Prenatal maternal obesity and neurodevelopment: The mediating role of the microbiome and metabolome

Project Summary Impaired emotion regulation (ER) is a risk factor for a wide range of neuropsychiatric conditions and safeguarding its development could have important implications on mental health. Pre-pregnancy obesity has long been associated with indicators of impaired ER in children – e.g., elevated mood symptoms, increased negative emotional intensity, and increased rates of psychiatric disorders with ER deficits such as depressive and anxiety disorders. Despite these well documented associations, mechanistic studies in humans that link pre-pregnancy obesity with offspring ER development are scarce. Our proposal aims to address this research gap. We will examine the overarching hypothesis that pre-pregnancy maternal obesity negatively influences offspring ER development through its effects on the maternal gut microbiome and metabolome. Our innovative design includes longitudinal assessments of the maternal microbiome and metabolome, repeated assessments of ER- related brain systems in the offspring using fetal and infant MRI scans, and behavioral assays of ER in the offspring through the first 24 months of life. Using these multimodal assessments and longitudinal design, we will test whether (a) the maternal gut microbiome during gestation is influenced by maternal obesity; (b) the maternal gut microbiome is associated with maternal metabolites within tryptophan and tyrosine metabolic pathways; and (c) maternal metabolites in turn correlate with ER development measured with brain (fetal and infant MRI) and behavioral correlates. Our study is uniquely positioned to address these aims leveraging an ongoing human birth cohort study (HOPE cohort, supported by Duke University) of mother-infant dyads enriched for obesity (50% of enrollees with pre-pregnancy BMI>=30, confirmed by medical record). The HOPE cohort includes an extensive battery of biospecimens and clinical/demographic measures with pregnant women enrolled during the first trimester gestation and their children followed into the first few years of life. With over 1 million children born yearly in the US to mothers who experienced pre-pregnancy obesity, the ER developmental impact of pre-pregnancy obesity is a substantial and mounting concern – and disproportionately impacts low income and minoritized populations. Mechanistic research in humans that links pre-pregnancy obesity with offspring ER development and psychiatric risk is critical to advancing prevention efforts.