Background: Dental caries, a dysbiotic biofilm disease driven by polymicrobial acidogenesis, often coexists with type 2 diabetes (T2D). Previous studies suggest covarying relationships between circulating and salivary metabolites in patients with T2D. However, the role of hyperglycemia-induced saccharide migration from plasma to saliva in caries pathogenesis remains unclear. Here, we developed a novel method for untargeted metabolomics profiling of trace saliva from sublingual and submandibular glands, comparing this profile with those of plasma and whole saliva in participants with T2D (n = 31) and those with normoglycemia (n = 30). This comparison aimed to determine how circulating saccharide migration into the oral cavity and its subsequent microbial consumption are linked to dental caries. Additionally, shotgun metagenomic sequencing was combined with this analysis to investigate the cariogenic impact of circulating saccharide migration on the composition and function of supragingival biofilm using MetaPhlAn4 and HUMAnN3 pipelines.
Results: The metabolomics profiles of glandular saliva showed intermediate dissimilarity between plasma and whole saliva, reflecting cardiometabolic traits more sensitively than whole saliva. Glucose and fructose showed a decreasing positive correlation with glycemic parameters in the order of plasma, glandular saliva, and whole saliva, suggesting systemic-to-oral migration and subsequent microbial consumption. Saccharide migration was more pronounced in participants with dental caries and plaque accumulation, coinciding with shifts in supragingival microbiota, including depletion of Streptococcus sanguinis, Corynebacterium durum, and Rothia aeria, and enrichment of Streptococcus mutans, Veillonella parvula, and Actinomyces sp. oral taxon 448. Glycolytic potential increased at the community level. Improved glycemic control reduced fructose migration and mitigated dysbiosis, decreasing fructose phosphotransferase abundance and shifting the S. mutans-S. sanguinis balance. Experimental validation demonstrated that fructose promotes S. mutans dominance over S. sanguinis in dual-species biofilms.
Conclusions: This study establishes saccharide migration as a metabolic driver of supragingival dysbiosis in T2D. The findings highlight the role of both glucose and fructose in caries pathogenesis and suggest that glycemic control could serve as an effective strategy as part of caries control. Video Abstract.
Keywords: Dental caries; Glycemic control; Oral microbiome; Saccharide migration; Salivary metabolomics; Shotgun metagenomics; Supragingival biofilm; Type 2 diabetes.
© 2025. The Author(s).