Project 2: Relating the functional capacities of the GI and nasal microbiomes to immune development in children from traditional and modern exposures

项目总结 自20世纪80年代以来，过敏性疾病的流行率在全球范围内急剧上升， 影响少数民族和年幼儿童。过敏性疾病，包括哮喘，是一种免疫紊乱。 系统，这是由出生前和出生后暴露，特别是早期生命微生物暴露和 在发育中的婴儿中的殖民。迫切需要了解微生物定植的影响。 以及它们在生命早期的功能能力以及它们调节健康发育的机制 免疫系统。过敏性疾病日益流行的显著例外包括生活在 在奶牛场，特别是遵循传统农业(TA)生活方式的阿米什家庭，作为增加的农场 暴露或不同的微生物，与预防过敏性疾病有关。 我们将检验肠道和呼吸道微生物及其产品影响局部和远端的总体假设 调节呼吸道过敏和感染的免疫反应。该项目将纵向分析 从TA、农场和非农场团体(WISC+，来自项目I)收集血液、粪便和鼻腔样本 确定WISC+儿童微生物群功能能力的差异。为了实现这一目标，我们 将对来自WISC+的纵向样本执行元基因组、元转录组和代谢组学 学习。然后，我们将对这些数据以及基因表达和DNA进行综合分析 来自项目I的甲基化(DNaM)数据，以确定肠道和呼吸道微生物群之间的关系， 免疫发展与呼吸道疾病和过敏性疾病的表现。最后，我们会 分析MARI研究的数据，以确定与自然呼吸结果相关的微生物基因 感染(项目一，目标2)。我们将评估基线鼻部微生物遗传学和组间差异 TA儿童与郊区非哮喘儿童与郊区哮喘儿童的功能能力比较 (MARI)，并比较基础微生物基因表达与宿主细胞基因转录、dNaM和数量 以及呼吸道疾病的严重性。这些在WISC+和MARI中的实验也将提供一个列表 在农场和TA群体中数量增加并具有遗传特征或预测的微生物 与低发病率和过敏过敏有关的代谢物，将在#年提供给研究人员 项目III。这将使我们能够根据细菌/代谢物与 在农业环境中发展强有力的免疫反应。从整合中获得的信息 这项提案中概述的多组数据将导致对下一代候选细菌的循证选择 产生益生菌，可以抑制致病细菌或病毒，或调节宿主的次生代谢产物 上皮细胞或免疫细胞用于增强对呼吸道感染和过敏的自然抵抗力 预防。我们致力于学习TA和与农场相关的自然获得的健康益处 使所有儿童受益的无毒、预防性治疗方法的发展。

PROJECT SUMMARY The prevalence of allergic disease has risen drastically worldwide since the 1980s, disproportionately affecting racial minority and young children. Allergic diseases, including asthma, are disorders of the immune system, which is shaped by pre- and postnatal exposures, particularly by early life microbial exposures and colonization in the developing infant. There is a critical need to understand the impact of microbial colonization and their functional capacity in early life and the mechanisms by which they regulate the development of healthy immune systems. Notable exceptions to the increasing prevalence of allergic diseases include children living on dairy farms, and particularly Amish families, who follow a traditional agrarian (TA) lifestyle, as increased farm exposures or diverse microbes, have been associated with protection against allergic disease. We will test the overall hypothesis that gut and airway microbes and products influence local and distal immunological responses that regulate respiratory allergy and infections. This project will analyze longitudinally collected blood, stool and nasal samples from the TA, farm, and non-farm groups (WISC+, from Project I) to identify differences in the functional capacity of the microbiomes of WISC+ children. To accomplish this goal, we will perform metagenomic, meta-transcriptomic and metabolomics on longitudinal samples from the WISC+ study. We will then perform an integrative analysis of these data together with the gene expression and DNA methylation (DNAm) data from Project I to identify relationships between the gut and airway microbiomes, immune development and the expression of respiratory illnesses and allergic sensitization. Finally, we will analyze data from the MARI study to identify microbial genes associated with the outcomes of natural respiratory infections (Project I, Aim 2). We will assess group differences in the baseline nasal microbial genetics and functional capacities of TA children vs. suburban children without asthma vs. suburban children with asthma (MARI) and compare baseline microbial gene expression to host cell gene transcription, DNAm and the number and severity of respiratory illnesses. These experiments in WISC+ and MARI will also provide a list of “select microbes” that are increased in abundance in the farm and TA groups and have genetic features or predicted metabolites linked to low rates of illness and allergic sensitization, which will be provided to investigators in Project III. This will allow us to identify and select bacteria/metabolites based on their association with the development of vigorous immune responses in farming environments. Information gained from the integration of multi-omic data outlined in this proposal will lead to evidence-based selection of candidate bacteria for the next generation of probiotics, secondary metabolites that can inhibit pathogenic bacteria or viruses, or modulate host epithelial or immune cells to be used to boost naturally occurring resistance to respiratory infection and allergy prevention. We are committed to learning from the naturally-acquired health benefits of TA and farm-related exposures to inform the development of non-toxic, prophylactic treatments that could benefit all children.