PROJECT SUMMARY/ABSTRACT Adverse childhood experiences (ACEs), traumatic experiences encountered during early life stages, can profoundly impact health and well-being into adulthood. ACE prevalence is high, with one in three children having at least one ACE. Children belonging to racial or ethnic minority groups are disproportionately affected by ACEs. Several health issues in children are strongly associated with ACEs, including asthma, sleep disturbances, infection risk, obesity, and behavioral issues. Additionally, children with multiple ACEs are at high risk of dental caries and untreated oral health care needs, even those with access to preventive dental care. The objective of this study is to investigate the possible biological factors underlying ACE-associated dental caries, with the overall goal of mitigating caries disparity in children with early-life adversity. ACEs function as biological stressors that affect neuroendocrine–immune (NEI) system responses. Recently, the brain–gut–microbiome axis, describing the bidirectional, biochemical interactions of the gut microbiome with the NEI system, was identified as a potential root cause of ACE-associated health conditions. Dental caries is a diet- and host factor–dependent disease in which a dysbiotic oral microbiome generates an acidic environment, leading to enamel demineralization. Our published work identified 10 salivary immunological markers that co- occur with caries-associated bacterial species and are significantly elevated in children with caries compared with caries-free children. Some of these markers are also elevated in children with ACEs. We propose the existence of a brain–oral microbiome axis, supported by multiple reports describing the salivary induction of NEI stress response markers that may alter the oral microbiome. We hypothesize that children with ACEs present with oral microbiome dysbiosis, increased dental caries, and immune dysregulation, including alterations in salivary stress or immunological molecules. This study aims to examine the associations among ACEs, the oral microbiome, dental caries, and salivary stress and immunological biomarkers in children. The innovative study design includes (1) strategies for enrolling a clinically meaningful, sex-balanced study population with an ACE prevalence that resembles the national average; (2) a comprehensive investigation of salivary markers, the oral microbiome, actual caries experiences, and covariate factors; and (3) a high-resolution metagenomics oral microbiome investigation. Study findings will contribute to understanding ACE-associated dental caries by identifying potential causative mechanisms at the oral microbiome level. The knowledge generated by this study has the potential to directly impact the clinical management of children with ACEs, promoting medical–dental integrated and trauma-informed approaches to ACE identification and caries prevention. Future policies may benefit from considering the contrib...