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.

项目概要： 营养不良仍然是我们这个时代最大的人类发展挑战之一。 据估计，有 1.51 亿 5 岁以下儿童（即全球人口的 22.2%）发育迟缓， 儿童时期发病和死亡的风险、认知发展欠佳、教育水平较差 的结果，以及成年后经济生产力和收入的降低，这一点已越来越受到重视。 生长障碍可能在子宫内开始，并在婴儿早期恶化，环境肠道； 功能障碍（EED）已被认为是一种重要的致病因素，是一种获得性、亚临床的疾病。 与长期暴露于不卫生的环境有关的小肠状况 病原体持续存在，组织学特征包括粘膜炎症、绒毛变钝、屏障完整性改变、 尽管 EED 据称与不良健康和营养结果有关。 对于低收入和中等收入国家 (LMIC) 的幼儿，我们对 EED 的了解相对有限。 研究差距包括婴儿 EED 对随后生长发育不良的作用以及可能的影响 母亲 EED 对不良分娩结局的作用。 Vitamins-5 试验 (ToV5) 是一项单独随机、双盲、安慰剂对照试验 (R01 HD83113；ClinicalTrials.gov：NCT02305927) 孕妇维生素 D3（胆钙化醇）补充剂 在坦桑尼亚达累斯萨拉姆注册后，对 2,300 名感染艾滋病毒的孕妇进行了研究。 在该试验中，母亲们在怀孕期间、分娩时以及她们的情况下每月进行一次门诊随访。 使用 ToV5 研究中收集的数据和血清样本，主要研究了儿童每月产后门诊就诊的情况。 当前提案的目标是评估 1) 婴儿 EED 和线性生长之间的关系，即 12 个月时的年龄别身长 Z 得分 (LAZ)；2) 婴儿 EED 与发育之间的关系， 根据 12 个月大时的看护者报告的早期发育指数 (CREDI) 进行测量；以及 3) 母亲怀孕期间 EED 与出生结果（主要是婴儿出生体重）之间的关系 我们还致力于 4) 检查 EED、全身炎症和妊娠期之间的关系。 来自新开发的 11 重多种微量营养素和 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 CD14 (sCD14)、胰岛素样组成 生长因子 1 (IGF-1)、成纤维细胞生长因子 21 (FGF21)、α-1-酸性糖蛋白 (AGP)、C 反应性 蛋白 (CRP)、铁蛋白、可溶性转铁蛋白受体 (sTfR)、视黄醇结合蛋白 4 (RBP4)、甲状腺球蛋白 (Tg)、 和恶性疟原虫暴露（HRP2）；以及抗鞭毛蛋白/抗脂多糖 Igs。 将有助于我们了解 EED 对中低收入国家的影响，特别是与经济增长不良相关的影响 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。