Unveiling the Causal Roles of the Oral Microbiome-Host Metabolism-Inflammation Axis in Periodontitis: A Mendelian Randomisation Study.

Periodontitis is a common chronic inflammatory disease with a complex pathogenesis involving oral microbiota dysbiosis, systemic metabolic disturbances, and inflammatory responses. Although observational studies have suggested close associations between these biological factors and periodontitis, the causal relationships remain unclear. Elucidating the causal roles and interactions of these factors is crucial for effective prevention and treatment of the disease. In this study, we utilised large-scale genome-wide association study data and applied a two-sample Mendelian randomisation (MR) framework. We systematically evaluated the independent causal effects of 43 oral microbial taxa, 1,400 blood metabolites, and 91 inflammatory proteins on periodontitis risk. Direct effects were assessed using univariable MR (UVMR), while multivariable MR (MVMR) was used to analyse interactions. Mediation MR analysis was further performed to explore potential causal pathways. UVMR analysis found that family Pasteurellaceae (OR = 0.953) and genus Veillonella (OR = 0.943) were statistically significantly associated with a reduced risk of periodontitis. Further analyses revealed 45 blood metabolites and 4 inflammatory proteins with genetically supported causal relationships to periodontitis. Mediation analysis indicated that the protective effect of family Pasteurellaceae on periodontitis risk is partially mediated by the regulation of circulating 4-hydroxychlorothalonil, with a mediation proportion of 3.54%. This study provides the first systematic genetic evidence for the causal roles and potential mediation mechanisms of oral microbiota, blood metabolites, and inflammatory proteins in the development of periodontitis. The findings offer new insights into the role of the oral microbiome-host metabolism-inflammation axis in periodontitis aetiology.