Undernutrition, microbiota maturation, and adaptive immunity in Bangladeshi children

孟加拉国儿童的营养不良、微生物群成熟和适应性免疫

• 批准号: 10718949
• 负责人: Benjamin Lee
• 金额: $ 48.23万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718949
• 关键词: 10 year old; 2 year old; 5 year old; Achievement; Acute; Address; Adult; Affect; Age; Anthropometry; Bangladesh; Bangladeshi; Biological Markers; Birth; Cells; Cessation of life; Child; Child Development; Child Mortality; Childhood; Chronic; Cohort Studies; Communicable Diseases; Communities; Conceptions; Cross-Sectional Studies; Cryopreservation; Data; Defect; Development; Diarrhea; Disease; Evaluation; Failure; Feces; Goals; Growth; Growth and Development function; Health; Human; Immune; Immune system; Immunologics; Impairment; Infection; Inflammation; Inflammatory; Interdisciplinary Study; Intervention; Knowledge; Lead; Life; Longitudinal Studies; Longitudinal cohort; Maintenance; Malnutrition; Measures; Mediating; Metabolic Pathway; Metabolism; Methodology; Methods; Minority; Modeling; Morbidity - disease rate; Nature; Neurocognitive; Organ; Outcome; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Pneumonia; Predisposition; Principal Investigator; Process; Public Health; Research Design; Resource-limited setting; Risk; Role; Sampling; Shapes; Structure; T-Cell Development; T-Lymphocyte; T-cell diversity; T-cell receptor repertoire; Taxonomy; Testing; Underweight; Weight; Work; adaptive immunity; fecal microbiota; gut inflammation; gut microbiota; high risk; immunological diversity; improved; infection risk; innovation; insight; intestinal maturation; longitudinal dataset; metagenomic sequencing; microbiome; microbiota; mortality; obesity risk; pathogen exposure; prevent; proteogenomics; systemic inflammatory response

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.

项目总结/摘要 Benjamin Lee，MD -主要研究者（PI） 儿童营养不良影响到全世界约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， 表现为生长障碍，导致功能性免疫缺陷，增加对严重 感染.然而，除了严重急性营养不良（SAM）的最极端形式外， 营养不良儿童风险增加的原因尚有待令人信服地证明。这可能是 部分原因是以前的方法学限制，例如依赖于共同发现的横截面评估， 确定高危儿童和使用免疫评估的基本方法。该项目将 通过纵向评估儿科免疫学未充分探索的方面来解决这一知识缺口， 在孟加拉国达卡进行的一项出生队列研究中， （提供）。在目标1中，多学科研究小组将首先使用粪便宏基因组测序， 研究肠道微生物群成熟对生长表型的关键贡献， 这些影响持续到童年后期。来自这个社区的SAM儿童以前 表现出微生物成熟受损。这项研究将评估是否类似的扰动，沿着 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 这些儿童的T细胞多样性和全身炎症的测量，沿着探索性分析， 单细胞蛋白基因组学，以确定每个生长表型独特的免疫细胞谱。最后，影响 肠道微生物群对这些免疫结果的影响将被研究。这个项目将使用谨慎的情况下选择 在一个特征明确的纵向队列中， 微生物群发育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“前1000年”的根本重要方面作出重大贡献。 ”从受孕到2岁的窗口期，对建立健康成长至关重要， 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儿童因感染而死亡的资源有限的情况下， 最为普遍。