Oral Microbiome Dysregulation as a Contributor to Depressive Symptoms and Altered Brain Connectivity in a High-Risk Sample of Youth

/Abstract Depressive symptoms represent a serious challenge to youth mental health. There is therefore an urgent need for the identification of possible mechanisms underlying risk for youth depressive symptoms. This is especially crucial for certain high-risk populations, such as youth with a history of adversity exposure. Dysregulation of the oral microbiome, the community of microorganisms inhabiting the human oral cavity, may function as a mechanism underlying risk for depressive symptoms in youth. The oral microbiome is a compelling putative mechanism for youth depressive symptoms because it is manipulable via non-invasive interventions, such as probiotic supplementation, while, at the same time, remarkably resilient to insults once it has stabilized in early adulthood. Indeed, oral microbiome dysregulation has been linked to depressive symptoms, experimentally in animal models and observationally in human youth. However, in order for potential mechanisms underlying this link to be elucidated, there is a need for research that examines the oral microbiome and depressive symptoms longitudinally, that examines the microbiome at a functional level, and that incorporates neuroimaging to better understand depressive symptom etiology. The current project will address these gaps by leveraging a 3-year longitudinal study of youth, ages 6-16 at the first timepoint (N=152), with the first 2 timepoints completed and the 3rd underway. This project oversamples for adversity-exposed youth (N=66), a population at increased risk of both depressive symptoms and oral microbiome dysregulation. Oral microbiome composition and depressive symptoms will have been assessed at all three timepoints, and functional Magnetic Resonance Imaging (fMRI) conducted at the final timepoint. We will analyze the relationship between the oral microbiome and depressive symptoms, and the relationship between the oral microbiome and functional brain connectivity. We hypothesize that elevated pathogenic taxa, increased pro-inflammatory functions of the oral microbiome, and decreased aromatic amino acid precursor biosynthesis will be associated with increased depressive symptoms. We further hypothesize these same indicators of oral microbiome dysregulation will also be associated with altered functional brain connectivity, especially within the affective limbic network, reward network, default mode network, and cognitive control network. This project’s findings will yield critical understanding about potential peripheral mechanisms underlying depressive symptoms in both typically developing and high-risk youth. Project Number: 1F31MH139356-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Naomi Gancz | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $42,489 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F01A-S (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11241799