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

摘要 过去几十年来，食物过敏（FA）患病率不断上升，与此同时，肥胖和糖尿病的发病率也在不断上升 流行病首先在发达国家，现在遍布世界各地。这就提出了一个问题：母亲是否 代谢紊乱是否与儿童 FA 患病率上升有关？研究结果来自 我们和其他人都支持母亲代谢紊乱可能会增加儿童 FA 的风险。然而， 潜在的分子机制尚未得到很好的研究。此外，众所周知，发展风险 即使在控制了母亲的代谢条件后，不同儿童的 FA 差异也很大。这个 提出了另一个问题：早期生活环境和/或遗传因素可以在多大程度上改变 母亲代谢状况与儿童 FA 发育之间的关系？这个提议，高度 受我们之前有趣的工作和有希望的初步数据的启发，旨在系统地调查 母体和脐带血代谢组的纵向关系（综合表征 母体和胎儿循环代谢物）与波士顿出生队列 (BBC) 中 FA 儿童发育的关系。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 患有 FA 的儿童）。我们建议解决以下三个新颖的具体目标： 目标 1. 审查 母体和脐带血代谢组与儿童 FA 发育的前瞻性关联。我们 假设不利的母体和脐带血代谢组谱可以独立地和共同地 增加儿童 FA 风险。我们将进一步探讨所鉴定的 FA 相关代谢物是否可以解释或 改变母亲代谢紊乱对儿童 FA 风险的影响。目标 2. 检验婴儿的作用 母体和脐带代谢组与儿童 FA 发育之间关系的喂养模式。我们 假设婴儿喂养模式（包括母乳喂养和持续时间，以及固体食物的时间和类型） 食物介绍）可能会改变目标 1 中观察到的关联。目标 3. 探索胎儿基因组的作用 在目标 1 和 2 中观察到的关联中。最后，我们寻求整合多维数据 （流行病学、临床、代谢组学和基因组数据）以更好地描述新生儿未来的风险 FA的发展。这将是第一个整合尖端技术的大规模前瞻性出生队列研究 代谢组学解决生命历程框架下 FA 早期代谢起源的关键问题。 因此，我们的提案完全有能力获得关于 FA 早期代谢风险的新见解，并确定新的 从母体代谢紊乱到儿童 FA 发育途径中的代谢生物标志物。这样的 信息将提高我们识别患有 FA 高风险新生儿的能力，并实施更多措施 有效的个性化干预，以在最早的发育窗口降低 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.