Evaluating the ecological hypothesis: early life salivary microbiome assembly predicts dental caries in a longitudinal case-control study

Abstract

Background Early childhood caries (ECC)—dental caries (cavities) occurring in primary teeth up to age 6 years—is a prevalent childhood oral disease with a microbial etiology. Streptococcus mutans was previously considered a primary cause, but recent research promotes the ecologic hypothesis, in which a dysbiosis in the oral microbial community leads to caries. In this incident, density sampled case-control study of 189 children followed from 2 months to 5 years, we use the salivary bacteriome to (1) prospectively test the ecological hypothesis of ECC in salivary bacteriome communities and (2) identify co-occurring salivary bacterial communities predicting future ECC. Results Supervised classification of future ECC case status using salivary samples from age 12 months using bacteriome-wide data (AUC-ROC 0.78 95% CI (0.71–0.85)) predicts future ECC status before S. mutans can be detected. Dirichlet multinomial community state typing and co-occurrence network analysis identified similar robust and replicable groups of co-occurring taxa. Mean relative abundance of a Haemophilus parainfluenzae/Neisseria/Fusobacterium periodonticum group was lower in future ECC cases (0.14) than controls (0.23, P value < 0.001) in pre-incident visits, positively correlated with saliva pH (Pearson rho = 0.33, P value < 0.001) and reduced in individuals who had acquired S. mutans by the next study visit (0.13) versus those who did not (0.20, P value < 0.01). In a subset of whole genome shotgun sequenced samples (n = 30), case plaque had higher abundances of antibiotic production and resistance gene orthologs, including a major facilitator superfamily multidrug resistance transporter (MFS DHA2 family PBH value = 1.9 × 10−28), lantibiotic transport system permease protein (PBH value = 6.0 × 10−6) and bacitracin synthase I (PBH value = 5.6 × 10−6). The oxidative phosphorylation KEGG pathway was enriched in case plaque (PBH value = 1.2 × 10−8), while the ABC transporter pathway was depleted (PBH value = 3.6 × 10−3). Conclusions Early-life bacterial interactions predisposed children to ECC, supporting a time-dependent interpretation of the ecological hypothesis. Bacterial communities which assemble before 12 months of age can promote or inhibit an ecological succession to S. mutans dominance and cariogenesis. Intragenera competitions and intergenera cooperation between oral taxa may shape the emergence of these communities, providing points for preventive interventions.

Bacterial community modifies host genetics effect on early childhood caries

“…To incorporate the salivary microbiome, we performed a secondary analysis of a previously conducted incidence-density sampled case-control study nested within COHRA2 (2019 data freeze) (Blostein et al 2022). In this substudy, cases were children with primary dentition white spots, dental lesions, or fillings at or before the 60-month visit.…”

“…To summarize the salivary bacterial community, we used a community state type (CST) variable derived in the initial case-control substudy (Blostein et al 2022). We used Dirichlet multinomial mixture models to identify samples with similar bacterial communities (CSTs) (Holmes et al 2012).…”

“…Two CSTs characterized by Streptococcus were predominant at the 2-month visit and were not associated with case status. At later visits, two CSTs characterized by Haemophilus parainfluenzae and Nesisseria were more common among controls and two CSTs characterized by Streptococcus and Veillonella were more common among cases (Blostein et al 2022). To preserve sample size within CST-strata, we collapsed together the two CSTs predominant at the 2-month visit (‘Early-life Streptococcus -dominated CSTs’), the two control-associated CSTs ( Haemophilus/Neisseria CSTs), and the two case-associated CSTs ( Streptococcus/Veillonella CSTs).…”

“…Previously, the acidogenic bacteria Streptococcus mutans was considered the primary microbial agent of ECC (Pitts et al 2017). However, the salivary microbiome of children under two years of age can predict future ECC with reasonable accuracy, before salivary S. mutans detection (Grier et al 2020; Blostein et al 2022), suggesting an ecological dysbiosis in the microbial community contributes to ECC (Takahashi and Nyvad 2010; Pitts et al 2017). Prior studies testing for interactions between bacterial and host genetic risk factors for ECC have considered only S. mutans (Slayton et al 2005; Meng et al 2019).…”

Advances in AI‐based cancer cytopathology

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