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: 9262327
• 负责人: AUGUSTO A LITONJUA
• 金额: $ 49.9万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262327
• 关键词: 6 year old; Accounting; Affect; Age; Allergic Disease; Asthma; Bacteroides; Bifidobacterium; Birth; Child; Child health care; Childhood; Childhood Asthma; Chronic; Chronic Disease; Clinical Trials; Collection; Complex; Coupled; Data; Developed Countries; Developing Countries; Development; Diagnosis; Disease model; Environment; Environmental Exposure; Epidemic; Family Sizes; Feces; Genetic; Genetic Markers; Genotype; High Prevalence; Hygiene; Hypersensitivity; Immune system; Infant; Inflammatory; Intestines; Lactobacillus; Lead; Life; Life Style; Live Birth; Longitudinal Studies; Low Prevalence; Metabolic; Modeling; Outcome; Pattern; Perinatal; Play; Population; Pregnancy; Prospective Studies; Public Health; Resources; Risk; Risk Factors; Role; Sampling; Shapes; Source; Specimen; Structure; Supplementation; Taxon; Testing; Time; Vitamin D; Vitamin D Deficiency; Vitamin D2; Whole-Genome Shotgun Sequencing; atopy; base; case control; cohort; disability; early life exposure; exome sequencing; genetic profiling; genome wide association study; genome-wide; gut microbiome; gut microbiota; interest; metabolomics; microbial; microbial community; microbiome; microbiota; microorganism; model development; novel; postnatal; prenatal; programs; prospective; response

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.

项目总结/摘要 哮喘和过敏性疾病仍然是主要的公共卫生问题， 全球使用。大多数哮喘在6岁之前被诊断出来。因此，产前和生命早期的接触， 在哮喘和过敏症的发展中起重要作用。在发现家庭之间的反向关联的基础上， 根据体型和特应性，人们推测，早期接触微生物的减少解释了过敏性疾病的流行 (the“卫生假说”）。最初的卫生假说经历了变化和完善，现在被用来 不仅意味着微生物暴露的减少，而且可能意味着微生物的种类和范围的变化。 再加上不断变化的环境。从数量上讲，肠道植物群是最重要的产后微生物来源， 刺激免疫系统。工业化和非工业化地区儿童肠道植物群的差异有显著性 发展中国家认为，富裕国家哮喘的高发病率可能是由于 小婴儿肠道植物群。这种“生态失调漂移”的概念，即与西方化有关的环境力量， 生活方式导致发展中的微生物群远离规范，这可能解释了为什么许多慢性炎症 哮喘等疾病与西方化的生活方式有关。生态失调是一种潜在的机制， 环境与早期发育的免疫系统相互作用，以编程慢性疾病的风险。 虽然有越来越多的研究正在调查肠道微生物组在哮喘中的作用， 他们曾检查在某一时间点取得的粪便样本。由于肠道微生物组经历快速变化， 在1岁至3岁之间建立之前，需要进行纵向研究。 此外，还没有研究考虑到宿主的遗传背景，这可能决定了发育， 以及在面对生态失调时会患上哮喘的人。这一提议的首要假设是， 维生素D缺乏症在产前，产后和产后期间，除了宿主遗传影响，导致 早期肠道生态失调在适当的宿主遗传背景下，生态失调会增加 哮喘的发展。虽然我们已经收集了大量其他相关风险的信息，但这一建议将 重点关注维生素D作为主要关注点。我们将两个维生素D临床试验人群放在一起- 维生素D治疗儿童哮喘的临床试验（VDAART）和哥本哈根前瞻性研究 （COPSAC 2010）-通过前瞻性收集怀孕和生命早期的暴露，我们将利用这些暴露来测试我们的 假设本提案是对FOA RFA-OD-16-004《环境对儿童健康结果的影响》的回应 （ECHO）儿科队列（UG 3/UH 3）。 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）。 代谢功能），直到6岁，与产前和围产期维生素D缺乏有关。 我们还将研究影响肠道微生物组这些模式的宿主遗传标记。然后我们将 研究这些微生物群变化模式与6岁以下哮喘的关系。 该项目的研究结果将指出早期环境暴露与环境影响相互作用的潜在机制。 发展肠道微生物组和宿主赋予哮喘的风险。