Microbiota and Allergic Asthma Precision Prevention (MAAP2)

这个应用程序建立在我们最初的P01的研究结果之上，旨在研究 环境因素，特别是宠物、婴儿肠道菌群和儿童过敏性哮喘。我们已经表明 1）狗改变了家中灰尘的微生物组成，2）在有狗的家庭出生的孩子 肠道微生物群和IgE的不同发育模式，3）肠道微生物组成的不同模式 与2岁时对多种过敏原致敏和 4年，这种模式受到许多母亲特征的影响，4）对多种食物敏感 2年时吸入性过敏原与10年时的哮喘密切相关，5）粪便的代谢特征 6）12，13-DiHOME，粪便中的代谢物，促进Th 2的发展 7）在另一项研究中， 在患有哮喘的母亲所生的新生儿中，胎粪微生物群是不同的。我们的补充小鼠研究 已经表明：1）用狗从家里灌入灰尘可以减少过敏原引起的肺部炎症 致敏和呼吸道合胞病毒（RSV）感染，2）狗尘灌胃小鼠增加， 约氏乳杆菌在其盲肠中的作用;约翰逊氏菌能保护 过敏原和呼吸道合胞病毒引起的肺部炎症;约翰逊氏菌会改变骨髓的功能 来源的树突状细胞，5）口服补充L.约翰逊氏菌改变了血清代谢谱， 6）L.补充约翰逊的母亲被保护免受过敏原攻击， RSV感染。总的来说，这些研究结果显示了母亲因素的影响，为这一点提供了依据。 应用程序的重点是怀孕期间母体肠道和阴道微生物，以及这些与 婴儿肠道微生物发育和过敏性哮喘风险。项目1侧重于孕产妇的关系 环境和饮食因素，包括母亲和婴儿的肠道微生物，对儿童的发展， 2岁时哮喘表型高危。项目2提议详细审查各种关系 母婴微生物群、母乳成分和IgE发育之间的关系， 孕妇目前患有过敏性哮喘。项目3与项目1协同互动 并且还使用了来自10岁的过敏性哮喘病例和最初P01出生队列中的对照的标本 研究肠道微生物产生的代谢产物与降低过敏性炎症的风险有关，以及如何 它们从母体转移到后代中。项目4将使用小鼠模型来检查 母体微生物群的操纵与后代免疫发育之间的关系。我们 预计这些研究将表明，针对母亲肠道微生物群的干预措施 在妊娠期间和出生后的高危新生儿中使用抗过敏药物可降低儿童期过敏性哮喘的风险。 这些发现将为预防过敏性哮喘的合理策略提供基础。

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.