Maternal and Cord Blood Metabolome, Infant Feeding, and Development of Food Allergy in a Prospective Birth Cohort

摘要 在过去的几十年里，食物过敏症(FA)的患病率不断上升，同时肥胖和糖尿病也在不断增加 流行病，先是在发达国家，现在是全世界。这就引出了一个问题，即母亲是否 代谢紊乱在病因上与儿童FA患病率上升有关吗？来自以下方面的研究成果 美国和其他国家支持母体代谢紊乱可能会增加儿童FA的风险。然而， 其潜在的分子机制还没有得到很好的研究。此外，很好地观察到发展的风险 不同儿童的FA差异很大，即使在控制了母亲的代谢状况后也是如此。这 提出了另一个问题：早期生活环境和/或遗传因素能在多大程度上改变 母体代谢状况与FA儿童发育的关系？这项提议，高度 在我们之前有趣的工作和有希望的初步数据的激励下，旨在系统地研究 母体和脐带血代谢组的纵向关系(全面描述 波士顿出生队列(BBC)中的母体和胎儿循环代谢物)与儿童FA发展的关系。我们 将利用BBC广泛的临床和流行病学数据库、FA表型以及现有的 来自1,500对母婴(包括300对)的母体和脐带代谢物以及全基因组的基因数据 儿童FA)。我们建议解决以下三个新的具体目标：目标1.审查 母体和脐带血代谢组与FA儿童发育的前瞻性关联。我们 假设不良的母血和脐带血代谢组谱可以独立和联合 增加儿童FA的风险。我们将进一步探索已确定的FA相关代谢物是否可以解释或 修改母亲代谢紊乱对儿童FA风险的影响。目的2.检查婴儿的角色 喂养方式在母体和脐带代谢体与胎儿发育关系中的作用我们 假设婴儿的喂养模式(包括母乳喂养和持续时间，以及固体的时间和类型 食物引入)可能改变在目标1中观察到的关联。目的3.探索胎儿基因组的作用 在目标1和目标2中观察到的关联。最后，我们寻求整合多维数据 (流行病学、临床、代谢和基因组数据)，以更好地描述新生儿未来患心脏病的风险 FA的发展。这将是第一项大规模的预期出生队列研究，将尖端技术 代谢组学在生命过程框架下解决有关FA早期代谢起源的关键问题。 因此，我们的建议将对FA的早期代谢风险获得新的见解，并确定新的 代谢物生物标记物在FA从母体代谢紊乱到儿童发育的途径中的作用。是这样的 信息将提高我们识别发生FA的高危新生儿的能力，并实施更多 有效的个性化干预，在发育的最早窗口降低FA风险。

ABSTRACT The rising prevalence of food allergies (FA) in the past decades is in parallel with growing obesity and diabetes epidemics, first in developed countries and now across the world. It raises the question whether maternal metabolic disorders are etiologically related to the rising prevalence of FA in children? Research findings from us and others have lent support that maternal metabolic disorders may increase the risk of child FA. However, the underlying molecular mechanisms are not well studied. Besides, it is well-observed that risk of developing FA varies greatly across individual children, even after controlling for maternal metabolic conditions. This raises another question: To what degree can early life environment and/or genetic factors modify the associations between maternal metabolic conditions and child development of FA? This proposal, highly motivated by our intriguing previous work and promising preliminary data, aims to systematically investigate the longitudinal relationships of maternal and cord blood metabolome (a comprehensive characterization of maternal and fetal circulating metabolites) with child development of FA in the Boston Birth Cohort (BBC). We will leverage the BBC’s extensive clinical and epidemiological databases, FA phenotypes, along with existing maternal and cord metabolomic and genome-wide genotype data from 1,500 mother-infant pairs (including 300 children with FA). We propose to address the following three novel specific aims: Aim 1. To examine prospective associations of maternal and cord blood metabolome with child development of FA. We hypothesize that unfavorable maternal and cord blood metabolome profiles can independently and jointly increase child FA risk. We will further explore whether the identified FA-associated metabolites can explain or modify the impact of maternal metabolic disorders on child FA risk. Aim 2. To examine the role of infant feeding pattern in the relationships between maternal and cord metabolome and child development of FA. We hypothesize that infant feeding pattern (including breastfeeding and duration, and the timing and type of solid food introduction) may modify the associations observed in Aim 1. Aim 3. To explore the role of fetal genome in the associations observed in Aims 1 and 2. Finally, we seek to integrate multi-dimensional data (epidemiological, clinical, metabolomic and genomic data) to better characterize newborns’ future risk for development of FA. This would be the first large-scale prospective birth cohort study to integrate cutting-edge metabolomics to address critical questions about early-life metabolic origins of FA under a life course frame. As such, our proposal is well-poised to gaining new insight on early metabolic risk of FA and to identify novel metabolite biomarkers in the pathways from maternal metabolic disorders to child development of FA. Such information will improve our ability to identify newborns at high risk of developing FA and implement more effective personalized intervention to mitigate FA risk at the earliest developmental windows.