PROJECT SUMMARY/ABSTRACT Early environmental exposures are strongly implicated in the development of later diseases. The early life microbiome provides a developmental context for understanding health and disease across the life course. In the modern era, mothers and children routinely encounter microbiome perturbing exposures including cesarean section, infant formula, and antibiotics during pregnancy and in the child's first year after birth. Compelling basic science and epidemiological research from our group and others shows that perturbation of the pre-conception, prenatal, and early childhood microbiome contributes to adverse health outcomes. These connections are particularly strong for upper and lower airway health. Population-based studies document associations between asthma and early antibiotic exposure, and children with asthma have distinct microbiome signatures from unaffected children. Complementary mouse models show a causal association between perturbed microbiota and airway disease. However, key knowledge gaps remain. First, existing studies lack diversity and are often underpowered to evaluate the extent to which microbiome-perturbing exposures such as medication use, cesarean section, and infant formula underlie racial/ethnic disparities in outcomes such as the higher prevalence of asthma in Black and Hispanic children compared to White children. Second, few studies have examined the microbiome across critical time windows (preconception, pregnancy, delivery, infancy, and early childhood). ECHO provides a unique opportunity to address these gaps and study the developmental role of the early life microbiome in later health in a large, diverse U.S. cohort. We will recruit 500 pregnant people and their resulting offspring from Middlesex County, NJ, one of the most diverse counties in the U.S., into the national ECHO cohort. Our proposed scientific focus is on the early life microbiome and exposure to microbiome-perturbing exposures (cesarean section, infant formula, and medication use) in relation to upper and lower airway health. Our specific aims are to: (1) Characterize social determinants and racial/ethnic disparities in common microbiome-perturbing exposures during critical early life periods in the ECHO-wide cohort and evaluate associations with longitudinal microbiome structures in mothers and children; (2) Estimate associations between microbiome-perturbing exposures and child outcomes, with a focus on upper and lower airway health; (3) Recruit 500 pregnant participants reflecting the unique diversity of Middlesex County, NJ; and (4) (Exploratory) Examine the extent to which maternal microbiome perturbation in the 12 months before conception is associated with adverse upper and lower airway outcomes in children. The addition of NJ contributes unique diversity to the ECHO consortium. In turn, our team's ECHO-wide research at a national scale will yield knowledge that informs clinical and public health interventions that pr...