Unraveling the biological state of children with Environmental enteric dysfunction

项目摘要/摘要 影响超过7.95亿5岁以下儿童的儿童营养不良是最严重的问题之一 阻碍人类繁荣的因素。目前的饮食干预未能改善许多长期的饮食习惯。 营养不良的长期后遗症，包括直线生长迟缓(发育迟缓)和异常的中枢神经 系统(CNS)开发。这一失败表明，我们对营养不良生物学状态的理解 是不完整的，传统的食物疗法未能针对营养不良依赖的病理的关键驱动因素 在以后的生活中表现出来。我们实验室的研究提供了第一个证据，表明肠道发育受损 微生物区系在发育迟缓中起着因果作用。因此，对儿童营养不良的多维观点 认为在发育迟缓和异常的中枢神经系统上移动针可能需要几个生物状态轴 营养不良儿童的发育。最近，一种非常流行但知之甚少的疾病 环境肠道功能障碍(EED)被发现是全球45%的儿童发育迟缓的原因。 除了发育迟缓，患有EED的儿童通常没有症状；因此，EED是通过活检来诊断的。 以及绒毛钝化、隐窝增生和慢性炎性浸润的组织病理学证据。 小肠的固有层下层。由于获取上肠道活组织检查的挑战 在全球健康环境中的儿童，大多数研究依赖于血浆或粪便标记物(而不是组织学 证据)表明潜在的肠病，严重混淆了我们对EED发病机制的理解。在……里面 此外，没有经过验证的EED模型存在，进一步阻碍了我们开发生物标记物和治疗的能力 为了EED。这项提案的目标是对确诊为EED的儿童采取多维视角。 为了了解EED发病的分子和微生物特征，这可能有助于 作为新的生物标志物和治疗靶点。使用蛋白质组学和培养无关的方法进行调查 患有EED的儿童的生物状态，这项提案的第一个目标将确定健康儿童与 儿童和患有EED的儿童，确定血浆和EED之间的蛋白质组共丰度网络 儿童EED的十二指肠间室，并鉴定可能与EED相关的上肠微生物 与指示炎症和损伤的十二指肠蛋白质共同变化。利用操控的能力 诺生菌小鼠的微生物群落组成和营养景观，这项建议的第二个目标 将通过一项纵向研究来检验EED发病机制中上肠道微生物区系的因果关系 EED患儿上肠道培养微生物的导入及序贯清除 并评估其对宿主肠病的影响。成功完成这项工作 该提案将揭开对EED发病机制的隐藏见解，启发对抗EED的新治疗方法 儿童发育迟缓和中枢神经系统发育异常与儿童营养不良有关。

PROJECT SUMMARY/ABSTRACT Affecting more than 795 million children under the age of 5, childhood undernutrition is one of the greatest impediments to the flourishing of humankind. Current dietary interventions fail to ameliorate many of the long- term sequelae of undernutrition, including linear growth-faltering (‘stunting’) and abnormal central nervous system (CNS) development. This failure suggests that our understanding of the biological state of undernutrition is incomplete, and that traditional food therapies fail to target key drivers of undernutrition-dependent pathologies that manifest later in life. Work from our lab has provided the first evidence that impaired development of the gut microbiota plays a causal role in stunting. Thus, a multi-dimensional view of childhood undernutrition that considers several axes of biological state may be required to move the needle on stunting and abnormal CNS development seen in undernourished children. Recently, a highly prevalent but poorly understood condition known as Environmental enteric dysfunction (EED) has been found to cause 45% of childhood stunting globally. Aside from growth-faltering, children with EED are typically asymptomatic; thus, EED is diagnosed by biopsy and histopathologic evidence of villous blunting, crypt hyperplasia, and chronic inflammatory infiltration within the sub-lamina propria of the small intestine. Due to the challenge of obtaining upper-intestinal biopsies from children in a global health setting, most studies have relied on plasma or fecal markers (rather than histologic evidence) indicating an underlying enteropathy, severely muddling our understanding of EED pathogenesis. In addition, no validated model of EED exists, further hampering our ability to develop biomarkers and treatments for EED. The goal of this proposal is to take on a multi-dimensional view of children with biopsy confirmed EED in order to understand the molecular and microbial features that underly EED pathogenesis and that may serve as novel biomarkers and therapeutic targets. Employing proteomic and culture-independent methods to survey the biological state of children with EED, the first aim in this proposal will identify differences between healthy children and children with EED, determine the proteomic co-abundance network between the plasma and duodenal compartments of children with EED, and identify putative EED-causal upper-intestinal microbes that co-vary with duodenal proteins indicative of inflammation and injury. Leveraging the ability to manipulate microbial community composition and nutrient landscape in gnotobiotic mice, the second aim of this proposal will test the causality of the upper-intestinal microbiota in EED pathogenesis through a longitudinal study introducing microbes cultured from the upper-intestinal tract of children with EED and by sequentially removing members of this community and assessing the effects on host enteropathy. Successful completion of this proposal will unlock hidden insights into EED pathogenesis, inspiring new therapeutic approaches to combat childhood stunting and abnormal CNS development associated with childhood undernutrition.