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

项目总结： 营养不良仍然是我们这个时代人类发展面临的最大挑战之一。2017年，一个 据估计，有1.51亿5岁的儿童(即全球人口的22.2%)发育迟缓，而且还在增加 他们在儿童时期患病和死亡的风险，认知发展不佳，教育程度较低 结果，以及更低的经济生产率和成年后的收入。它越来越受到人们的赞赏 这种生长障碍可能始于子宫，并在婴儿早期恶化；最近，环境肠道 功能障碍(EED)被认为是一个重要的致病因素。EED是一种获得性的亚临床 与慢性暴露在不卫生的环境中有关的小肠状况 病原体依然存在。组织学特征包括黏膜炎症，绒毛钝化，屏障完整性改变， 并降低肠道吸收能力。尽管据称EED与不良的健康和营养结果有关 在中低收入国家(LMIC)的幼儿中，我们对EED的了解相对有限。 研究空白包括婴儿EED对随后的不良生长和发育的作用，以及可能的 母体EED在不良分娩结局中的作用 维生素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)补充孕妇维生素D3(胆钙化醇) 在坦桑尼亚达累斯萨拉姆对2300名感染艾滋病毒的孕妇进行了调查。在注册后加入 在这项试验中，母亲们在怀孕期间每月去诊所就诊，在分娩时进行跟踪，然后用她们的 孩子每月产后门诊就诊。使用ToV5研究中收集的数据和血清样本，主要 当前提案的目标是评估1)婴儿EED和线性增长之间的关系，即， 2)婴儿智力缺陷与发育的关系， 以12个月龄的Caregier报告的早期发育指数(CREDI)衡量；以及3) 孕期母体发育迟缓与出生结局，主要是婴儿出生体重和 怀孕的持续时间。我们的目标还包括检查EED、全身炎症和 来自新开发的11-多重微量营养素生物标志物和EED评估工具 (MEEDAT)；由肠道脂肪酸结合蛋白(I-FABP)、可溶性CD14(SCD14)、胰岛素样物质组成 生长因子-1、成纤维细胞生长因子21、α-1-酸性糖蛋白、C反应 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/抗内毒素免疫球蛋白。总体而言，这项拟议的研究 将有助于我们理解EED在LMIC中的后果，特别是与低增长相关的后果 和不良分娩结局，使用两种评估EED的创新方法，即抗鞭毛蛋白/抗内毒素 IGS和MEEDAT。

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.