From gingiva to brain: cadmium promotes stroke via vascular mechanisms in periodontitis while vitamin k protects

Abstract

Abstract Aim To investigate systemic circulatory vascular immune mediators associated with the periodontitis–stroke link and to elucidate underlying cellular mechanisms. Methods We analyzed 4,164 adults from NHANES 2009–2014 using multivariable regression, restricted cubic spline, subgroup, and cross-sectional mediation to evaluate associations among periodontitis, stroke, cadmium, and vitamin K. Mechanistic pathways were explored via integrated bulk transcriptomic and single-cell RNA sequencing, including cell-type enrichment, intercellular communication, trajectory inference, and in silico gene perturbation. Results Periodontitis was significantly associated with increased stroke odds. Blood cadmium was positively associated with periodontitis–stroke comorbidity (OR = 1.998, 95%CI:1.55%–2.57%) with nonlinear dose–response, whereas vitamin K intake was inversely associated (OR = 0.787, 95%CI:0.633%–0.979%). In exploratory cross-sectional mediation analyses under theoretical model assumptions, cadmium statistically accounted for 14.23% of the periodontitis–stroke association, while vitamin K accounted for 2.43%. Cadmium-related transcriptional programs were enriched in endothelial and myeloid cells, linked to neutrophil–endothelial interactions, inflammatory activation, and MMP9 signaling. Vitamin K-associated signatures were enriched in neutrophils and mast cells, involving pro-resolving pathways such as PROS1–AXL and ANXA1–FPR. Trajectory and virtual knockout analyses provided in silico support for their potential regulatory roles in immune balance. Conclusions Periodontitis-related systemic alterations showed differential associations with cadmium (pro‑inflammatory) and vitamin K (pro‑resolving) signatures through immunovascular mechanisms, and these may be jointly associated with stroke susceptibility. All findings are associative and require prospective validation.