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

摘要 普遍的孕产妇抗逆转录病毒疗法(检测和治疗和选择B Plus)的出现已有很大改善 暴露于艾滋病毒但未感染(HEU)的儿童的健康、发展和生存前景 以每年150万的速度增长。然而，这些领域的糟糕结果一直存在，并在根本上 机制尚不清楚，尤其是神经发育的机制。最近关于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到中度的神经发育折衷。 这项研究将研究感染HEU和HIV的儿童的神经发育情况。 撒哈拉以南非洲未暴露未感染(HUU)(SSA)。此外，我们还将研究看似合理和潜在的 可修改的机制，包括肠道微生物群和母乳成分的变化。恰如其分 在婴儿期建立健康的肠道微生物群越来越被认为对大脑有影响 发展。婴儿肠道微生物群可能会受到许多与HEU儿童相关的因素的影响， 包括母亲接触药物和健康状况不佳、婴儿接触抗生素、喂养做法和母乳 组成。最近的研究表明，HEU婴儿肠道微生物组的组成和图谱存在差异。 孩子们与他们年龄匹配的HUU同龄人。某些母乳的形态和浓度 寡糖，这是一种非营养性的多糖，可以作为益生菌、病原体阻滞剂或 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。一定的战略重点 作为益生元的补充食品和使用特定HMO的母乳补充提供了两种 为HEU儿童提供有希望的干预途径，也是可能使其他部分受益的战略 处于神经发育不良结果风险的普通人群。这个新颖的项目将利用正在进行的 对HEU和HEU中的肠道微生物组和母乳HMO谱进行详细系列样本收集的队列 胡家的孩子。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和HUU儿童中，告知艾滋病毒暴露对 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群之间的关系。 多样性和组成，并将增加关于早期婴儿肠道微生物组变化和 艾滋病毒内外的神经发育。在目标3中，我们将考察 特定HMO的浓度和神经发育结果，并将直接为确定和 测试候选保健组织补充剂，以促进婴儿健康和生长。该项目将产生关键的 为在SSA和其他低资源环境中使用以改进开发的未来临床试验提供信息的证据 在高浓缩铀儿童方面，以及补充促进母乳喂养的现有努力的战略。

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.