Multi-omic approaches to mechanisms of vitamin D, environmental influences, and the microbiome on asthma

多组学方法研究维生素 D、环境影响和微生物组对哮喘的作用机制

• 批准号: 10019614
• 负责人: AUGUSTO A LITONJUA
• 金额: $ 263.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019614
• 关键词: 6 year old; Affect; Age; Allergic Disease; Asthma; Bacteroides; Bifidobacterium; Birth; Child; Child Health; Childhood; Childhood Asthma; Chronic; Chronic Disease; Clinical Trials; Collection; Complex; Coupled; Data; Developed Countries; Developing Countries; Development; Diagnosis; Disease model; Environment; Environmental Exposure; Epidemic; Exposure to; Family Sizes; Genetic; Genetic Markers; Genotype; High Prevalence; Hygiene; Hypersensitivity; Immune system; Immunization; Infant; Inflammatory; Intestines; Lactobacillus; Lead; Life; Life Style; Longitudinal Studies; Low Prevalence; Metabolic; Modeling; Outcome; Pattern; Pediatric cohort; Play; Population; Pregnancy; Prospective Studies; Public Health; Resources; Risk; Risk Factors; Role; Shapes; Source; Structure; Supplementation; Testing; Time; Vitamin D; Vitamin D Deficiency; Whole-Genome Shotgun Sequencing; antenatal; atopy; case control; cohort; disability; dysbiosis; early life exposure; exome sequencing; genetic profiling; genome wide association study; genome-wide; gut microbiome; gut microbiota; interest; metabolomics; microbial; microbial community; microbiome; microbiome composition; microbiota; microorganism; model development; multiple omics; novel; pediatric health outcomes; perinatal period; postnatal; postnatal period; prenatal; programs; prospective; response; stool sample

PROJECT SUMMARY / ABSTRACT Asthma and allergic diseases continue to be major public health problems resulting in significant disability and resource utilization globally. Most asthma is diagnosed before the age of six. Thus, prenatal and early life exposures play an important role in the development of asthma and allergies. On the basis of finding an inverse association between family size and atopy, it was postulated that reduced microbial exposure in early life explains the epidemic of allergic diseases (the “hygiene hypothesis”). The original hygiene hypothesis has undergone changes and refinement, and is now taken to mean not just simply a reduced microbial exposure, but perhaps changes in the breadth and types of microorganisms coupled with changing environments. The gut flora is, quantitatively, the most important postnatal source of microbial stimulation of the immune system. Significant differences between the gut flora of children in industrialized and developing nations suggest that the high prevalence of asthma in affluent nations may be due to changes in the intestinal flora of young infants. This concept of “dysbiotic drift,” whereby environmental forces related to Westernized lifestyles leads to a shift of the developing microbiota away from the norm, may explain why many chronic inflammatory conditions, such as asthma, are associated with Westernized lifestyles. Dysbiosis is a potential mechanism by which the environment interacts with the early developing immune system to program risk for chronic disease. While there are a growing number of studies that are investigating the role of the intestinal microbiome in asthma, these have examined stool samples obtained at one point in time. Since the intestinal microbiome undergoes rapid changes before it becomes established between the ages of 1 and 3 years of life, longitudinal studies are needed. Additionally, no studies have accounted for the host genetic background, which may determine both the development of dysbiosis and who develops asthma when faced with dysbiosis. The overarching hypothesis of this proposal is that vitamin D deficiency in the pre-, peri-, and immediate post-natal periods, in addition to host genetic influences, lead to intestinal dysbiosis in early life. Dysbiosis, in the proper host genetic context, then increases the risk for development of asthma. While we have collected information on a host of other relevant exposures, this proposal will focus on vitamin D as the primary exposure of interest. We have put together 2 vitamin D clinical trial populations – Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) – with prospective collection of exposures during pregnancy and early life, that we will leverage to test our hypotheses. This proposal is in response to FOA RFA-OD-16-004, Environmental Influences on Child Health Outcomes (ECHO) Pediatric Cohorts (UG3/UH3). In these cohorts, we will first determine the patterns of change in the early intestinal microbiome (both composition and metabolic function) up to age 6 years that are related with vitamin D deficiency in the prenatal and perinatal periods. We will also investigate genetic markers of the host that affect these patterns in the intestinal microbiome. We will then investigate the relationship of these patterns of change in the microbiome with the presence of asthma by age 6 years. Findings from this project will point to potential mechanisms by which early environmental exposures interact with the developing intestinal microbiome and the host to confer risk for asthma.

项目摘要 /摘要 哮喘和过敏性疾病仍然是主要的公共卫生问题，导致严重的残疾和资源 全球利用。大多数哮喘是在六岁之前诊断出的。那是产前和早期生活的暴露 在哮喘和过敏发展中的重要作用。根据发现家庭之间的反相关性 尺寸和特应性，据张贴，早期的微生物暴露降低解释了过敏性疾病的流行 （“卫生假设”）。原始的卫生假设经历了变化和改进，现在被带到 不仅是减少微生物暴露的意思，而且微生物的广度和类型可能会发生变化 再加上不断变化的环境。肠道菌群是定量的，是微生物的最重要的产后来源 刺激免疫系统。工业化和 发展中国家表明，情感国家哮喘的高患病率可能是由于变化 年轻婴儿的肠菌群。这种“不植物漂移”的概念，环境力量与西方化有关 生活方式会导致发展中的微生物群体转移到规范上，这可以解释为什么许多慢性炎症 哮喘等疾病与西化生活方式有关。营养不良是一种潜在的机制 环境与早期发展的免疫系统相互作用，以编程慢性疾病的风险。 尽管越来越多的研究正在研究肠道微生物组在哮喘中的作用，但 这些检查了在一个时间点获得的粪便样品。由于肠道微生物组很快经历 在建立1至3年的生命年龄之间的变化之前，需要进行纵向研究。 此外，没有研究宿主遗传背景，这可能决定了发展 患有营养不良的人，患有营养不良时患哮喘。该提议的总体假设是 除了宿主遗传影响外，铅，周期和立即产后和立即产生的维生素D缺乏症。 早期肠道营养不良。在适当的宿主遗传环境中，营养不良，然后增加 哮喘的发展。尽管我们已经收集了有关其他许多相关暴露的信息，但该建议将 专注于维生素D作为关注的主要暴露。我们汇总了2个维生素D临床试验人群 - 维生素D产前哮喘还原试验（VDAART）和哥本哈根关于儿童哮喘的前瞻性研究 （COPSAC2010） - 随着怀孕和早期生活期间的预期暴露，我们将利用来测试我们的 假设。该建议是对FOA RFA-OD-16-004的回应，环境对儿童健康成果的影响 （Echo）小儿队列（UG3/UH3）。 在这些队列中，我们将首先确定早期肠道微生物组的变化模式（组成和 代谢功能）直至6岁，与产前和围产期的维生素D缺乏有关。 我们还将研究影响肠道微生物组中这些模式的宿主的遗传标记。然后我们会 研究微生物组中这些变化模式与哮喘的存在的关系，到6岁。 该项目的发现将指出潜在的机制，使早期环境暴露与之相互作用 开发肠道微生物组和宿主，以达到哮喘的会议风险。