Objective: This study aimed to investigate the causal relationship between metabolites and periodontitis using Mendelian randomization (MR) and validate findings through gingival crevicular fluid (GCF) metabolomic profiling.
Methods and materials: A two-sample MR analysis used genetic data from 486 metabolite Genome-Wide Association Study (GWAS) and periodontitis statistics, with IVW as the primary method, supported by MR-Egger, weighted median, and weighted mode. Sensitivity analyses included Cochran’s Q, MR-Egger, and MR-PRESSO tests. GCF metabolomics compared 5 periodontitis patients and 5 controls, identifying differential metabolites via t-tests and PLS-DA, with KEGG pathway enrichment.
Results: MR 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, 1.059–6.03), 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. GCF metabolomics revealed 75 upregulated and 245 downregulated metabolites, with pathway enrichment in lipid, amino acid, and vitamin metabolism. Notably, betaine—protective in MR analysis—was significantly reduced in periodontitis, aligning with its anti-inflammatory role.
Conclusion: This study indicates that some circulating metabolites (e.g., betaine) may protect against periodontitis. Integrating MR and GCF analyses, we identified key metabolic risk factors. Clinically, metabolites like betaine and glycerol 3-phosphate could serve as non-invasive early biomarkers, providing new avenues for personalized periodontitis prevention and treatment.