Causal network between periodontitis and systemic inflammation: Triangulating evidence from Mendelian randomization and sequencing datasets

Abstract Background Periodontitis, an inflammatory condition, results from the immune response to pathogenic microorganisms. Gingival defects from periodontitis enable these microorganisms, along with immune cells and inflammatory proteins, to enter the bloodstream, potentially causing systemic inflammation and contributing to systemic diseases. Conversely, systemic diseases can worsen periodontitis by inducing inflammation. Methods In this study, we investigated the connection between periodontitis and blood immune cell phenotypes/circulating inflammation‐associated proteins using bidirectional Mendelian randomization (MR). We also analyzed the interplay between immune cells, inflammation proteins, and periodontitis through a two‐step mediation analysis. Besides, we utilized sensitivity analyses, including the MR‐PRESSO outlier test, MR Egger intercept, Cochran's Q statistic, Steiger filter, and leave‐one‐out analysis. Confounder‐related instrumental variants were filtered through the Open Targets Genetics. Additionally, the results were supported by triangulation of high‐throughput sequencing dataset analyses and animal models. Results MR analysis identified three proteins—programmed cell death 1 ligand 1 (PD‐L1), eotaxin, and neurturin (NRTN)—with protective roles against periodontitis, alongside three proteins—protein S100‐A12 (S100A12), C‐X‐C motif chemokine ligand (CXCL) 11, and sulfotransferase 1A1 (SULT1A1)—identified as risk factors. Furthermore, our study revealed 16 immunocyte phenotypes causally linked to periodontitis. Conversely, periodontitis was associated with heightened circulating levels of CXCL 9/10/11. Notably, periodontitis influenced the characteristics of circulating immune cells, particularly regulatory T cells (Treg), maturation stages of T cells, and conventional dendritic cells (cDC). Additionally, single‐cell and bulk‐RNA sequencing and animal models verified the above results. Conclusions This study underscores the close connection between periodontitis and systemic inflammation, laying the groundwork for targeted immunotherapy against periodontitis and supporting the link between periodontitis and systemic diseases. Plain Language Summary This study explored the bidirectional causal relationship between periodontitis and systemic inflammation, demonstrating a causal relationship between periodontitis and specific circulating inflammatory proteins and immune cell phenotypes, indicating that the treatment of periodontitis needs to consider the systemic inflammatory state and that the systemic inflammatory state may be involved in the link between periodontitis and systemic diseases.