Aflatoxin Exposure, Growth Faltering, and the Gut Microbiome among Children in Rural Guatemala

项目摘要 黄曲霉毒素B1(AFB1)是生长在玉米上的黄曲霉和寄生曲霉产生的致癌物质。 鉴于发育迟缓和其他营养障碍在低收入和中等收入国家中的高流行率， 玉米消费量大，接触黄曲霉毒素的作用值得研究。观测报告已经 显示了黄曲霉毒素暴露与儿童生长发育之间的联系。然而，大多数都是横断面的， 没有评估黄曲霉毒素的季节变化、食物制备和生长的动态变化。在……里面 此外，关于黄曲霉毒素可能如何影响生长的生物机制数据也没有。我们将继续前进 通过评估饮食、黄曲霉毒素暴露的时间变化来研究黄曲霉毒素与儿童生长发育的科学 来自危地马拉农村的一群未来儿童的成长步履蹒跚，这个国家拥有世界上最大的 世界上儿童发育迟缓和黄曲霉毒素暴露的最高比率。此外，我们将使用生物反应器来 研究可能的生物学机制，特别是直接黄曲霉毒素-肠道微生物组相互作用。 我们假设，接触黄曲霉毒素会引起炎症和干扰，从而对儿童生长发育产生负面影响 肠道微生物群。在目标1中，我们将前瞻性地评估黄曲霉毒素暴露和身高年龄差异。 185名6-9岁至24-27个月儿童的运动轨迹。我们将使用以下方法评估黄曲霉毒素暴露情况 血清AFB1-白蛋白加合物水平，我们将测量全身和肠道炎症的生物标志物。在AIM 2、我们将评估黄曲霉毒素暴露、发育迟缓状态和肠道微生物组组成之间的关系。 和功能。我们将使用16S rRNA基因扩增子和全基因组来评估每个儿童的粪便微生物群 基因组测序确定不同AFB1暴露水平和代谢途径的关键物种和代谢途径 发育迟缓状态。同时，我们将使用接种了粪便样本的生物反应器来评估 肠道微生物群组成对不同水平的黄曲霉毒素B 1的暴露。在目标3中，我们将评估黄曲霉毒素的影响 暴露对微生物营养代谢的影响及肠道微生物区系对黄曲霉毒素的影响 通过监测关键营养代谢物(如短链脂肪酸)和黄曲霉毒素B-1来解毒/代谢 生物反应器中的生物转化产物。我们还将评估炎症、黄曲霉毒素和 基于三个目标的结果，使用通径分析，微生物组组成对儿童发育迟缓的影响。 意义和创新：通过多学科方法利用对公开的 人口和流行病学、毒理学、环境工程和人类微生物组方面的专业知识，我们 将能够评估黄曲霉毒素暴露对生长的影响以及肠道可能的调节作用 微生物组。 影响：R01提案的完成将促进对黄曲霉毒素生理机制的了解- 中介生长限制，为缓解黄曲霉毒素的新公共卫生战略指明了方向 暴露和微生物群导向治疗。

Project Summary Aflatoxin B1 (AFB1) is a carcinogen produced by Aspergillus flavus and A. parasiticus which grow on maize. Given the high prevalence of stunting and other nutritional disorders in low- and middle-income countries where maize is highly consumed, the role of aflatoxin exposure is worth investigating. Observational reports have shown associations between aflatoxin exposure and child growth. However, most have been cross-sectional and have not assessed seasonal variations in aflatoxin, food preparation, and dynamic changes in growth. In addition, biological mechanistic data on how aflatoxin may exert impact on growth is missing. We will advance the science of aflatoxin and child growth by assessing temporal changes in diet, aflatoxin exposure, and growth faltering in a prospective cohort of children from rural Guatemala, a country that has one of the highest rates of child stunting and aflatoxin exposure in the world. In addition, we will use bioreactors to investigate possible biological mechanisms, specifically direct aflatoxin-gut microbiome interactions. We hypothesize that aflatoxin exposure negatively impacts child growth by inducing inflammation and disrupting the gut microbiome. In Aim 1, we will prospectively evaluate aflatoxin exposure and height-for-age difference trajectories among 185 children between 6-9 and 24-27 months of age. We will assess aflatoxin exposure using serum AFB1-albumin adduct levels, and we will measure biomarkers of systemic and gut inflammation. In Aim 2, we will evaluate the association between aflatoxin exposure, stunting status, and gut microbiome composition and function. We will evaluate the fecal microbiome of each child using 16S rRNA gene amplicon and whole genome sequencing to identify key species and metabolic pathways for differing AFB1 exposure levels and stunting status. In parallel, we will use bioreactors inoculated with fecal samples to evaluate the response of the gut microbiome composition to varying levels of AFB1 exposure. In Aim 3, we will evaluate the impact of aflatoxin exposure on microbial nutrient metabolism and the impact of gut microbiota on aflatoxin detoxification/metabolism by monitoring key nutrient metabolites (e.g., short-chain fatty acids) and AFB1 biotransformation products in bioreactors. We will also evaluate the effect of inflammation, aflatoxin, and microbiome composition on child stunting based on the results from the three aims using path analysis. Significance and Innovation: Through a multidisciplinary approach that leverages access to an exposed population and expertise on epidemiology, toxicology, environmental engineering and human microbiome, we will be able to evaluate the impact of aflatoxin exposure on growth and its possible mediation by the gut microbiome. Impact: Completion of this R01 proposal will advance understanding of the physiologic mechanism of aflatoxin- mediated growth restriction, pointing the way toward new public health strategies for mitigation of aflatoxin exposure and for microbiome-directed treatments.