Interactions between Environmental Microbiome, Maternal Immunity, Neonatal Epigenome and Respiratory Microbiome Development as Determinants of Asthma In Childhood

环境微生物组、母体免疫力、新生儿表观基因组和呼吸道微生物组发育之间的相互作用是儿童哮喘的决定因素

• 批准号: 9395215
• 负责人: Susan Veronica Lynch
• 金额: $ 24.37万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395215
• 关键词: 1 year old; AIDS/HIV problem; Address; Age; Allergic; Allergic Disease; Antibiotics; Asthma; Biological Assay; Birth; Cells; Characteristics; Child; Childhood; Childhood Asthma; Chronic Disease; Chronology; Communities; Consumption; Cues; DNA Methylation; Data; Development; Disease; Disease Outcome; Economic Burden; Environmental Exposure; Environmental Tobacco Smoke; Epidemiology; Event; Exhibits; Exposure to; FOXP3 gene; Farming environment; Fever; Genetic; House Dust; Hypermethylation; Hypersensitivity; IL2RA gene; IL4 gene; IgE; Immune; Immunity; Infant; Infection; Interferons; Interleukin-13; Knowledge; Lead; Life; Lipids; MADH3 gene; Maternal Exposure; Mediterranean Diet; Meta-Analysis; Metabolism; Microbe; Mitogens; Mothers; Nature; Neonatal; Nursery Schools; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Plant Roots; Play; Predisposition; Pregnancy; Recording of previous events; Relative Risks; Risk; Risk Factors; Role; Sampling; Smoking; Stress; Structure; Taxonomy; Testing; Third Pregnancy Trimester; Time; Tuberculosis; Umbilical Cord Blood; Water; Weight; Wheezing; asthmatic; base; cohort; disorder risk; emerging adult; epigenome; flu; gut microbiota; in utero; inner city; methylome; microbial; microbial community; microbiome; microbiota; neonate; novel; offspring; persistent symptom; postnatal; pregnant; prenatal; prenatal exposure; promoter; respiratory; response; study population

Asthma is the most common chronic disease of childhood, with an economic burden that exceeds that of tuberculosis and HIV/AIDS combined. Epidemiologic evidence suggests that the origins of disease occur during pre-school years even when chronic symptoms appear in early adulthood. Moreover, several risk factors for childhood asthma suggest that the disease may have its beginnings already in utero, and the maternal milieu during pregnancy may contribute to disease risk. These data suggest that the trajectory to childhood asthma and related outcomes (e.g., allergic sensitization, wheeze) may begin prenatally, when maternal environmental exposures calibrate set points for responses to post-natal environmental cues. Our preliminary data (mostly collected in our birth cohort, the Infant Immune Study: IIS) suggest that mechanisms rooted in the environmental microbiome, the maternal immune milieu, the child's immune epigenome at birth and early-life microbiota play a prominent role in this trajectory: a) microbial community structure in house dust is associated with asthma-related outcomes; b) the maternal prenatal immune milieu (expressed as the ratio between the amounts of IFN and IL13 produced by mitogen-stimulated maternal PBMC isolated during the third trimester of pregnancy) influences asthma risk in the child; c) DNA methylation in cord blood immune cells from IIS neonates is associated with the maternal prenatal immune milieu (IFN:IL13 ratio) to which the child was exposed in utero; d) the neonatal methylome differs in children who do and do not become asthmatic by age 9, and SMAD3 hypermethylation predicts asthma selectively in children born to asthmatic mothers; e) neonatal microbiome perturbation is associated with significantly different relative risk of allergy at age 2 and asthma at age 4. The nature and chronology of these events lead us to hypothesize that the pregnant mother's immune profile, influenced by environmental exposures, modifies the child's epigenome in utero, postnatal airway microbiome development, and the trajectory to allergy and asthma during childhood. To test this hypothesis, we will leverage abundant existing information and well-characterized, banked samples from the IIS population. We propose to characterize the child's immune methylome at birth and its relationships with the prenatal maternal immune milieu (IFN:IL13 ratio), respiratory microbiota development, and asthma and allergic disease outcomes from birth to age 9 yrs (Specific Aim 1); and to characterize environmental (house dust) microbial exposures and post-natal (<1 year old) respiratory microbiota and to assess their relationship with maternal prenatal immune profile, neonatal epigenome, and child's risk for asthma, allergy and related outcomes from birth to age 9 yrs (Specific Aim 2). To our knowledge, this is the first time that a single study examines all of these characteristics and their mutual relations in the context of childhood asthma and allergy. This proposal aims to fill this gap in knowledge to address the role of the hypothesized causal pathway in the development of childhood disease.

哮喘是儿童期最常见的慢性疾病，其经济负担超过儿童 结核病和艾滋病毒/艾滋病的结合流行病学证据表明疾病的起源发生在以下时期。 即使在成年早期出现慢性症状，学龄前儿童也会出现这种情况。 儿童哮喘表明这种疾病可能已经在子宫内开始，而母亲的环境 怀孕期间可能会增加疾病风险。这些数据表明儿童哮喘的发展轨迹。 相关的结果（例如过敏、喘息）可能在产前就开始出现 环境暴露可校准对产后环境线索反应的设定点。 我们的初步数据（主要在我们的出生队列中收集，即婴儿免疫研究：IIS）表明 植根于环境微生物组、母体免疫环境、儿童免疫的机制 出生时的表观基因组和生命早期的微生物群在此轨迹中发挥着重要作用：a）微生物群落 室内灰尘的结构与哮喘相关的结果有关；b) 母亲的产前免疫环境； （表示为有丝分裂原刺激的母体 PBMC 产生的 IFN- 和 IL13 量之间的比率 在妊娠晚期分离）影响儿童哮喘风险 c） 脐带 DNA 甲基化； IIS 新生儿的血液免疫细胞与母体产前免疫环境相关（IFN:IL13 比率） d) 接触和未接触的儿童的新生儿甲基化组有所不同； 9 岁时患有哮喘，SMAD3 高甲基化可选择性地预测患有哮喘的儿童的哮喘 e) 新生儿微生物群扰动与显着不同的过敏相对风险相关 2岁时，4岁时患哮喘。 这些事件的性质和时间顺序引导我们与怀孕母亲的免疫系统作斗争 受到环境暴露的影响，改变了孩子在子宫内、产后的表观基因组 气道微生物群的发育，以及儿童时期过敏和哮喘的轨迹来测试这一点。 假设，我们将利用 IIS 中丰富的现有信息和特征明确、存储的样本 我们建议描述儿童出生时的免疫甲基化及其与免疫甲基化的关系。 产前母体免疫环境（IFN-:IL13 比率）、呼吸道微生物群发育、哮喘和过敏 从出生到 9 岁的疾病结果（具体目标 1）；并描述环境特征（室内灰尘）； 微生物暴露和产后（<1 岁）呼吸道微生物群，并评估它们与 母亲产前免疫特征、新生儿表观基因组以及儿童哮喘、过敏和相关结果的风险 从出生到 9 岁（具体目标 2），这是第一次通过单一研究对所有人群进行调查。 该建议在儿童哮喘和过敏的背景下研究了这些特征及其相互关系。 旨在填补这一知识空白，以解决发达因果路径在发展中的作用 儿童时期的疾病。