This application builds on the findings of our initial P01 designed to examine relationships between environmental factors, especially pets, the infant gut microbiota and pediatric allergic asthma. We have shown that: 1) dogs alter the microbial composition of dust in homes, 2) children born into homes with dogs have different developmental patterns of gut microbiota and of IgE, 3) a distinct pattern of gut microbial composition at 1 month of age is related to heightened risk of sensitization to multiple allergens at 2 years and of asthma at 4 years, and this pattern is influenced by numerous maternal characteristics, 4) sensitization to multiple food and inhalant allergens at 2 years is strongly related to asthma at 10 years, 5) the metabolic profiles of stools are related to later allergic sensitization 6) 12,13-DiHOME, a metabolite in stool, promotes development of Th2 lymphocytes and lowers development of Treg lymphocytes in an in vitro assay, and 7) in another study, the meconial microbiota is distinct in neonates born to mothers with asthma. Our complementary mouse studies have shown that: 1) gavaging with dust from homes with dogs reduces lung inflammation from allergen sensitization and from respiratory syncytial virus (RSV) infection, 2) dog dust gavaged mice have increases in Lactobacillus johnsonii in their ceca 3) oral administration of live L. johnsonii confers protection against pulmonary inflammation induced by allergen and RSV, 4) L. johnsonii alters the function of bone marrow- derived dendritic cells, 5) mice orally supplemented with L. johnsonii have altered serum metabolic profiles, and 6) mouse pups born to L. johnsonii-supplemented mothers are protected against allergen challenge and RSV infection. Collectively these findings showing the influence of maternal factors provide the basis for this application's focus on the maternal gut and vaginal microbiotas during pregnancy, and how these relate to infant gut microbial development and risk of allergic asthma. Project 1 focuses on the relationship of maternal environmental and dietary factors, including maternal and infant gut microbiotas, to the child's developing a high-risk for asthma phenotype by age 2 years. Project 2 proposes a detailed examination of relationships between maternal and child microbiota, breast milk composition and IgE development amongst a cohort of pregnancies in which the mother has current allergic asthma. Project 3 synergistically interacts with Projects 1 & 2 and also uses specimens from 10-year-old allergic asthma cases and controls in the initial P01 birth cohort to examine gut microbes producing metabolites associated with a lowered risk of allergic inflammation and how they are transferred from mother and established in offspring. Project 4 will use mouse models to examine the relationships between manipulation of maternal microbiota and immune development in offspring. We anticipate that together these studies will show that interventions directed at the gut microbiota of mothers during pregnancy and of high-risk neonates after birth could reduce the risk of allergic asthma in childhood. Such findings would provide the foundations of a rational strategy to prevent allergic asthma.
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