Genetic evidence strengthens the bidirectional connection between gut microbiota and periodontitis: insights from a two-sample Mendelian randomization study

Abstract

Background: Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis.

Materials and methods: A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation.

Results: 2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10-1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05-1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03-1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01-1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00-1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70-0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated.

Conclusions: The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.

Keywords: Extra-oral inflammatory comorbidity; Gut microbiota; Mendelian randomization; Oral-gut axis; Periodontitis; Probiotics.

Fig. 1

The core design and key assumptions of the present MR study. IVW inverse-variance weighted, the main analysis to investigate the association between exposure and outcome, LD linkage disequilibrium, it is used to calculate the correlations between SNPs; MR Mendelian randomization, SNP single nucleotide polymorphism, as genetic instrumental variables for the exposure and outcome, MR-PRESSO Mendelian randomization pleiotropy RESidual Sum and Outlier, a method for testing and correcting pleiotropic biases in SNPs

Fig. 2

Results of the primary IVW analysis. A The volcano plot illustrates the link between 196 gut microbiota and periodontitis risk. The X-axis represents the beta-value, the Y-axis represents the logarithmic p-value with a base of 10, P < 0.05 is considered as statistically significant. Red and green star points represent the risk and protective microbiota genera for periodontitis, respectively. B The lollipop plot further depicts six statistically significant gut microbiota genera by p-value rank, the size of the points represents the number of SNPs, and the color of the points represents the beta-value. CI confidence interval, IVW inverse-variance weighted, OR odds ratio; SNP single nucleotide polymorphism

Fig. 3

Forest plot of the MR analyses for the associations between gut microbiota genera and risk of periodontitis. CI confidence interval, MR Mendelian randomization; OR odds ratio

Fig. 4

Results of sensitivity analyses for potential confounders. A The PhenoScanner database was examined for previously recognized confounders associated with SNPs of genome-wide significance (P < 1 × 10 ⁻⁵), the results demonstrate that 74% of the SNPs are novel in the database. B The bar chart displays the types and counts of diseases and traits related with the included SNPs. C The UpSet Venn diagram depicts the link between the included SNPs as well as the data sets of diseases and traits. SNP single nucleotide polymorphism

Fig. 5

Results of the reverse MR analysis. A The volcano plot illustrates the effect of periodontitis on genetically predicted composition of 196 gut microbiota. The X-axis represents the beta-value, the Y-axis represents the logarithmic p-value with a base of 10, P < 0.05 is considered as statistically significant. Red and green triangle points represent the microbial genera up and down regulated by periodontitis, respectively. B The lollipop plot further depicts six statistically significant intestinal microbial genera by p-value rank, the size of the points represents the number of SNPs, and the color of the points represents the beta-value. IVW inverse-variance weighted, SNP single nucleotide polymorphism