Unveiling the link between oral microbial α-diversity, advanced cardiovascular-kidney-metabolic syndrome, and mortality

Background Prior studies have linked oral microbial diversity to separate cardiometabolic endpoints, yet none have applied the cardiovascular-kidney-metabolic (CKM) framework.Objective This study aimed to evaluate the association between oral microbiome α-diversity and advanced CKM, mortality, and potential mediators.Design We analyzed 6,044 adults (≥30 years) from NHANES 2009–2012. 402 all-cause deaths (144 CVD deaths) were recorded. Four α-diversity metrics (observed amplicon sequence variants (ASVs), Faith's PD, Shannon–Weiner index, Simpson index) from 16S rRNA sequencing of oral rinse samples were used to assess associations with advanced CKM (logistic regression) and all-cause/CVD mortality (Cox regression). Restricted cubic splines (RCS) and generalized additive models (GAM) characterized dose–response shapes. The findings were verified through four sets of sensitivity analyses. Mediation analyses examined two candidate mediators—a 49-item frailty index and the systemic immune-inflammation index (SII).Results Higher α-diversity was inversely associated with advanced CKM (strongest for Faith's PD, per 1-SD: OR = 0.91, 95% CI 0.86–0.98, Q4 vs Q1 OR = 0.70, 95% CI 0.58–0.84, p-trend < 0.001). All four α-diversity metrics were inversely associated with all-cause mortality, with Observed ASVs and Faith's PD exhibiting L-shaped dose-response patterns (p-nonlinear = 0.017 and 0.012, respectively), the Shannon–Weiner index exhibited a strictly linear inverse association (p-nonlinear = 0.445; EDF = 1.00), and the Simpson index showed a near-linear pattern (p-nonlinear = 0.05, p-overall < 0.001, EDF = 1.92). For CVD mortality, Shannon–Weiner index (per 1-SD: HR = 0.79, 95% CI 0.68–0.92, Q4 vs Q1 HR = 0.62, 95% CI 0.39–1.00, p-trend = 0.018) and Simpson index (HR = 0.82, 95% CI 0.72–0.93, Q4 vs Q1 HR = 0.57, 95% CI 0.35–0.93, p-trend = 0.024) maintained the most robust associations. Findings were robust across four sensitivity analyses. Exploratory mediation analyses estimated that the indirect effect of frailty on mortality was 14.30%–37.20%.Conclusion This study suggests that oral microbiome α-diversity may be associated with CKM risk, and frailty may represent a potential mediator.