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.
The microbial community colonizing a newborn baby's gastrointestinal tract is very important for the ongoing development of that community, which has a strong impact on the optimal development of the baby's immune system, leading to better child and adult health and specifically the prevention of allergy and allergic asthma. This collection of projects will identify relationships between factors influencing a mother's gastrointestinal and vaginal microbes during pregnancy, and how these factors and the mother's microbes affect her newborn's gastrointestinal microbial community and immune system development from birth through the first years of life in both human and mouse studies. We believe that taken together these advances in understanding will lay the foundation for a strategy for the primary prevention of allergies and asthma.
| Durack, Juliana; Boushey, Homer A; Huang, Yvonne J (2018) Incorporating the airway microbiome into asthma phenotyping: Moving toward personalized medicine for noneosinophilic asthma. J Allergy Clin Immunol 141:82-83 |
| Wegienka, Ganesa; Sitarik, Alexandra; Bassirpour, Gillian et al. (2018) The associations between eczema and food and inhalant allergen-specific IgE vary between black and white children. J Allergy Clin Immunol Pract 6:292-294.e2 |
| Sitarik, Alexandra Rene; Kasmikha, Nena Sabri; Kim, Haejin et al. (2018) Breast-feeding and delivery mode modify the association between maternal atopy and childhood allergic outcomes. J Allergy Clin Immunol 142:2002-2004.e2 |
| Cassidy-Bushrow, A E; Burmeister, C; Havstad, S et al. (2018) Prenatal antimicrobial use and early-childhood body mass index. Int J Obes (Lond) 42:1-7 |
| Sitarik, A R; Havstad, S; Levin, A M et al. (2018) Dog introduction alters the home dust microbiota. Indoor Air 28:539-547 |
| Sitarik, Alexandra R; Bobbitt, Kevin R; Havstad, Suzanne L et al. (2017) Breast Milk Transforming Growth Factor ? Is Associated With Neonatal Gut Microbial Composition. J Pediatr Gastroenterol Nutr 65:e60-e67 |
| Johnson, Christine C; Ownby, Dennis R (2017) The infant gut bacterial microbiota and risk of pediatric asthma and allergic diseases. Transl Res 179:60-70 |
| Havstad, Suzanne; Sitarik, Alexandra R; Johnson, Christine Cole et al. (2017) Allergic sensitization in American children of Middle Eastern ethnicity at age 2. Ann Allergy Asthma Immunol 119:464-466 |
| Fonseca, W; Lucey, K; Jang, S et al. (2017) Lactobacillus johnsonii supplementation attenuates respiratory viral infection via metabolic reprogramming and immune cell modulation. Mucosal Immunol 10:1569-1580 |
| Cassidy-Bushrow, Andrea E; Sitarik, Alexandra R; Havstad, Suzanne et al. (2017) Burden of higher lead exposure in African-Americans starts in utero and persists into childhood. Environ Int 108:221-227 |
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