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.

项目摘要/摘要 童年不足的营养不良是影响7.95亿以上儿童，是最大的儿童。 人类荧光的障碍。目前的饮食干预措施无法改善许多长期 术语后遗症的后遗症，包括线性的生长疗法（“发育迟缓”）和异常中枢神经 系统（CNS）开发。这种失败表明我们对营养不良的生物状态的理解 是不完整的，并且传统的食物疗法无法针对营养不良依赖性病理的关键驱动因素 这在以后的生活中表现出来。我们实验室的工作提供了第一个证据，表明肠道发展受损 微生物群在发育迟缓中起因果作用。那是童年不足的多维观点， 认为可能需要几个生物状态轴以在发育迟缓和CNS异常的情况下移动针头 在营养不良的儿童中看到的发展。最近，一个非常普遍但知之甚少的状况 被称为环境肠功能障碍（EED），在全球造成了45％的儿童期。 除了生长阶段，EED儿童通常是渐近的。因此，通过活检诊断EED 以及绒毛钝，加密增生和慢性炎症性浸润的组织病理学证据 小肠的亚较小属。由于挑战是从 在全球健康环境中的儿童，大多数研究都依赖于血浆或粪便标记（而不是组织学 证据）表明潜在的肠病，严重混乱了我们对EED发病机理的理解。 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志物和治疗的能力 对于EED。该提案的目的是对活检确认的儿童进行多维儿童的视野 为了理解在EED发病机理下的分子和微生物特征，可以使用 作为新型的生物标志物和治疗靶标。采用蛋白质组学和与文化无关的方法进行调查 EED儿童的生物状态，该提案的第一个目标将确定健康之间的差异 EED儿童和儿童，确定血浆和等离子体之间的蛋白质组学共育网络 EED儿童的十二指肠隔室，并确定假定的EED效果上肠里微生物 与十二指肠蛋白共同变化，指示炎症和损伤。利用操纵的能力 gnotobiotic小鼠中的微生物社区组成和营养景观，该提案的第二个目的 将通过一项纵向研究来测试EED发病机理上肠里菌群的因果关系 引入从EED儿童的上层肠道中培养的微生物，然后依次去除 这个社区的成员并评估对宿主肠病的影响。成功完成 提案将解锁对EED发病机理的隐藏见解，激发了新的治疗方法 与儿童营养不良有关的儿童发育迟缓和异常中枢神经系统发育。

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