Perfluoroalkyl Substances and the Gut Microbiome and Fecal Metabolome: Implications for Obesity Risk in Hispanic Children

摘要 儿童肥胖是一个高度优先的公共卫生问题，因为它增加了共病的风险，包括 心血管疾病、脂肪肝和2型糖尿病。更好地理解影响 触发生命早期肥胖的发展是迫切需要的。这一点在西班牙裔美国人中尤为重要， 在幼年肥胖率高的少数群体。除了不良的饮食和缺乏体育活动，早期的生活 暴露于环境化学品，这是在服务不足的社区，独立贡献 to childhood儿童obesity肥胖.人体研究表明，即使在怀孕期间接触低水平的聚乙烯， 全氟烷基物质（PFAS）与婴儿体重迅速增加和儿童期风险增加有关 肥胖出生后，母乳喂养是PFAS意外传播给婴儿的主要来源， 抵消了延长母乳喂养的一些好处。最近的研究结果表明，发育中的肠道微生物组 暴露于母乳PFAS，这可能会改变肠道细菌和粪便代谢物，导致肥胖。 尽管如此，人类研究主要集中在产前PFAS暴露，之前没有研究 研究了母乳PFAS对婴儿快速生长和婴儿期肠道微生物组的影响， 在此期间，干预措施有可能预防儿童肥胖症的发展。我们的总体 有一种假说认为，母乳中PFAS浓度越高，婴儿生长和儿童期就越快 肥胖的风险，这些影响是由婴儿肠道的组成和功能的改变来解释的 微生物组这一假设是基于我们的初步数据，这表明婴儿的肠道 细菌与婴儿体重和6个月大的母乳PFAS有关。我们的多学科团队 的研究人员提议在208对西班牙裔母亲-孩子的队列中测试这一假设， 在1、6、12、18、24和36个月以及6岁时的儿童生长。这项研究将测量母乳 PFAS浓度并使用存档乳房样本表征婴儿肠道微生物组和粪便代谢组 1个月和6个月时的乳汁和粪便样本，以促进我们对致肥胖效应的机制理解 的PFAS暴露，同时占产前PFAS暴露使用新生儿干血斑。我们的目标是 确定生命早期暴露于母乳PFAS与以下因素相关的程度：1） 1-月至6岁（目标1A）和快速生长和儿童肥胖的风险（目标1B）以及2）变化 肠道微生物谱和粪便代谢物（目标2）。我们的最终目标（目标3）是将母乳PFAS 暴露，肠道微生物组和粪便代谢组学特征，以确定儿童的亚组， 快速增长和肥胖的风险。这项研究提供了一个独特的机会，以促进我们对乳腺癌的理解。 牛奶PFAS，并可能确定可用于抵消肥胖风险的预防措施，包括筛查 母乳PFAS和益生菌的使用，以促进生长的有益肠道细菌在生命早期。

ABSTRACT Childhood obesity is a high priority public health issue as it increases the risk of co-morbid diseases, including cardiovascular disease, fatty liver disease, and type 2 diabetes. An improved understanding of the factors that trigger the development of early life obesity is urgently needed. This is especially important among Hispanics, a minority group with high rates of obesity in early life. Beyond poor diet and a lack of physical activity, early life exposure to environmental chemicals, which are higher in underserved communities, independently contribute to childhood obesity. Human studies show that even at low levels of exposure during pregnancy, poly- and perfluoroalkyl substances (PFAS) are associated with rapid infant weight gain and greater risk for childhood obesity. Postnatally, breastfeeding is a primary source of inadvertent PFAS transmission to infants, potentially offsetting some benefits of extended breastfeeding. Recent findings suggest that the developing gut microbiome is exposed to breast milk PFAS, which may alter gut bacteria and fecal metabolites that contribute to obesity. Despite this, human studies have largely focused on prenatal PFAS exposure, and no prior studies have examined the effects of breast milk PFAS on rapid infant growth and the gut microbiome during infancy, a critical period in which interventions have the potential to prevent the development of childhood obesity. Our overarching hypothesis is that higher concentrations of breast milk PFAS contribute to more rapid infant growth and childhood obesity risk, and that these effects are explained by alterations in the composition and function of the infant gut microbiome. This hypothesis is based on results from our preliminary data, which demonstrate that infant gut bacteria are associated with infant weight and breast milk PFAS at 6-months of age. Our multidisciplinary team of investigators propose to test this hypothesis in a cohort of 208 Hispanic mother-child pairs with assessments of child growth at 1, 6, 12, 18, 24, and 36-months as well as at 6yr of age. This study will measure breast milk PFAS concentrations and characterize the infant gut microbiome and fecal metabolome using archived breast milk and stool samples at 1- and 6-months to advance our mechanistic understanding of the obesogenic effects of PFAS exposure while accounting for prenatal PFAS exposure using newborn dried blood spots. Our aims are to determine the extent to which early life exposure to breast milk PFAS are associated with: 1) child weight from 1-month to 6 years (Aim 1A) and the risk of rapid growth and childhood obesity (Aim 1B) as well as 2) changes in gut microbial profiles and fecal metabolites (Aim 2). Our ultimate goal (Aim 3) is to integrate breast milk PFAS exposure, gut microbiome, and fecal metabolomics profiles to identify subgroups of children that are at increased risk for rapid growth and obesity. This study offers a unique opportunity to advance our understanding of breast milk PFAS and may identify preventive measures that could be used to offset obesity-risk, including screening for breast milk PFAS and the use of probiotics to promote growth of beneficial gut bacteria in early life.