Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.
Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study.
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DOI：
10.1016/j.ebiom.2017.02.024
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发表时间：
2017-04
期刊：
影响因子：
11.1
通讯作者：
MAL-ED Network Investigators
中科院分区：
文献类型：
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作者：
Kosek MN;MAL-ED Network Investigators
生活在这些环境中的儿童肠道病原体患病率高，肠道炎症水平高，肠道通透性异常，全身炎症标志物高，与生活在美国或欧洲的儿童相比，出生后获得性线性生长缺陷。这项研究提供了经验证据，证明肠道感染改变了炎症和通透性的粪便标志物。在这些人群中观察到的大部分线性生长不足，以及全身性炎症的标志物似乎是用于鉴定儿童线性生长失败的最有希望的预测性生物标志物。环境肠病（EE）被假设为生长停滞的介质，但很少有前瞻性研究评估了将肠道病原体暴露、肠道炎症和渗透性与生长联系起来的途径。MAL-ED研究代表了一种新的分析框架，并结合使用前所未有的数据量明确评估了多种推定的EE途径。尽管有证据表明，肠道炎症和肠道通透性改变是经常存在的，肠道病原体暴露和肠道功能障碍之间的关联存在，观察到的EE对幼儿生长迟缓的影响很小。环境性肠病（EE）是频繁和大量肠道感染对肠道的不利影响，导致持续的免疫激活和通透性改变，已被认为是低收入和中等收入人群儿童生长失败的关键决定因素。一个理论驱动的系统模型，严格评估肠道病原体，肠道通透性，肠道和全身炎症影响儿童生长的途径，在病因学，风险因素和肠道感染和营养不良的相互作用以及对儿童健康和发育的后果（MAL-ED）出生队列研究的框架内进行，包括来自八个国家的儿童。对来自多个地点的1253名儿童的非肠道粪便样本（N = 22，846）进行了一组40种肠道病原体和粪便中髓过氧化物酶、α-1-抗胰蛋白酶和新蝶呤浓度的评价。在这些儿童中，还测量了尿乳果糖：甘露醇（L：M）（N = 6363）和血浆α-1-酸性糖蛋白（AGP）（N = 2797）。时间采样设计用于创建非肠道粪便中的肠道病原体检测、肠道通透性和炎症的生物标志物、全身性炎症以及0-2岁儿童年龄的长度和体重变化之间的拟议机制途径的有向非循环图。这些人群中的儿童经常发生肠道感染，肠道和全身炎症水平较高。较高的肠道病原体负荷，特别是那些被归类为肠侵袭性或引起粘膜破坏的病原体，与肠道和全身炎症的生物标志物浓度升高相关，并且通过这些相关性，间接与线性和重量生长减少相关。全身性炎症与线性生长减少相关的证据比肠道炎症更强;重量体生长减少则相反。虽然贾第虫与生长减少有关，但这种联系并不受任何生物标志物的影响。大量的实证证据有助于这一分析支持EE的概念模型。EE对幼儿生长迟缓的影响很小，但在分析中，无症状肠道感染归因于生长失败的多个机制途径有统计学支持。EE最有力的证据是肠道病原体与通过全身炎症介导的线性生长之间的关联。.
Children living in these settings had a high prevalence of enteropathogens, high levels of intestinal inflammation, abnormal intestinal permeability, high markers of systemic inflammation, and postnatal acquired linear growth deficits when compared to children living in the US or Europe This study contributes empiric evidence to demonstrate that enteric infection alters both fecal markers of inflammation and permeability Current markers of enteropathy fail to account for a large portion of the observed shortfalls in linear growth in these populations, and markers of systemic inflammation appear as the most promising predictive biomarkers for identifying linear growth failure in children Environmental enteropathy (EE) is hypothesized as a mediator of growth faltering, but few prospective studies have evaluated pathways linking enteropathogen exposure, intestinal inflammation and permeability, and growth. The MAL-ED study represents a novel analytical framework and explicitly evaluates multiple putative EE pathways in combination and using an unprecedented quantity of data. Despite evidence that gut inflammation and altered gut permeability are frequently present and that associations between enteropathogen exposure and gut dysfunction exist, the observed attributable effects of EE on growth faltering in young children were small. Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation. .