Influence of infant gut microbiome and breastmilk HMOs on neurodevelopment in children exposed to HIV

婴儿肠道微生物组和母乳 HMO 对 HIV 感染儿童神经发育的影响

• 批准号: 10381036
• 负责人: SARAH F. BENKI-NUGENT
• 金额: $ 68.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381036
• 关键词: Africa South of the Sahara; Age; Age-Months; Animal Model; Antibiotics; Attention; Binding; Biological; Birth; Brain; Breast Feeding; Child; Clinical Trials; Cognition; Cognitive; Complement; Data; Development; Drug Exposure; Epithelial Cells; Exhibits; Exposure to; Food; Future; General Population; Growth; HIV; HIV Infections; Health; Hearing; Human; Human Milk; Immune; Immunomodulators; Immunosuppression; Impairment; Infant; Infant Health; Inflammatory; Influentials; Informal Social Control; Intervention; Lactation; Language; Link; Literature; Longitudinal cohort; Memory; Milk; Mother-to-child HIV transmission; Motor; Motor Skills; Oligosaccharides; Outcome; Pattern; Pharmaceutical Preparations; Polysaccharides; Population; Populations at Risk; Pregnant Women; Prospective Studies; Resource-limited setting; Risk; School-Age Population; Supplementation; Testing; Viral; Woman; antiretroviral therapy; bacteriome; co-infection; cognitive ability; cohort; early childhood; enteric pathogen; executive function; feeding; gastrointestinal epithelium; gut inflammation; gut microbiome; gut microbiota; improved; infancy; infant gut microbiome; infant morbidity; microbiome; microbiome alteration; microbiome composition; neurodevelopment; novel; pathogen; prebiotics; processing speed; prospective; sample collection; skills

ABSTRACT The advent of universal maternal antiretroviral therapy (test and treat and Option B Plus) has vastly improved health, development, and survival prospects for children exposed to HIV but uninfected (HEU), a population that grows by 1.5 million each year. However, poor outcomes in these domains have persisted, and underlying mechanisms remain unclear, particularly for neurodevelopment. Recent prospective studies of birth and infant cohorts suggest mild to moderate neurodevelopmental compromise in motor, language and cognitive outcomes. This study will examine neurodevelopment in a unique longitudinal cohort of children with HEU versus HIV unexposed uninfected (HUU) in sub-Saharan Africa (SSA). Additionally, we will examine plausible and potentially modifiable mechanisms, including alterations in the gut microbiome and breastmilk composition. Proper establishment of a healthy gut microbiome in infancy is increasingly recognized as influential for brain development. The infant gut microbiome could be compromised by numerous factors relevant for HEU children, including maternal drug exposure and poor health, infant antibiotic exposure, feeding practice, and breastmilk composition. Recent studies suggest differences in composition and profile of the infant gut microbiome in HEU children vs. their age-matched HUU counterparts. Profile and concentration of certain human milk oligosaccharides, which are nonnutritive glycans that can function as prebiotics, as pathogen blockers, or as immune modulators, may also differ in lactating women infected with HIV. Strategic emphasis of certain complementary foods as prebiotics and supplementation of human breastmilk using specific HMOs offer two promising avenues for intervention for HEU children and are strategies that may also benefit other subsets of the general population at risk for poor neurodevelopmental outcomes. This novel project will leverage an ongoing cohort with detailed serial specimen collection for gut microbiome and breastmilk HMO profile in both HEU and HUU children. In Aim 1, we will compare motor, language, cognition, self-regulation and executive function skills in HEU vs HUU children at 24 and 36 months to inform on the impact of HIV exposure on neurodevelopment in early childhood. In Aim 2, we will examine the relation between these outcomes and early infant gut microbiome diversity and composition, and will add to still nascent literature on early infant gut microbiome changes and neurodevelopment both in and outside the context of HIV. In Aim 3, we will examine the relation between concentration of specific HMOs and neurodevelopmental outcomes, and will directly inform efforts to identify and test candidate HMO supplements for promoting infant health and growth. This project will generate critical evidence to inform future clinical trials for use in SSA and other low-resource settings to improve development in HEU children and strategies to complement existing efforts to promote breastfeeding.

抽象的 通用母体抗逆转录病毒疗法的出现（测试和治疗以及选项B Plus）大大改善了 暴露于艾滋病毒但未感染的儿童的健康，发展和生存前景（HEU），这是一个人口 每年增长150万。但是，这些领域的不良结果持续了下来，并基础 机制仍然不清楚，特别是对于神经发育。最近对出生和婴儿的前瞻性研究 队列建议在运动，语言和认知结果中轻度至中度的神经发育妥协。 这项研究将检查独特的HEU与HIV儿童纵向队列中的神经发育 撒哈拉以南非洲（SSA）未接触的未感染（HUU）。此外，我们将检查合理的且可能 可修改的机制，包括肠道微生物组和母乳组成的改变。恰当的 在婴儿期建立健康的肠道微生物组越来越被认为对大脑的影响 发展。婴儿肠道微生物组可能会因与heu儿童相关的许多因素而损害 包括孕产妇药物暴露和健康状况不佳，婴儿抗生素暴露，喂养实践和母乳 作品。最近的研究表明，HEU婴儿肠道微生物组的组成和谱图差异 儿童与年龄匹配的Huu对手。某些人牛奶的剖面和浓度 寡糖是非营养的糖，可以用作益生元，作为病原体阻滞剂或作为 免疫调节剂在感染HIV的妇女方面也可能有所不同。某些战略重点 使用特定HMO的互补食品作为益生元和补充人类母乳的补充提供了两种 有望为HEU儿童进行干预的途径，并且是可能受益于其他子集的策略 神经发育结果不良的普通人群。这个小说项目将利用持续的 肠道微生物组和母乳HMO轮廓的详细串行标本收集的队列在HEU和 胡子的孩子。在AIM 1中，我们将比较运动，语言，认知，自我调节和执行功能技能 在24和36个月的Heu vs Huu儿童中，以告知HIV暴露对神经发育的影响 幼儿。在AIM 2中，我们将研究这些结果与早期婴儿肠道微生物组之间的关系 多样性和组成，并将增加有关早期婴儿肠道微生物组变化和 神经发育在艾滋病毒的背景下和之外。在AIM 3中，我们将研究 特定HMO和神经发育结果的浓度，并将直接告知识别和 测试候选HMO补充剂以促进婴儿的健康和成长。该项目将产生关键 有证据为未来的临床试验提供信息，以用于SSA和其他低资源设置以改善开发 在HEU儿童和策略中，以补充促进母乳喂养的现有努力。