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 (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.