Undernutrition, microbiota maturation, and adaptive immunity in Bangladeshi children

项目概要/摘要 本杰明·李，医学博士 – 首席研究员 (PI) 儿童期营养不良影响着全世界约 2 亿儿童，并与 儿童因传染病死亡的风险增加。人们普遍认为营养不良 以生长障碍为表现，导致功能性免疫缺陷，增加对严重疾病的易感性 感染。然而，除了最极端形式的严重急性营养不良（SAM）之外，免疫学 营养不良儿童风险增加的依据尚未得到令人信服的证实。这可能是 部分原因是以前的方法学限制，例如依赖共同创立的横断面评估 识别风险最高的儿童并使用基本的免疫评估方法。该项目将 通过对儿科免疫尚未充分探索的方面进行纵向评估来解决这一知识差距 孟加拉国达卡进行的出生队列研究显示营养不良和健康儿童的发育情况 （提供）。在目标 1 中，多学科研究团队将首先使用粪便宏基因组测序来 研究肠道微生物群成熟对生长表型的关键贡献在头两年 生活，以及这些影响持续到童年后期。来自该社区的 SAM 儿童以前曾 证明微生物群成熟受损。这项研究将评估是否存在类似的扰动以及 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 各种形式的生长障碍，包括生长障碍、发育迟缓和体重不足。在目标 2 中，该项目将评估 对这些儿童的 T 细胞多样性和全身炎症进行测量，并使用 单细胞蛋白质基因组学可识别每种生长表型独特的免疫细胞特征。最后，影响 将研究肠道微生物群对这些免疫结果的影响。本项目将采用谨慎的案例选择 在一个特征明确的纵向队列中，以解决与营养不良有关的关键知识差距， 微生物群的发育以及免疫多样性的发育和维持。在此获得的知识 将为人们基本理解“前 1000 个 “生命的日子”，从受孕到 2 岁的窗口期对于建立健康成长和发育至关重要 儿童的发展。最终，这项工作可能有助于了解所需的干预措施，以改善儿童和 发展，特别是在资源有限、因感染导致营养不良和儿童死亡的地区 最普遍。

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.