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 通用孕产妇抗逆转录病毒疗法（检测和治疗以及选项 B Plus）的出现极大地改善了 暴露于艾滋病毒但未感染的儿童 (HEU) 的健康、发展和生存前景，这一人群 每年增长150万。然而，这些领域的不良结果仍然存在，并且潜在的 机制仍不清楚，特别是对于神经发育。最近的出生和婴儿前瞻性研究 队列研究表明，运动、语言和认知结果存在轻度至中度的神经发育损害。 这项研究将检查一个独特的纵向队列的 HEU 儿童与 HIV 儿童的神经发育情况 撒哈拉以南非洲地区 (SSA) 的未暴露未感染者 (HUU)。此外，我们将检查合理的和潜在的 可改变的机制，包括肠道微生物组和母乳成分的改变。恰当的 人们越来越认识到在婴儿期建立健康的肠道微生物群对大脑有影响 发展。婴儿肠道微生物组可能会受到与 HEU 儿童相关的多种因素的影响， 包括孕产妇药物接触和健康状况不佳、婴儿抗生素接触、喂养方式和母乳 作品。最近的研究表明 HEU 中婴儿肠道微生物组的组成和特征存在差异 儿童与同龄 HUU 同伴。某些母乳的概况和浓度 寡糖，是非营养性聚糖，可以作为益生元、病原体阻断剂或作为 免疫调节剂，在感染艾滋病毒的哺乳期妇女中也可能有所不同。某些战略重点 作为益生元的补充食品和使用特定 HMO 补充母乳提供了两种 对 HEU 儿童进行干预的有希望的途径，并且这些策略也可能使其他儿童群体受益 普通人群面临神经发育不良风险。这个新颖的项目将利用正在进行的 HEU 和 HEU 中肠道微生物组和母乳 HMO 概况的详细连续样本收集队列 胡孩子们。在目标 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 个月和 36 个月的 HEU 与 HUU 儿童中进行比较，以了解 HIV 暴露对神经发育的影响 幼儿期。在目标 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，并将添加到关于早期婴儿肠道微生物组变化和 HIV 背景下和之外的神经发育。在目标 3 中，我们将研究之间的关系 特定 HMO 和神经发育结果的集中度，并将直接为识别和神经发育结果的努力提供信息 测试候选 HMO 补充剂促进婴儿健康和生长的作用。该项目将产生关键 为未来在 SSA 和其他资源匮乏环境中使用的临床试验提供信息，以促进发展 HEU 儿童的健康状况以及补充现有促进母乳喂养努力的战略。