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

项目 2：将胃肠道和鼻腔微生物群的功能能力与传统和现代暴露儿童的免疫发育联系起来

• 批准号: 10634247
• 负责人: Irene M Ong
• 金额: $ 30.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634247
• 关键词: 2 year old; Activities of Daily Living; Affect; Allergic; Allergic Disease; Amish; Anti-Allergic Agents; Anti-Bacterial Agents; Asthma; Bacteria; Bifidobacterium; Biological Assay; Birth; Blood; Cells; Child; Clinical; Cohort Studies; Color; Computer Analysis; Consumption; Corynebacterium; DNA Methylation; Dairying; Data; Data Analyses; Data Set; Development; Disease; Distal; Environment; Epithelial Cells; Epithelium; Exposure to; Family; Farm; Farming environment; Feces; Food; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health Benefit; Hemophilus; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Infant; Infection; Inflammation; Learning; Life; Life Style; Link; Lung; Measures; Metabolic; Metagenomics; Microbe; Microbial Genetics; Modernization; Moraxella; Mucous Membrane; Multiomic Data; Newborn Infant; Nose; Nutrient; Organ; Outcome; Pathogenicity; Pattern; Plasma; Prevalence; Prevention; Primary Prevention; Probiotics; Property; Prophylactic treatment; Proteome; Research Personnel; Research Project Grants; Resistance; Respiratory Tract Infections; Risk; Sampling; School-Age Population; Severities; Shapes; Solid; Systems Analysis; Testing; Thinness; Viral; Viral Respiratory Tract Infection; Wheezing; Wisconsin; airway epithelium; candidate selection; cohort; data integration; evidence base; experimental study; gastrointestinal epithelium; gut colonization; gut microbiome; gut microbiota; immunoregulation; longitudinal analysis; metabolome; metabolomics; metatranscriptome; metatranscriptomics; microbial; microbial colonization; microbiome; microbiota; microorganism; multiple omics; nasal microbiome; next generation; novel; pathogen; pathogenic bacteria; pathogenic virus; peripheral blood; postnatal; prenatal; prenatal exposure; racial minority; respiratory; respiratory colonization; respiratory health; respiratory microbiome; respiratory microbiota; response; secondary metabolite; suburb; transcriptome; treatment strategy

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.

项目摘要 自20世纪80年代以来，过敏性疾病的患病率在全球范围内急剧上升， 影响到少数民族和儿童。过敏性疾病，包括哮喘，是免疫系统的紊乱。 系统，这是由出生前和出生后的接触，特别是由早期生活微生物的接触， 在发育中的婴儿中定植。我们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和它们调节健康发育的机制。 免疫系统过敏性疾病日益普遍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， 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物影响局部和远端 调节呼吸道过敏和感染的免疫反应。本项目将纵向分析 从TA、农场和非农场组（WISC+，来自项目I）采集血液、粪便和鼻样本， 确定WISC+儿童微生物组功能能力的差异。为了实现这一目标，我们 将对来自WISC+的纵向样本进行宏基因组学、元转录组学和代谢组学研究 study.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DNA甲基化（DNAm）数据，以确定肠道和气道微生物组之间的关系， 免疫发育和呼吸道疾病和过敏性致敏的表达。最后我们将 分析来自MARI研究的数据，以确定与自然呼吸道疾病结果相关的微生物基因。 感染（项目I，目标2）。我们将评估基线鼻微生物遗传学的组间差异， TA儿童与郊区非哮喘儿童与郊区哮喘儿童的功能能力 （MARI），并将基线微生物基因表达与宿主细胞基因转录、DNAm和数量进行比较。 和呼吸道疾病的严重程度。WISC+和MARI中的这些实验还将提供一个“选择”列表， 在农场和TA组中丰度增加并且具有遗传特征或预测的“微生物” 与低发病率和过敏性致敏相关的代谢物，这些代谢物将在 项目三.这将使我们能够根据细菌/代谢物与微生物的相关性来识别和选择细菌/代谢物。 在农业环境中产生强烈的免疫反应。从以下方面获得的信息： 该提案中概述的多组学数据将导致下一个候选细菌的循证选择 产生益生菌，次级代谢产物，可以抑制病原菌或病毒，或调节宿主 上皮细胞或免疫细胞，用于增强对呼吸道感染和过敏的天然抵抗力 预防我们致力于从TA和农场相关的自然获得的健康益处中学习 因此，我们需要对儿童的接触情况进行评估，以便为开发无毒的预防性治疗提供信息，从而使所有儿童受益。