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

危地马拉农村儿童的黄曲霉毒素暴露、生长迟缓和肠道微生物组

• 批准号: 10586566
• 负责人: Rosa Krajmalnik-Brown
• 金额: $ 54.35万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586566
• 关键词: Affect; Aflatoxin B1; Aflatoxins; Age Months; Albumins; Aspergillus flavus; Biological; Biological Markers; Biological Models; Bioreactors; C-reactive protein; Carbohydrates; Carcinogens; Child; Child Health; Consumption; Country; Data; Diet; Dose; Drug Metabolic Detoxication; Environmental Engineering technology; Epidemiology; Erythrocyte Sedimentation Rate; Exposure to; Funding; Genomics; Growth; Guatemala; Harvest; Height; High Prevalence; High-Throughput DNA Sequencing; Human Microbiome; Hydrolysis; Inflammation; International; Investments; Leukocyte L1 Antigen Complex; Maize; Measurement; Measures; Mediating; Mediation; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Metagenomics; Modeling; Molecular; Monitor; National Institute of Environmental Health Sciences; Nutrient; Nutrition Disorders; Pathway interactions; Pediatrics; Physiological; Population; Prospective cohort; Public Health; Reporting; Risk; Role; Rural; Sampling; Science; Seasonal Variations; Seasons; Seminal; Serum; Starch; Structure; Time; Toxicology; USAID; Volatile Fatty Acids; Work; adduct; dietary; dysbiosis; experimental study; fecal microbiome; food preparation; genome sequencing; gut inflammation; gut microbes; gut microbiome; gut microbiota; health organization; improved; inflammatory marker; innovation; interdisciplinary approach; low and middle-income countries; microbial; microbial community; microbiome; microbiome composition; nutrient metabolism; prospective; rRNA Genes; remediation; response; systemic inflammatory response; transcriptomics; whole genome

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.

项目摘要 黄曲霉毒素B1（AFB 1）是由黄曲霉和曲霉产生的一种致癌物质。寄生在玉米上。 鉴于低收入和中等收入国家发育迟缓和其他营养失调的发病率很高， 由于玉米消费量很大，黄曲霉毒素暴露的作用值得研究。观察报告显示， 显示了黄曲霉毒素暴露与儿童生长之间的联系。然而，大多数都是跨部门的， 没有评估黄曲霉毒素的季节性变化、食物制备和生长的动态变化。在 此外，缺乏关于黄曲霉毒素如何影响生长的生物学机制数据。我们将推进 通过评估饮食的时间变化，黄曲霉毒素暴露， 来自危地马拉农村的未来儿童群体的增长步履蹒跚，危地马拉是一个拥有世界上 世界上儿童发育迟缓和黄曲霉毒素暴露率最高的国家。此外，我们将使用生物反应器， 研究可能的生物学机制，特别是直接的黄曲霉毒素-肠道微生物组相互作用。 我们假设黄曲霉毒素暴露通过诱导炎症和破坏生长发育而对儿童生长产生负面影响。 肠道微生物组在目标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个月和24-27个月的儿童的轨迹。我们将使用以下方法评估黄曲霉毒素暴露情况： 血清黄曲霉毒素B1-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中 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联 和功能我们将使用16 S rRNA基因扩增子和全基因组技术评估每个儿童的粪便微生物组。 基因组测序，以确定不同AFB 1暴露水平的关键物种和代谢途径， 发育迟缓同时，我们将使用接种粪便样本的生物反应器来评估 肠道微生物组组成对不同水平的AFB 1暴露的影响。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以及肠道微生物群对黄曲霉毒素的影响 通过监测关键营养代谢物（例如，短链脂肪酸）和黄曲霉毒素B1 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 微生物组组成对儿童发育迟缓的影响，基于使用路径分析的三个目标的结果。 重要性和创新：通过多学科方法， 人口和流行病学，毒理学，环境工程和人类微生物组的专业知识，我们 将能够评估黄曲霉毒素暴露对生长的影响及其可能的肠道介导 微生物组 影响：R 01提案的完成将促进对黄曲霉毒素生理机制的理解- 介导的生长限制，为减轻黄曲霉毒素的新公共卫生策略指明了方向 暴露和针对微生物组的治疗。