Assessing the relationship between environmental enteric dysfunction and poor growth via a newly developed 11-plex assay

通过新开发的 11 重检测评估环境肠道功能障碍与生长不良之间的关系

• 批准号: 10021657
• 负责人: CHRISTOPHER P DUGGAN
• 金额: $ 18.52万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-21 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021657
• 关键词: 5 year old; Adult; Affect; Age; Age-Months; Assessment tool; Biological Assay; Biological Markers; Biological Sciences; Birth; Birth Weight; Birth length; Blood; C-reactive protein; CD14 gene; Caregivers; Child; Child Mortality; Childhood; Cholecalciferol; Chronic; Clinic Visits; Cognitive; Data; Development; Economics; Enrollment; Enteral; Environment; Environmental Epidemiology; Exposure to; Failure; Ferritin; Flagellin; Functional disorder; Growth; Growth and Development function; HIV; Health; Height; Histologic; Human Development; Hygiene; Hypertension; Immunoglobulins; Individual; Infant; Inflammation; Insulin-Like Growth Factor I; Intestinal permeability; Intestines; Knowledge; Language; Length; Life; Link; Lipopolysaccharides; Longitudinal cohort study; Malnutrition; Measures; Methods; Micronutrients; Morbidity - disease rate; Mothers; Motor; Mucositis; Orosomucoid; Outcome; Permeability; Personal Satisfaction; Plasmodium falciparum; Population; Postpartum Period; Pregnancy; Pregnant Women; Productivity; RBP4 gene; Randomized; Reporting; Research; Risk; Role; Sampling; Serum; Severities; Small Intestines; Somatotropin; Standardization; Supplementation; Surrogate Mothers; TFRC gene; Tanzania; Thyroglobulin; Time; Villous; Vitamins; absorption; adverse birth outcomes; base; burden of illness; cholecalciferol supplementation; cognitive development; double-blind placebo controlled trial; enteric pathogen; fibroblast growth factor 21; gastrointestinal; hormone resistance; improved; in utero; indexing; infancy; inflammatory disease of the intestine; innovation; intestinal fatty acid binding protein; low and middle-income countries; microbial; mortality; neurodevelopment; nutrition; screening; work-study

Project Summary: Undernutrition remains one of the greatest human development challenges of our time. In 2017, an estimated 151 million children < 5 years of age (i.e., 22.2% of the global population) were stunted, increasing their risk for morbidity and mortality in childhood, suboptimal cognitive development, poorer educational outcomes, and lower economic productivity and earnings in adulthood. It has been increasingly appreciated that growth failure can begin in utero and worsen during early infancy; recently, environmental enteric dysfunction (EED) has been hypothesized as an important causal factor. EED is an acquired, subclinical condition of the small intestine associated with chronic exposure to an unhygienic environment where enteric pathogens persist. Histologic features include mucosal inflammation, villous blunting, altered barrier integrity, and reduced intestinal absorptive capacity. Despite EED’s purported link to poor health and nutrition outcomes in young children in low- and middle- income countries (LMICs), our knowledge of EED is relatively limited. Research gaps include the role of infant EED on subsequent poor growth and development and the possible role of maternal EED on adverse birth outcomes. The Trial of Vitamins-5 (ToV5) is an individually randomized, double-blind, placebo-controlled trial (R01 HD83113; ClinicalTrials.gov: NCT02305927) of maternal vitamin D3 (cholecalciferol) supplementation conducted among 2,300 HIV-infected pregnant women in Dar es Salaam, Tanzania. Following enrollment into the trial, mothers were followed-up at monthly clinic visits during pregnancy, at delivery, and then with their child at monthly postpartum clinic visits. Using data and serum samples collected in the ToV5 study, the main objectives of the current proposal are to assess 1) the relationship between infant EED and linear growth, i.e., length-for-age Z-score (LAZ) at 12 months of age; 2) the relationship between infant EED and development, measured by the Caregiver-Reported Early Development Index (CREDI) at 12 months of age; and 3) the relationship between maternal EED during pregnancy and birth outcomes, primarily infant birth weight and duration of gestation. We also aim to 4) examine relationships between the EED, systemic inflammation, and micronutrient biomarkers from a newly developed 11-plex multi-micronutrient and EED assessment tool (MEEDAT); consisting of intestinal fatty acid–binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF21), alpha-1-acid glycoprotein (AGP), C-reactive protein (CRP), ferritin, soluble transferrin receptor (sTfR), retinol binding protein 4 (RBP4), thyroglobulin (Tg), and Plasmodium falciparum exposure (HRP2); and anti-flagellin/anti-LPS Igs. Overall, this proposed research will contribute to our understanding of the consequences of EED in LMICs, specifically related to poor growth and adverse birth outcomes, using two innovative methods for assessing EED, namely anti-flagellin/anti-LPS Igs and MEEDAT.

项目摘要： 营养不良仍然是我们时代人类发展面临的最大挑战之一。2017年， 估计有1.51亿5岁以下儿童（即，全球人口的22.2%）发育迟缓， 儿童期发病率和死亡率的风险，认知发育欠佳，教育程度较低， 结果，以及成年后较低的经济生产力和收入。人们越来越认识到， 生长障碍可在子宫内开始，并在婴儿早期恶化;最近，环境肠道 功能障碍（EED）已被假设为一个重要的致病因素。EED是一种获得性亚临床 与长期暴露于不卫生的环境相关的小肠状况， 病原体持续存在。组织学特征包括粘膜炎症、绒毛钝化、屏障完整性改变， 和降低的肠吸收能力。尽管EED据称与健康和营养不良有关， 在低收入和中等收入国家的幼儿中，我们对EED的了解相对有限。 研究差距包括婴儿EED对随后不良生长和发育的作用以及可能的 产妇EED对不良出生结局的作用。 Vitamin-5试验（ToV 5）是一项个体随机、双盲、安慰剂对照试验（R 01 HD 83113; ClinicalTrials.gov：NCT 02305927）补充母体维生素D3（胆钙化醇） 在坦桑尼亚达累斯萨拉姆的2 300名感染艾滋病毒的孕妇中进行。入组后， 在这项试验中，母亲们在怀孕期间，分娩时每月进行一次门诊随访，然后与他们的 每月产后门诊就诊。使用ToV 5研究中收集的数据和血清样本， 目前建议的目的是评估1）婴儿EED和线性生长之间的关系，即， 12月龄时的年龄别身长Z评分（LAZ）; 2）婴儿EED与发育之间的关系， 在12个月龄时通过看护者报告的早期发育指数（CREDI）测量;以及3） 妊娠期母体EED与出生结局（主要是婴儿出生体重）之间的关系， 妊娠期。我们还旨在4）检查EED，全身炎症， 来自新开发的11重多重微量营养素和EED评估工具的微量营养素生物标志物 （MEEDAT）;由肠脂肪酸结合蛋白（I-FABP）、可溶性CD 14（sCD 14）、胰岛素样 生长因子1（IGF-1），成纤维细胞生长因子21（FGF 21），α-1-酸性糖蛋白（AGP），C-反应性 蛋白质（CRP）、铁蛋白、可溶性转铁蛋白受体（sTfR）、视黄醇结合蛋白4（RBP 4）、甲状腺球蛋白（Tg）， 和恶性疟原虫暴露（HRP 2）;和抗鞭毛蛋白/抗脂多糖免疫球蛋白。总的来说，这项研究 将有助于我们理解低收入国家EED的后果，特别是与增长不良有关的后果 和不良出生结局，使用两种创新方法评估EED，即抗鞭毛蛋白/抗LPS Igs和MEEDAT。