Effects of Human Milk Oligosaccharides and Gut Microbiome on Growth and Morbidity in HIV-Exposed Uninfected Infants

项目摘要/摘要 尽管全球卫生努力在预防艾滋病毒母婴传播方面取得了成功，但仍有越来越多的 而且经常被忽视的是感染艾滋病毒的未感染(HEU)人群，他们的增长风险要高得多 与未接触艾滋病毒的未感染(HUU)婴儿相比，婴儿的步履蹒跚、感染发病率和死亡率更高。其作用机制 HEU婴儿生长不良和易受感染的原因尚不清楚，但最近的证据 这意味着婴儿肠道微生物群的扰动是一个关键机制。母乳滋养婴儿的肠道 微生物群，贡献了近三分之一的细菌群落。母乳的第三大成分 是人乳低聚糖(HMOS)。HMO作为益生元，支持共生肠道的生长 细菌和影响免疫系统的发育。因此，母乳中含有益生元(HMOS)和 益生菌(细菌)对婴儿肠道微生物群的定植和发育至关重要。鲜为人知 关于特定的HMOS和可能与生长相关的特定肠道细菌之间的关系 以及HEU婴儿的发病率。新的证据表明，母亲感染艾滋病毒会改变HMO的组成 HEU婴儿的微生物多样性低于HUU婴儿。考虑到HMO对 微生物组的发育和免疫功能，即使是HMO组成的微小差异也可能 对HEU婴儿的生长和健康结局的重要影响。HMOS可能是一种可行的干预措施 改善HEU婴儿的生长和发病率。拟议的研究将评估两者之间的联系 母体HIV感染、HMO组成和婴儿肠道微生物群，并鉴定HMO介导的 与HEU婴儿发病率和线性生长相关的途径。我们将前瞻性地注册并跟随 在肯尼亚感染艾滋病毒和未感染艾滋病毒的妇女及其婴儿，这是一个艾滋病毒和艾滋病高发地区 童年发育不良。这项研究的目的是：1)评估HMO的组成和母乳的差异 随着时间的推移，感染艾滋病毒和未感染艾滋病毒的妇女之间的微生物区系，2)了解母乳作为一种 合生体影响细菌群落和婴儿微生物组多样性，以及3)决定HMOS 与HEU和HEU的直线增长和腹泻、肺炎和肠道功能障碍的发生率有关 胡氏婴幼儿。这项纵向研究的结果将有助于我们理解生长和 HMOS和婴儿肠道微生物组的作用，为设计干预措施提供关键数据 在非洲这一脆弱且不断增长的人口中，优化高吸毒症儿童的成长和健康结果。

PROJECT SUMMARY/ABSTRACT Despite the success in global health efforts to prevent mother-to-child transmission of HIV, there is a growing and often overlooked HIV-exposed uninfected (HEU) population with substantially higher risk of growth faltering, infectious morbidity, and mortality than HIV-unexposed uninfected (HUU) infants. The mechanisms responsible for poor growth and susceptibility to infection in HEU infants are unclear, but recent evidence implicates perturbations in the infant gut microbiome as a critical mechanism. Breast milk seeds the infant gut microbiome, contributing nearly one-third of bacterial communities. The third largest component of breast milk are human milk oligosaccharides (HMOs). HMOs serve as prebiotics, supporting growth of commensal gut bacteria and influencing development of the immune system. Thus, breast milk contains prebiotics (HMOs) and probiotics (bacteria) fundamental for colonization and development the infant gut microbiome. Little is known about the relationship between specific HMOs and specific gut bacteria that may be associated with growth and morbidity in HEU infants. Emerging evidence suggests that maternal HIV infection alters HMO composition and HEU infants have reduced microbial diversity than HUU infants. Given the influence of HMOs on microbiome development and immune function, even a small difference in HMO composition could have important implications for growth and health outcomes in HEU infants. HMOs may be a feasible intervention to improve growth and morbidity in HEU infants. The proposed study will evaluate the association between maternal HIV infection, HMO composition, and the infant gut microbiome, and identify HMO-mediated pathways associated with morbidity and linear growth in HEU infants. We will prospectively enroll and follow HIV-infected and HIV-uninfected women and their infants in Kenya, a region with high prevalence of HIV and poor childhood growth. The study aims to: 1) evaluate the differences in HMO composition and breast milk microbiota between HIV-infected and HIV-uninfected women over time, 2) understand how breast milk as a synbiotic influences bacterial communities and infant microbiome diversity, and 3) determine whether HMOs are associated with linear growth and incidence of diarrhea, pneumonia, and enteric dysfunction in HEU and HUU infants. Results from this longitudinal study will inform our understanding of mechanisms of growth and the role of HMOs and the infant gut microbiome, providing critical data for the design of interventions to optimize growth and health outcomes in HEU children in Africa, a vulnerable and growing population.