Multi-omic approaches to mechanisms of vitamin D, environmental influences, and the microbiome on 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 全球利用率。大多数哮喘是在六岁之前被诊断出来的。因此，产前和早期的生命暴露对 在哮喘和过敏症的发展中起着重要作用。在发现家庭与家庭之间存在反向关联的基础上 体型和特应性，据推测，早期接触微生物的减少解释了变态反应性疾病的流行 (“卫生假说”)。最初的卫生假说经过了修改和完善，现在被用来 这不仅意味着减少微生物的接触，而且可能意味着微生物的广度和类型的变化 加上不断变化的环境。从数量上讲，肠道菌群是微生物出生后最重要的来源 刺激免疫系统。工业化与非工业化儿童肠道菌群的显著差异 发展中国家认为，富裕国家哮喘的高患病率可能是由于 婴幼儿的肠道菌群。这个概念是“非生物漂移”，即与西方化有关的环境力量 生活方式导致发育中的微生物区系偏离正常，这可能解释了为什么许多慢性炎症性疾病 哮喘等疾病与西方化的生活方式有关。生物失调是一种潜在的机制，通过这种机制 环境与早期发育的免疫系统相互作用，对慢性病的风险进行编程。 虽然越来越多的研究正在调查肠道微生物群在哮喘中的作用， 他们检查了在某个时间点上获得的粪便样本。因为肠道微生物群经历了快速的 在1岁到3岁之间形成之前的变化，需要进行纵向研究。 此外，还没有研究考虑宿主遗传背景，这可能决定两者的发育 当面临生物失调时，谁会患上哮喘。这项提议的首要假设是 除宿主遗传影响外，出生前、围产期和出生后即刻的维生素D缺乏症，铅 到早期生命中的肠道生物失调。在适当的宿主遗传背景下，生物失调会增加患上 哮喘的发展。虽然我们已经收集了许多其他相关暴露的信息，但这项提案将 重点关注维生素D作为主要的暴露兴趣。我们已经收集了两组维生素D临床试验人群- 维生素D产前哮喘缓解试验(VDAART)和哥本哈根儿童哮喘前瞻性研究 (COPSAC2010)-通过预期收集怀孕和早期生活中的暴露，我们将利用这些信息来测试我们的 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)儿童队列(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(成分和 代谢功能)在6岁以下，与产前和围产期维生素D缺乏有关。 我们还将研究宿主的遗传标记，这些标记影响肠道微生物组中的这些模式。到时候我们会的 研究这些微生物组变化模式与6岁前哮喘的关系。 该项目的发现将指出早期环境暴露与 发展肠道微生物群和宿主以增加哮喘的风险。

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.