Microbiota and Allergic Asthma Precision Prevention (MAAP2)

此应用程序构建在我们最初的P01的结果基础上，该P01旨在检查 环境因素，特别是宠物、婴儿肠道微生物区系和儿童过敏性哮喘。我们已经展示了 那就是：1)狗改变了家里灰尘的微生物组成，2)在养狗的家里出生的孩子 肠道微生物区系和IgE的不同发育模式，3)肠道微生物组成的不同模式 1个月龄与2岁时对多种过敏原致敏的风险增加和2岁时哮喘的风险增加有关 4)对多种食物敏感 吸入性过敏原在2岁时与10岁时哮喘密切相关，5)粪便代谢谱 与后期过敏反应有关粪便中的代谢物DiHOME可促进Th2细胞的发育 在一项体外试验中，淋巴细胞和抑制Treg淋巴细胞的发育，以及在另一项研究中， 母亲患有哮喘的新生儿的胎粪微生物区系明显不同。我们互为补充的小鼠研究 研究表明：1)用狗狗家中的灰尘灌胃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)狗粉尘灌胃小鼠有增加 约翰逊乳杆菌在口服活的约翰逊乳杆菌的Ceca时提供保护作用 变应原和呼吸道合胞病毒引起的肺部炎症，4)约翰逊氏菌改变骨髓功能- 来源的树突状细胞，5)口服强生乳杆菌的小鼠改变了血清代谢特征， 6)补充约翰逊乳杆菌的母亲所生的小鼠受到保护，不受过敏原挑战和 呼吸道合胞病毒感染。总而言之，这些发现显示了母性因素的影响，为此提供了基础 应用程序的重点是怀孕期间的母体肠道和阴道微生物，以及这些微生物如何与 婴儿肠道微生物发育与过敏性哮喘风险。项目1侧重于母婴之间的关系 环境和饮食因素，包括母婴肠道微生物群，对儿童发育的影响 2岁以下为哮喘表型的高危人群。项目2提出了对关系的详细检查 母婴微生物区系、母乳成分和IgE发育之间的关系 母亲目前患有过敏性哮喘的怀孕。项目3与项目1协同互动 -2，也使用了最初P01出生队列中10岁过敏性哮喘病例和对照组的样本 检查肠道微生物产生与降低过敏性炎症风险相关的代谢物，以及如何 它们是从母亲那里转移过来的，在后代中建立起来。项目4将使用鼠标模型来检查 母体微生物区系的操纵与子代免疫发育的关系。我们 预计这些研究将表明，针对母亲肠道微生物区系的干预措施 在怀孕期间和出生后对高危新生儿进行干预可以降低儿童过敏性哮喘的风险。 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.