Strain-level profiling reveals the impact of prolonged areca nut chewing on oral microbiome

The areca nut is a widely consumed psychoactive substance linked to an elevated risk of oral diseases, including oral cancer. Although it is well-established that areca nut chewing disrupts oral microbiota composition, its impact on microbial functions, specifically the underlying strain-level diversity remains elusive, calling for advanced exploration to uncover hidden dynamics. In this study, we constructed a well-defined cohort of 80 long-lived individuals, comprising habitual areca nut chewers and age-matched non-chewers, to investigate the long-term effects of areca nut exposure on the oral microbiome. Species and function-level profiling revealed significant alterations in microbial community structure, including marked shifts in <em>Streptococcus</em> associated with disruption of the thiamine diphosphate salvage pathway. Strain-resolved analysis further identified extensive single nucleotide variations in <em>Neisseria</em> genes <em>btuD</em> and <em>bacA</em>, which are essential for cobalamin transmembrane transport. Notably, similar strain-level alterations were observed in oral cancer patients, suggesting that areca nut chewing may disturb oral vitamin homeostasis and contribute to disease development. Moreover, the combined exposure to areca nut chewing and smoking was associated with more pronounced functional shifts in the oral microbiome, particularly in metabolic pathways related to sulfur and nitrogen cycling. Together, these findings demonstrate that chronic areca nut use induces profound remodeling of the oral microbiome at both functional and genomic levels, providing novel insights into microbial mechanisms potentially linking lifestyle exposures to oral disease, cancer, and broader impacts on human health.