Unraveling the biological state of children with Environmental enteric dysfunction

揭示环境肠道功能障碍儿童的生物学状态

• 批准号: 10347356
• 负责人: Robert Yuzen Chen
• 金额: $ 5.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347356
• 关键词: Adoption; Affect; Age; Animal Model; Area; Aspirate substance; Bangladeshi; Behavior Therapy; Biological; Biological Markers; Biopsy; Child; Childhood; Chronic; Communities; Conflict (Psychology); Country; Culture-independent methods; DNA; Data; Development; Diagnosis; Diagnostic; Dietary Intervention; Disease; Duodenum; Enteral; Epithelial; Etiology; Exposure to; Failure; Food; Functional disorder; Gene set enrichment analysis; Germ-Free; Gnotobiotic; Goals; Growth; Histologic; Hyperplasia; Immunoassay; Impairment; Infection; Infiltration; Inflammation; Inflammatory; Injury; Intestinal permeability; Intestines; Investments; Lamina Propria; Life; Linear Algebra; Longitudinal Studies; Malnutrition; Measures; Microbe; Modeling; Molecular; Mus; Needles; Neuraxis; Nutrient; Oral; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Plasma; Play; Prevalence; Proteins; Proteome; Proteomics; Resources; Ribosomes; Role; Sampling; Series; Small Intestines; Surveys; Systems Biology; Testing; Tissues; Villous Atrophy; Work; bacterial community; combat; computational pipelines; effective therapy; environmental intervention; experimental study; global health; graph theory; gut dysbiosis; gut inflammation; gut microbiota; high risk; insight; intestinal injury; intestinal villi; long-term sequelae; low socioeconomic status; member; microbial; microbial community; microbial genomics; microbiota; mortality risk; mouse model; nervous system development; new therapeutic target; novel marker; novel therapeutic intervention; population health; theories; therapeutic target

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.

项目总结/摘要 儿童营养不良影响着超过7.95亿5岁以下的儿童，是最严重的营养不良之一。 阻碍了人类的繁荣。目前的饮食干预未能改善许多长期- 营养不良的长期后遗症，包括线性生长迟缓（“发育迟缓”）和中枢神经系统异常 系统（CNS）开发。这一失败表明我们对营养不良的生物学状态的理解 是不完整的，传统的食物疗法未能针对营养不足依赖性病理的关键驱动因素， 在以后的生活中显现出来。我们实验室的工作提供了第一个证据， 微生物群在发育迟缓中起着因果作用。因此，对儿童营养不良的多层面看法， 考虑到可能需要几个生物状态的轴来移动发育迟缓和异常CNS上的针 在营养不良的儿童中看到的发展。最近，一种高度流行但知之甚少的疾病 被称为环境肠道功能障碍（EED）已被发现导致全球45%的儿童发育迟缓。 除了生长迟缓外，患有EED的儿童通常无症状;因此，EED通过活检诊断 组织病理学证据显示绒毛变钝、隐窝增生和慢性炎症浸润 小肠的固有下层。由于难以获得上肠活检， 在全球健康环境中，大多数研究依赖于血浆或粪便标记物（而不是组织学标记物）。 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 此外，还没有有效的EED模型，这进一步阻碍了我们开发生物标志物和治疗方法的能力 对于EED。该提案的目的是对活检证实的EED儿童进行多维观察 为了了解EED发病机制的分子和微生物特征， 作为新的生物标志物和治疗靶点。采用蛋白质组学和非培养方法 EED儿童的生物学状态，该提案的第一个目标将确定健康儿童和健康儿童之间的差异。 儿童和患有EED的儿童，确定血浆和 患有EED的儿童的十二指肠隔室，并确定推定的EED致病上肠微生物， 与指示炎症和损伤的十二指肠蛋白质共变。利用操纵 微生物群落组成和营养景观在gnotobiotic小鼠，本提案的第二个目的 将通过纵向研究来检验上肠道微生物群在EED发病机制中的因果关系 引入从患有EED的儿童的上肠道培养的微生物， 该社区的成员，并评估对宿主肠病的影响。成功完成本 该提案将揭示EED发病机制的隐藏见解，激发新的治疗方法， 与儿童营养不良有关的儿童发育迟缓和中枢神经系统发育异常。

项目成果

Melding microbiome and nutritional science with early child development.

• DOI: 10.1038/s41591-021-01451-1
• 发表时间: 2021-09
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Chen RY;Mostafa I;Hibberd MC;Das S;Lynn HM;Webber DM;Mahfuz M;Barratt MJ;Ahmed T;Gordon JI
• 通讯作者: Gordon JI