to periodontitis, spanning amino acids, lipids, energy metabolism, and cofactors/vitamins. Protective metabolites included betaine (OR 0.478, 95% CI 0.235-0.975), laurate (0.51, 0.267-0.974), and glycerol 3-phosphate (0.312, 0.105-0.926), while phenylalanine (39.651, 2.173-723.565), pelargonate (2.527, 1.059-6.030), and 3-methylhistidine (1.481, 1.074-2.042) increased risk. Sensitivity analyses confirmed minimal heterogeneity, no pleiotropy (except 4-acetamidobutanoate), and no reverse causation. Gingival crevicular fluid metabolomics revealed 75 upregulated and 245 downregulated metabolites, with pathway enrichment in lipid, amino acid, and vitamin metabolism. Notably, betaine-protective in Mendelian randomization analysis-was significantly reduced in periodontitis, aligning with its anti-inflammatory role. CONCLUSION: This study indicates that some circulating metabolites (eg, betaine) may protect against periodontitis. Integrating Mendelian randomization and gingival crevicular fluid analyses, key metabolic risk factors were identified. Clinically, metabolites like betaine and glycerol 3-phosphate could serve as noninvasive early biomarkers, providing new avenues for personalized periodontitis prevention and treatment.