Causal effects of gut microbiota on the risk of periodontitis: a two-sample Mendelian randomization study

Abstract

Introduction: The oral cavity and the gut tract are interconnected, and both contain abundant natural microbiota. Gut microbiota may interact with oral flora and participate in the development of periodontitis. However, the specific role of certain gut microbiota taxa for periodontitis has not been investigated. Mendelian Randomization is an ideal method to explore causal relationships avoiding reverse causality and potential confounding factors. Thus, we conducted a two-sample Mendelian Randomization study to comprehensively reveal the potential genetic causal effect of gut microbiota on periodontitis.

Methods: SNPs strongly associated with 196 gut microbiota taxa (18,340 individuals) were selected as instrument variables, and periodontitis (17,353 periodontitis cases and 28,210 controls) was used as the outcome. The causal effect was analyzed via random effect inverse variance-weighted, weighted median, and MR-Egger. The sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests.

Results: Nine gut microbiota taxa (Prevotella 7, Lachnospiraceae UCG-008, Enterobacteriales, Pasteurellales, Enterobacteriaceae, Pasteurellaceae, Bacteroidales S24.7 group, Alistipes, and Eisenbergiella) are predicted to play a causal role in enhancing the risk of periodontitis (p< 0.05). Besides, two gut microbiota taxa (Butyricicoccus and Ruminiclostridium 6) have potentially inhibitive causal effects on the risk of periodontitis (p< 0.05). No significant estimation of heterogeneity or pleiotropy is detected.

Conclusion: Our study demonstrates the genetic causal effect of 196 gut microbiota taxa on periodontitis and provides guidance for the clinical intervention of periodontitis.

Keywords: Mendelian randomization; causal effect; gut microbiota; periodontitis; risk factor.

Figure 1

Schematic illustration of the causal relationship between gut microbiota and periodontitis through MR analyses. An overview of the two-sample MR study revealed the causal effect of specific gut microbiota taxa on periodontitis. There existed 9 taxa of gut microbiota that accelerated the initiation of periodontitis and 2 taxa of gut microbiota that reduced the risk of periodontitis. (MR, Mendelian randomization; SNPs, single nucleotide polymorphisms).

Figure 2

Preliminary MR analyses for the associations between gut microbiota and the risk of periodontitis. The circle from the outer to the inner represented the IVW, WM, and MR-Egger estimates, respectively. Gut microbiota was classified in order, phylum, class, family, and genus. The shades of color were reflections of the magnitude of the p-value as the label inside the circle. (MR, Mendelian randomization; IVW, inverse variance-weighted; WM, weighted median).

Figure 3

Forest plot of Mendelian randomization estimates between Gut microbiota and periodontitis. The figure showed the IVW estimates of significantly periodontitis-associated gut microbiota taxa. The red dots represent the IVW estimates, and the black bars represent the 95% confidence intervals of IVW estimates. The OR > 1 indicates increased risk while< 1 indicates decreased risk.

Figure 4

Scatter plots of the MR estimates for the significant causality of 11 gut microbiota taxa and the risk of periodontitis. (A) The causal effect of the genus Prevotella 7 on periodontitis; (B) The causal effect of genus Lachnospiraceae UCG008 on periodontitis; (C–K) Potential causal effect of 9 other gut microbiota taxa on periodontitis. The lines implying positive correlations moved diagonally upward from left to right, indicating a facilitative effect of gut microbiota on periodontitis. The horizontal and vertical lines indicated each correlation’s 95% confidence interval. The lines implying negative correlations move diagonally downward from left to right, indicating the inhibitory effect of gut microbiota on periodontitis. (MR, Mendelian randomization; SNPs, single nucleotide polymorphisms).