Investigating the causal impact of gut microbiota on periodontitis based on Mendelian randomization, bulk transcriptomics, and single-cell transcriptomics

Background Dysbiosis of the gut microbiota is closely associated with periodontitis (PD), yet whether a direct causal relationship exists and the underlying molecular mechanisms remain unclear. This study aims to identify key genes linking gut microbiota to PD, providing molecular targets for its precise prevention, diagnosis, and treatment. Methods Three PD-related transcriptomic datasets (GSE10334, GSE223924, GSE171213) were obtained from public databases. Through Mendelian randomization (MR), machine learning, and expression validation, key regulatory genes causally linking gut microbiota to PD were identified. Gingival tissue specimens from PD patients (n = 6) and healthy controls (n = 6) were used for independent validation via quantitative real-time PCR(qRT-PCR) and Western blot. Immune cell infiltration analysis and cell communication network analysis were further conducted using single-cell RNA sequencing data. Results MR analysis identified 22 gut microbiota taxa causally associated with PD (12 protective, OR<1; 10 risk-associated, OR>1). Transcriptomic analysis yielded seven candidate genes, which were narrowed to 4 feature genes via multi-algorithm machine learning. Cross-dataset validation confirmed three key genes—IL-19, NID2, and SH3D19—with consistent differential expression. Independent experimental validation confirmed significant upregulation of NID2 at both mRNA and protein levels in the PD group ( P < 0.01), while IL-19 and SH3D19 showed no statistically significant differences. Immune infiltration analysis revealed increased plasma cell infiltration and decreased CD8 + T cell infiltration in PD ( P < 0.05). Single-cell communication analysis showed that in controls, monocyte–neutrophil interactions predominated, whereas in PD, interactions along the monocyte/MDSC/neutrophil axis were additionally elevated. Conclusion This multi-omics study identified 22 gut microbiota taxa causally associated with PD, and IL-19, NID2, and SH3D19 as key dysregulated genes. Among these, NID2 emerged as a prioritized candidate linking gut dysbiosis to periodontitis, warranting further functional investigation. These findings provide molecular evidence for the oral-gut axis and offer potential biomarkers and therapeutic targets for PD.