Dysbiosis between the oral microbiome and host underpins the development of dental caries. Assembly of the oral microbiome occurs hours after birth and evolves over time in response to environmental exposures. Early life is therefore a critical window when the microbiome is particularly susceptible to environmental exposures, including nutritional and toxic chemicals. Large scale studies of the impact of early life environment exposures on microbiome trajectories and subsequent risk of pediatric caries, have been prevented due to a lack of technology to directly measure the fetal environmental exposures and lack of statistical measures to account for the high dimensional data generated by ?omic assays. We propose to overcome these limitations by combining metagenomic oral microbiome data with direct measures of fetal and postnatal exposure to essential elements and toxic metals as well as metabolomics data measured from the prenatal and early childhood periods using specialized tooth-matrix biomarkers that we have developed. The long term goal is to better understand the interaction of environment and the oral microbiome, and their separate and combined effects on caries development. The overall objective of this proposal is to identify environmental exposures and critical windows during development that impact the microbiome trajectory and modify caries risk. We leverage an existing population-based prospective cohort of 500 twins in which biosamples, clinical data and supporting data have already been collected from a substantial portion of participants. Our overarching hypothesis is that environmental exposures during early life alter the acquisition and maturation of the oral microbiome, and in the background of genetic risk, mediate oral health outcomes in childhood. Guided by strong preliminary data, this hypothesis will be tested by 1) determining the association between prenatal and early postnatal exposures with the assembly and evolution of the oral microbiome and 2) determining how early life exposures and oral microbiome trajectories contribute, separately and jointly, to caries risk. The approach is innovative in its technique of measuring biomarkers of environmental exposures in temporally assigned zones of deciduous teeth to reconstruct prenatal and early postnatal histories of exposure, measurement of the oral microbiome at 5 time points to construct trajectories, application of high dimensional statistical methods and leveraging of a twin cohort to assess gene x environment x microbiome interactions. The proposed research is significant because it will identify actionable environmental risk factors for pediatric dental caries and lay the foundation for future studies that can leverage these resources to better understand the interaction between environmental exposure mixtures and microbiome trajectories and impacts on oral health.
The oral microbiome is a major determinant of caries risk and its assembly and evolution is susceptible to environmental exposures. The proposed research is relevant to the NIDCR's mission to improve dental and oral health as it will identify the environmental exposures, and the critical time points, that influence the microbiome and modify caries risk. This can be translated into actionable interventions to reduce caries prevalence, and with further research building upon these findings, other oral diseases.
