Microbiome Influences on Asthma-Related Outcomes in Early Life

梁摘要：项目1 我们小组和其他人的观察表明，哮喘的风险起源于生命的早期。其中一些 牵连的儿童早期环境暴露，如农场和宠物，可以为机构和 新生儿肠道微生物群的发育。这反过来可能通过影响两者来影响哮喘风险。 儿童的免疫发育和对呼吸道感染(如鼻病毒感染)的反应。母性 产前因素，包括免疫表型和微生物区系，同样可能影响胎儿的发育。 儿童的微生物区系和哮喘风险。我们最近显示，居住在图森市的墨西哥裔美国学童， AZ的哮喘发病率是居住在附近墨西哥诺加利斯(MX)的人的四倍。我们还展示了 出生在密歇根州图森和诺加莱斯的婴儿，他们有祖先的血缘关系，接触的环境截然不同 家庭环境，并在1个月龄具有不同的肠道微生物区系特征。我们假定 暴露于Nogales中特定的微生物分类群，MX可能解释了对哮喘的相对保护作用，因为 与Tucson相比，这种保护是通过在婴儿的肠道微生物区系中差异播种来介导的 图森与密歇根州诺加莱斯的比较BEAM项目1将识别不同的早期生命微生物和 MX诺加莱斯地区与哮喘保护相关的免疫发育轨迹 亚利桑那州图森，以及促进它们的微生物群暴露。目标1将确定与以下因素相关的母体因素 哮喘保护，包括母体(肠道、阴道)和环境(灰尘、水)来源的特点 不同的微生物区系，以及可能与这些暴露有关的免疫学特征。 我们将使用多路细胞因子面板和CyTOF来广泛地对这些PBMC进行表型，以鉴定细胞 与儿童暴露、位置和哮喘结局相关的表型和特征。最后，我们 将从分娩过程中收集的脐带血中识别与 跨界差异微生物区系和免疫结果。目标2将确定婴儿肠道微生物区系，环境 和母体因素，以及婴儿免疫细胞特征和与哮喘保护相关的表型，在 早期生活和纵向研究：将2型哮喘患者出现喘息作为哮喘相关早期结局 2岁时的炎症(T2喘息，T2W)。此外，我们将使用单细胞分析来识别 细胞转录和发育与定位和对鼻病毒体外刺激的反应有关。 目标3将确定可能调节多态之间关联的特定微生物暴露 位于染色体17q的哮喘风险基因座和每个位置的喘息性下呼吸道疾病。这 创新项目利用纵向、多重组学方法来确定潜在的微生物和 暴露在截然不同的城市环境中的免疫途径，产前通过 早期生活，可能与哮喘保护或风险有关。

BEAMS ABSTRACT: Project 1 Observations by our group and others indicate that risk for asthma originates very early in life. Some of the implicated early childhood environmental exposures, such as to farms and pets, can inform establishment and development of the gut microbiome in the neonate. This in turn may affect asthma risk through influencing both the child’s immune development and response to respiratory infections such as those due to rhinovirus. Maternal prenatal factors, including immunological phenotype and microbiota, similarly may influence development of the child’s microbiota and asthma risk. We recently showed that Mexican-American schoolchildren living in Tucson, AZ, have a fourfold higher rate of asthma than those living in nearby Nogales, Mexico (MX). We also showed that infants born in Tucson and Nogales, MX, who are ancestrally related, are exposed to dramatically different home environments and have differential gut microbiota characteristics at 1 month of age. We postulate that exposure to specific microbial taxa in Nogales, MX may account for the relative protection against asthma as compared to Tucson, and that this protection is mediated by differential seeding of the infant’s gut microbiota in Tucson as compared to Nogales, MX. Project 1 of BEAMS will identify divergent early-life microbial and immune developmental trajectories associated with asthma protection in Nogales, MX compared with Tucson, AZ, and the microbiota exposures that promote them. Aim 1 will identify maternal factors related to asthma protection, including characteristics of maternal (gut, vagina) and environmental (dust, water) sources of differentially present microbiota, as well as immunologic characteristics which may relate to these exposures. We will extensively phenotype these PBMCs using multiplexed cytokine panels and CyTOF, to identify cellular phenotypes and characteristics that relate to exposures, location, and asthma outcomes in the child. Finally, we will identify differential DNA methylation patterns from cord blood collected during delivery that relate to the transborder differential microbiota and immune outcomes. Aim 2 will identify infant gut microbiota, environmental and maternal factors, and infant immune cellular characteristics and phenotypes related to asthma protection, in early life and longitudinally, using as an early asthma-related outcome the presence of wheezing with type 2 inflammation (T2 Wheezing, T2W) at age 2. Further, we will use single-cell analyses to identify differential cellular transcription and development related to location and in response to ex-vivo stimulation with rhinovirus. Aim 3 will identify the specific microbial exposures that may modulate the association between polymorphisms in the asthma risk locus at chromosome 17q and wheezing lower respiratory illnesses at each location. This innovative project utilizes a longitudinal, multiple-omics approach to identify potential microbiological and immunological pathways by which exposure to dramatically different urban environments, prenatally through early-life, may be associated with asthma protection or risk.