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

摘要 普及孕产妇抗逆转录病毒疗法（检测和治疗以及备选方案B Plus）的出现大大改善了 健康，发展和生存前景的儿童暴露于艾滋病毒，但未感染（高浓缩铀），人口， 每年增长150万。然而，这些领域的不良结果持续存在， 机制仍不清楚，特别是神经发育。近期出生和婴儿的前瞻性研究 队列研究表明，在运动、语言和认知结果方面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儿童与艾滋病毒高浓缩铀的神经发育 撒哈拉以南非洲（SSA）的未暴露未感染者（HUU）。此外，我们将研究合理的和潜在的 可改变的机制，包括肠道微生物组和母乳成分的改变。适当 在婴儿期建立健康的肠道微生物组越来越被认为对大脑有影响 发展婴儿肠道微生物组可能受到与高浓缩铀儿童相关的许多因素的影响， 包括产妇药物暴露和健康状况不佳、婴儿抗生素暴露、喂养习惯和母乳 混合物.最近的研究表明，高浓缩铀中婴儿肠道微生物组的组成和概况存在差异 儿童与年龄匹配的HUU对应物。某些人乳的特征和浓度 寡糖，其是非营养性聚糖，可用作益生元、病原体阻断剂或 在感染艾滋病毒的哺乳期妇女中，免疫调节剂也可能不同。某些战略重点 作为益生元的补充食品和使用特定HMO补充人类母乳提供了两个 这些战略也可能有益于高浓缩铀儿童的其他亚类群体， 一般人群有神经发育不良的风险。这个新项目将利用一个正在进行的 在HEU和HEU中收集肠道微生物组和母乳HMO特征的详细系列样本的队列 HUU儿童。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个月的高浓缩铀与高浓缩铀儿童中， 童年早期在目标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，并将增加对早期婴儿肠道微生物组变化的新生文献， 神经系统的发展，无论是在艾滋病病毒的背景下还是在艾滋病病毒的背景下。在目标3中，我们将研究 特定HMO的浓度和神经发育结果，并将直接为识别和 测试候选HMO补充剂促进婴儿健康和生长。该项目将产生关键的 为未来的临床试验提供证据，用于SSA和其他低资源环境，以改善发展 制定战略，以补充现有的促进母乳喂养的努力。

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.