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（FA）的患病率不断上升，同时肥胖和糖尿病的患病率也在不断上升 流行病，首先在发达国家，现在在全世界。这就提出了一个问题， 代谢紊乱在病因学上与儿童FA患病率的上升有关？研究结果来自 我们和其他人支持母亲代谢紊乱可能增加儿童FA的风险。然而，在这方面， 其潜在的分子机制尚未得到很好的研究。此外，据观察， FA在个体儿童之间差异很大，即使在控制母体代谢条件之后。这 提出了另一个问题：早期生活环境和/或遗传因素在多大程度上可以改变 母体代谢状况与儿童FA发展之间的关系？这一建议，高度 受我们以前有趣的工作和有希望的初步数据的激励，旨在系统地研究 母体和脐带血代谢组的纵向关系（ 母亲和胎儿的循环代谢物）与儿童在波士顿出生队列（BBC）中发生FA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，沿着现有的 来自1,500对母婴（包括300对）的母体和脐带代谢组学和全基因组基因型数据 FA的孩子）。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儿童FA发育的前瞻性关联。我们 假设不利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。我们将进一步探索已鉴定的FA相关代谢物是否可以解释或 改变母体代谢紊乱对儿童FA风险的影响。目标2.研究婴儿的角色 喂养方式与母体和脐带代谢组学和FA儿童发育的关系。我们 假设婴儿喂养模式（包括母乳喂养和持续时间，以及固体的时间和类型 食物引入）可能会改变目标1中观察到的关联。目标3：探讨胎儿基因组在 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、代谢组学和基因组学数据），以更好地描述新生儿未来的风险， FA的发展。这将是第一个大规模的前瞻性出生队列研究， 代谢组学，以解决关键问题的早期生活代谢的起源FA下的生命历程框架。 因此，我们的建议是准备好获得新的见解，早期代谢风险的FA和确定新的 代谢物生物标志物的途径，从母亲的代谢紊乱，以儿童的发展FA。等 这些信息将提高我们识别新生儿患FA的高风险的能力， 有效的个性化干预，以减轻FA风险在最早的发展窗口。

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.