Undernutrition, microbiota maturation, and adaptive immunity in Bangladeshi children

项目摘要/摘要 本杰明·李，医学博士-首席调查员(PI) 儿童营养不良影响着全球约2亿儿童，并与 儿童死于传染病的风险增加。人们普遍认为，营养不良，因为 表现为生长障碍，导致功能性免疫缺陷，增加对重症 感染。然而，除了最极端的严重急性营养不良(SAM)，免疫学上的 营养不良儿童风险增加的依据尚未得到令人信服的证明。这可能是 部分原因是以前的方法限制，例如依赖于共同建立的横断面评价 确定高危儿童并使用免疫评估的基本方法。这个项目将 通过对未被探索的儿科免疫方面的纵向评估来解决这一知识鸿沟 在孟加拉国达卡进行的出生队列研究中营养不良和健康儿童的发育 (提供)。在目标1中，多学科研究团队将首先使用粪便元基因组测序来 调查肠道微生物区系成熟对生长表型的关键贡献 生活，并将这些影响持续到童年后期。这个社区的患有SAM的儿童以前 表现出微生物区系成熟受损。这项研究将评估类似的扰动以及 多样性、分类群落结构和代谢途径的测量可能会影响患有其他疾病的儿童 各种形式的发育障碍，包括发育迟缓、发育迟缓和体重不足。在目标2中，项目将评估 这些儿童的T细胞多样性和全身炎症的测量，以及使用 单细胞蛋白质组学，以确定每个生长表型独有的免疫细胞图谱。最后，影响 肠道微生物区系对这些免疫结果的影响将进行调查。该项目将使用仔细的案例选择 在一个具有良好特征的纵向队列中，以解决与营养不良有关的关键知识差距， 微生物区系的发展，以及免疫多样性的发展和维持。在此获得的知识 将为基本理解“第一个1000”的根本重要方面做出重大贡献 生命的天数“从受孕到2岁的窗口期对建立健康的成长和 儿童的发展。最终，这项工作可能有助于提供必要的干预措施，以改善儿童和 发展，特别是在营养不良和感染导致儿童死亡的资源有限的环境中 是最普遍的。

PROJECT SUMMARY/ABSTRACT Benjamin Lee, MD – Principal Investigator (PI) Childhood undernutrition affects approximately 200 million children around the world and is associated with increased risk of child mortality from infectious diseases. It is generally accepted that undernutrition, as manifested by growth impairment, causes functional immune deficiency that increases susceptibility to severe infections. However, other than in the most extreme form of severe acute malnutrition (SAM), an immunologic basis for this increased risk in undernourished children has yet to be convincingly demonstrated. This may be due in part to previous methodologic limitations, such as reliance on cross-sectional evaluations that cofounded identification of children at highest risk and use of rudimentary methods of immune assessment. This project will address this knowledge gap via longitudinal evaluation of underexplored aspects of pediatric immune development in undernourished and healthy children from a birth cohort study conducted in Dhaka, Bangladesh (PROVIDE). In Aim 1, the multidisciplinary research team will first use stool metagenomic sequencing to investigate the critical contribution of gut microbiota maturation to growth phenotype during the first 2 years of life, and persistence of these effects into later childhood. Children with SAM from this community have previously demonstrated impaired microbiota maturation. This study will assess whether similar perturbations, along with measures of diversity, taxonomic community structure, and metabolic pathways may affect children with other forms of growth impairment, including growth failure, stunting, and underweight. In Aim 2, the project will evaluate measures of T cell diversity and systemic inflammation in these children, along with exploratory analyses using single-cell proteogenomics to identify immune cell profiles unique to each growth phenotype. Finally, the impact of the gut microbiota on these immune outcomes will be investigated. This project will use careful case selection in a well-characterized longitudinal cohort to address critical knowledge gaps relating to undernutrition, microbiota development, and development and maintenance of immune diversity. The knowledge gained herein will provide a major contribution to basic understanding of fundamentally important aspects of the “first 1000 days of life,” the window period from conception to age 2 most critical for establishment of healthy growth and development in children. Ultimately, this work may help inform needed interventions to improve children and development, particularly in resource-limited settings where undernutrition and child mortality due to infections is most prevalent.