Oral microbiome alpha diversity and all-cause, cardiovascular, and non-cardiovascular mortality in US adults: Evidence from the NHANES 2009-2019

Abstract

Background and aims: Knowledge about the association between oral microbiome diversity within individuals and cardiovascular disease (CVD) and non-CVD mortality is scarce. Besides, variation by sex and racial and ethnic groups, and the potential mediators of these associations remain unclear. We aimed to investigate the associations of oral microbiome alpha diversity with all-cause, CVD, and non-CVD mortality, and the interaction effects of sex and racial and ethnic groups and potential mediators in the associations.

Methods: The National Health and Nutrition Examination Survey (NHANES) is a population-based observational study, conducted periodically in Mexican American, Other Hispanic, Non-Hispanic (NH) White, NH Black, and other racial/ethnic participants. We linked 2009-12 survey data of 8199 adults to the mortality data until 2019. By analyzing RNA gene sequences from oral rinse samples, microbiome alpha diversity within individuals was assessed using operational taxonomic unit (OTU) richness. Potential mediators included obesity, diabetes mellitus, dyslipidemia, hypertension, and periodontitis. Multivariable Cox proportional hazards regression and causal mediation analysis were used.

Results: Baseline mean ± standard deviation (SD) age was 42.1 ± 15.1 years. Over a median follow-up of 9.1 years, 405 all-cause mortality occurred (CVD, 105; non-CVD, 300). Each 1-SD increment in OTU richness was inversely associated with all-cause mortality (hazard ratio [HR] 0.92, 95 % confidence interval [CI] 0.90-0.95), CVD mortality (HR, 0.92; 95 % CI, 0.90-0.95), and non-CVD mortality (HR, 0.92; 95 % CI, 0.90-0.95). With evidence of significant racial and ethnic groups-interaction (p <0.05), these associations were evident in Mexican American, NH White, and others racial/ethnic participants. None of the potential mediators significantly mediated the associations of OTU richness with all-cause, CVD, and non-CVD mortality.

Conclusions: Lower oral microbiome alpha diversity is associated with higher risk for all-cause, CVD, and non-CVD mortality, and the associations are varied by racial and ethnic groups.

Keywords: All-cause mortality; Alpha diversity; Cardiovascular disease; Cardiovascular mortality; Non-cardiovascular mortality; Oral microbiome.

Figure 2:. Adjusted dose-response association between OTU richness and risk for all-cause mortality

Note: OTU, operational taxonomic unit; RCS, restricted cubic spline; HR, hazard ratio; CL, confidence limit. Figure showing the adjusted dose-response association between baseline OTU richness of oral microbiome alpha diversity metrics and risk for all-cause mortality among adult participants of the National Health and Nutrition Examination Survey during 2009–2012 in the United States (n = 8199). OTU richness was coded using Cox proportional hazards regression-based RCS function with five knots located at the 5^th, 25^th, 50^th, 75^th, and 95^th percentiles of the distribution of OTU richness. Y-axis represents the HR to present the risk for all-cause mortality for any value of OTU richness compared to individuals with 129 units (median) of OTU richness. Dashed lines are 95% confidence intervals. Knots are represented by dots. Model adjusted for age, sex, race/ethnicity, current smoking, alcohol intake, daily total sugar intake, physical activity, obesity, diabetes mellitus, dyslipidemia, hypertension, oral hygiene practice, denture use, antibiotic use, periodontitis, CVD, asthma, chronic bronchitis, emphysema, liver disease, and cancer or malignancy.

Figure 3:. Forest plot for association of OTU richness with risk for all-cause mortality by race/ethnicity

Note: OTU, operational taxonomic unit; Mexi_Ame, Mexican American; Othe_His, Other Hispanic; NH_White, non-Hispanic White; NH_Black, non-Hispanic Black. Figure showing hazard ratio, 95% confidence intervals, and P-value (from multivariable Cox proportional hazards regression analysis) for the risk for all-cause mortality for 1-standard deviation (SD) increment in baseline OTU richness of oral microbiome alpha diversity among the adult participants of ‘National Health and Nutrition Examination Survey’ 2009–2010 and 2011–2012 in the United States (n = 8199). Number of all-cause mortality cases: Mexican American (53/1383), Other Hispanic (34/850), non-Hispanic White (172/3042), non-Hispanic Black (124/1958), and Others (22/966) Model adjusted for age, sex, race/ethnicity, current smoking, alcohol intake, daily total sugar intake, physical activity, obesity, diabetes mellitus, dyslipidemia, hypertension, oral hygiene practice, denture use, antibiotic use, periodontitis, CVD, asthma, chronic bronchitis, emphysema, liver disease, and cancer or malignancy. The 1-SD of OTU richness was equivalent to 44.032.