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.