Unraveling the Gut-Oral Axis: A Mendelian Randomization Analysis of Gut Microbiota Impact on Periodontitis via Circulating Inflammatory Proteins

<b>Aims/Background</b> Gut microbiota (GM) dysbiosis may exacerbate periodontitis by impairing intestinal barrier integrity and inducing systemic inflammation. However, the causal relationships and mediating roles of inflammatory proteins remain unclear. This study aimed to clarify these causal pathways and mediating mechanisms. <b>Methods</b> Two-sample and multivariable Mendelian randomization (MR) analyses were conducted to evaluate the causal association between GM and periodontitis using publicly available genome-wide association study (GWAS) data and FinnGen repository. Causal estimates were obtained through inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode approaches. Additionally, MR-Egger regression and Cochran's Q-test were applied to detect and correct for potential pleiotropy and heterogeneity. <b>Results</b> Significant causal relationships were identified between GM genetics and periodontitis risk. Protective effects were observed for the class <i>Actinobacteria</i> (odds ratio [OR]: 0.726, 95% confidence interval [CI]: 0.574-0.918; <i>p</i> = 0.007), the genus <i>Collinsella</i> (OR: 0.655, 95% CI: 0.456-0.941; <i>p</i> = 0.022), the genus <i>Ruminococcus 1</i> (OR: 0.692, 95% CI: 0.497-0.964; <i>p</i> = 0.029), the genus <i>Sutterella</i> (OR: 0.697, 95% CI: 0.541-0.897; <i>p</i> = 0.005), and the phylum <i>Actinobacteria</i> (OR: 0.712, 95% CI: 0.551-0.921; <i>p</i> = 0.010), whereas the genus <i>Alistipes</i> was identified as a risk factor (OR: 1.682, 95% CI: 1.240-2.280; <i>p</i> = 0.001). Furthermore, fractalkine potentially mediated 13.37% of the association between the phylum <i>Actinobacteria</i> and periodontitis. No evidence for reverse causation was found between periodontitis risk and the aforementioned six gut microbiota in the bidirectional MR analysis. <b>Conclusion</b> Specific GM taxa and fractalkine exert causal effects on periodontitis, supporting the existence of a gut-oral axis mediated by systemic inflammation. These findings suggest potential therapeutic strategies targeting GM dysbiosis and inflammatory pathways.