Characterizing the impact of the environmental exposome on the oral microbiome and its role in mortality: An exposome-wide association study

BACKGROUND: The oral microbiome is a critical interface between environmental influences and human health, but its response to the cumulative exposome remains poorly characterized. We investigated the associations among the environmental exposome, the oral microbiome, and all-cause mortality. METHODS: Among 6901 nationally representative U.S. adults, we implemented an Exposome-Wide Association Study (ExWAS) framework and the Deletion/Substitution/Addition algorithm to assess associations of 100 environmental chemical exposures with oral microbial diversity and taxa using survey-weighted linear regression models. Survey-weighted Cox proportional hazards models assessed associations between exposures and all-cause mortality. Multiple comparisons were controlled using the Benjamini-Hochberg false discovery rate. Mediation analysis explored the potential role of the oral microbiome in the exposure-mortality associations. RESULTS: Tobacco-related exposures, including volatile organic compound metabolites (2,5-dimethylfuran and furan), polycyclic aromatic hydrocarbons (PAHs; 2-hydroxyfluorene and 3-hydroxyfluorene), and nicotine metabolites, showed the strongest associations with oral microbiome composition. These patterns were marked by depletion of commensal genera such as Alloprevotella, Peptostreptococcus and Neisseria, and the enrichment of stress-tolerant taxa including Bifidobacterium and Lactobacillus. Most of these exposures, particularly PAHs, were nominally associated with higher all-cause mortality. Exploratory mediation analyses suggested that overall community structure and specific taxa (e.g., Bifidobacterium, Haemophilus) represent a potential mediation pathway in the associations of cadmium, furan, PAHs, and nicotine metabolites with mortality. CONCLUSIONS: The oral microbiome may serve as a sensitive biosensor of the chemical exposome and a potential intermediate factor linking environmental exposures to mortality risk. These hypothesis-generating findings highlight the oral cavity as a key arena for environmental health impacts.