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。一些 牵连幼儿环境暴露，如农场和宠物，可以告知机构和 新生儿肠道微生物组的发育。这反过来可能会影响哮喘的风险，通过影响两者， 儿童的免疫发育和对呼吸道感染（如鼻病毒感染）的反应。产妇 产前因素，包括免疫表型和微生物群，同样可能影响发育， 儿童的微生物群和哮喘风险我们最近发现，住在图森的墨西哥裔美国学童， 亚利桑那州的哮喘发病率是墨西哥（MX）附近诺加莱斯的四倍。我们还展示 出生在图森和诺加莱斯，MX的婴儿，他们的祖先有关系， 家庭环境，并在1个月龄时具有不同的肠道微生物群特征。我们推测 暴露于诺加莱斯中的特定微生物类群，MX可能是对哮喘的相对保护， 与图森相比，这种保护作用是由婴儿肠道微生物群的差异接种介导的， 图森相比，诺加莱斯，MX。BEAMS项目1将识别不同的早期微生物， 与MX的诺加莱斯的哮喘保护相关的免疫发育轨迹， 图森，亚利桑那州，以及促进它们的微生物群暴露。目标1将确定与下列因素有关的母体因素： 哮喘保护，包括母体（肠道，阴道）和环境（灰尘，水）来源的特征 差异存在的微生物群以及可能与这些暴露有关的免疫学特征。 我们将使用多重细胞因子组和CyTOF对这些PBMC进行广泛的表型分析，以鉴定细胞因子。 与暴露、位置和儿童哮喘结果相关的表型和特征。最后我们 将从分娩过程中收集的脐带血中鉴定与新生儿出生相关的差异DNA甲基化模式。 跨界差异微生物群和免疫结果。目标2将确定婴儿肠道微生物群，环境 与哮喘保护相关的母体因素、婴儿免疫细胞特征和表型， 早期生活和纵向，使用2型喘息的存在作为早期哮喘相关结局 炎症（T2喘息，T2W）在2岁。此外，我们将使用单细胞分析，以确定差异 与位置相关的细胞转录和发育以及对鼻病毒离体刺激的应答。 目的3将确定特定的微生物暴露，可能会调节多态性之间的关联 在染色体17 q的哮喘风险位点和每个位置的喘息性下呼吸道疾病。这 创新项目利用纵向的多组学方法来识别潜在的微生物， 通过免疫途径，产前暴露于截然不同的城市环境， 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.