VDAART FLORA ANCILLARY STUDY

描述(申请人提供)：哮喘是美国儿童慢性疾病最常见的原因，也是一个主要的健康问题，特别是在城市儿科人口中。大多数哮喘是在六岁之前被诊断出来的，大多数哮喘儿童对至少一种过敏原具有特应性。细菌肠道定植和维生素D暴露是城市化儿童中的两个不同因素，可能会影响肠道和全身水平的免疫功能，并可能增加过敏和哮喘的风险。在一项小型先导性研究中，我们发现，在母亲肠道中厌氧菌比例较高的孩子的脐带血中，抗炎免疫调节细胞因子IL-10增加。婴儿肠道的多样性在生命的前6个月对特应性皮炎具有保护作用。然而，对人类早期肠道菌群和特应性疾病的发展还没有足够的长期跟踪研究。在美国唯一一项产前维生素D哮喘干预试验(NIH资助号：U01 HL091528，联合PIs：Litonjua&Weiss)中，我们有一个独特的机会来评估肠道定植(母婴)对早期喘息、特应性皮炎和过敏性过敏风险的影响。此外，这项拟议的辅助研究将优化评估肠道定植和维生素D对过敏和哮喘发展的影响是否独立或关联的机会。我们建议在200对母亲-孩子中检验以下主要假设：(1)怀孕期间母亲维生素D水平较高将增加总的和特定的数量 母亲和儿童肠道菌群中的厌氧菌(脆弱双胞菌和乳杆菌)；(2)增加母亲肠道菌群和4个月大儿童肠道菌群中的厌氧菌数量将降低1岁时喘息、反复喘息(前一年有2例喘息报告)、特应性皮炎(湿疹)和对&gt；1过敏原的敏化风险。我们将考虑接触总的厌氧菌，以及特定的厌氧菌B脆弱菌和乳杆菌；为了进一步探索肠道菌群和维生素D是否通过共同途径影响过敏和喘息，我们将检验以下三个次要假设：3)怀孕期间母亲较高的维生素D水平将降低反复喘息、特应性皮炎和致敏的风险，部分原因是母亲肠道菌群和4个月大的婴儿肠道菌群中的厌氧菌数量增加。(4)母婴肠道菌群中总厌氧菌和特异性厌氧菌数量的增加会增加脐血中Foxp3+和IL-10+Treg细胞的频率和抗炎功能。(5)孕期补充维生素D会增加母婴粪便菌群的多样性/复杂性。这项提议具有时效性。由于母体肠道菌群组成的确定是我们假设的核心，这项辅助研究在父母临床试验VDAART的登记和交付期间的最后一年(2011年)早期启动是至关重要的。公共卫生报告：哮喘是一个主要的公共卫生问题，也是美国儿童慢性疾病最常见的原因。在40年的时间里，过敏性哮喘、过敏性鼻炎(干草热)和特应性皮炎(特应性湿疹)的患病率上升，哮喘的高流行率持续存在，特别是在美国的城市儿科人口中。如果我们确定孕妇或儿童肠道微生物群的成分对过敏、喘息或哮喘具有保护作用，并且这些成分随维生素D水平或饮食而异，这可能转化为对公众健康大有裨益的药物或饮食干预措施。(摘要结束)

DESCRIPTION (provided by applicant): Asthma is the most common cause of chronic childhood disease in the United States, and is a major health problem, particularly in urban pediatric populations. Most asthma is diagnosed before the age of six, and most children with asthma are atopic with sensitization to at least one allergen. Bacterial gut colonization and Vitamin D exposure are two factors that vary in children with urbanization, may influence immune function at the intestinal and systemic levels, and may increase the risk of allergy and asthma. In a small pilot study we found that the anti-inflammatory immunomodulatory cytokine IL-10 was increased in the cord blood of children whose mothers had a higher proportion of anaerobes in the gut. Infant gut diversity was protective against atopic dermatitis in the first 6 months of life. However, there has been no adequate long-term follow-up study of the gut flora in human early life and the development of atopic diseases. In the only U.S. pre-birth Vitamin D asthma intervention trial (NIH Grant number: U01 HL091528, co-PIs: Litonjua & Weiss), we have a unique opportunity to evaluate the influences of gut colonization (maternal and child) on the risk of early life wheeze, atopic dermatitis, and allergic sensitization. Moreover, this proposed ancillary study will optimize the chance to evaluate whether gut colonization and vitamin D influences on allergy and asthma development are independent or linked. We propose to test the following primary hypotheses in a subset of 200 mother:child pairs: (1) Higher levels of maternal vitamin D during pregnancy will increase numbers of total and specific anaerobes (B fragilis, and Lactobacillus) in the maternal and child intestinal flora; (2) Increased numbers of anaerobes in the maternal intestinal flora, and in the child intestinal flora at 4 months of age will reduce the risk of wheeze, recurrent wheeze (>2 reports of wheeze in the previous year), atopic dermatitis (eczema), and sensitization to >1 allergen at 1 year of age. We will consider exposures to total anaerobes, as well as the specific anaerobes B fragilis, and Lactobacillus; To further explore whether there are common pathways through which intestinal flora and vitamin D influence allergy and wheeze, we will test the following three secondary hypotheses: 3) Higher levels of maternal vitamin D during pregnancy will reduce the risk of recurrent wheeze, atopic dermatitis and sensitization in part through increasing numbers of anaerobes in the maternal intestinal flora, and in the child intestinal flora at 4 months of age. (4) Increased numbers of total and specific anaerobes in maternal and child intestinal flora will increase the frequency and anti-inflammatory function of Foxp3+ and IL-10+ Treg cells in cord blood.(5) Maternal supplementation with vitamin D during pregnancy will increase the diversity/complexity of maternal and child fecal flora. This proposal is time-sensitive. As ascertainment of the composition of maternal intestinal flora is central to our hypotheses, it is critically important that this ancillary study be initiated early in the final year (2011) of the enrollment and delivery period of the parent clinical trial VDAART. PUBLIC HEALTH RELVEANCE: Asthma is a major public health problem and the most common cause of chronic childhood disease in the United States. Over a 40 year period, allergic asthma, allergic rhinitis (hay fever) and atopic dermatitis (atopic eczema) prevalence increased, and the high prevalence of asthma persists, particularly in urban pediatric populations in the United States. If we identify components of maternal or childhood intestinal microbial flora that are protective against allergy, wheeze or asthma, and that vary with vitamin D levels or diet, this could be translated into pharmacologic or dietary interventions that would be of great benefit to public health. (End of Abstract)