The effect of the maternal plasma and breastmilk metabolome on the infant gut microbiome and growth

项目摘要 每年有100多万未感染艾滋病毒的儿童出生，其中大多数在撒哈拉以南非洲 非洲高浓缩铀婴儿的线性生长不良、感染性发病率和死亡率的风险增加， 未感染艾滋病病毒的同龄人。母乳喂养减少但不能消除儿童的不良健康结果 尽管通过抗逆转录病毒治疗改善了产妇健康，但仍有高浓缩铀婴儿。的生物学机制 母乳喂养的高浓缩铀婴儿的脆弱性仍不清楚。我们对如何做到这一点的理解 艾滋病毒感染影响母乳成分和母乳成分在发育不良中的作用 高浓缩铀婴儿的生长。从生物学角度看，全身性代谢功能障碍与 母亲感染艾滋病毒可能会改变母乳中的代谢物水平，从而影响婴儿的结局。我们 假设艾滋病毒会改变母体血浆和母乳的代谢组，这些改变将 与婴儿肠道微生物组和婴儿生长有关。 我们建议利用Tunza Mwana肯尼亚出生队列（NICHD 5 R 01 HD 096999），包括哺乳期 感染和未感染艾滋病毒的妇女及其婴儿。利用现有的母体血浆和母乳样本 我们将从60名队列参与者（30名感染艾滋病毒，30名未感染艾滋病毒）和前瞻性婴儿生长监测中， 扩展这一独特的队列，执行靶向代谢组学和机器学习，以表征代谢 母亲-母乳-婴儿三元组之间的关系，并确定血浆中的代谢组学特征， 母乳与婴儿肠道微生物组组成和生长相关。 具体目的是：1）确定母体血浆代谢物与母乳代谢物的相关性，以及 血浆和母乳代谢物如何在哺乳早期（3周）和哺乳后期（6个月）与HIV相关， 2)评估母乳代谢物如何影响婴儿3周时的肠道微生物组组成和多样性 3）鉴定母体血浆和母乳代谢物以及婴儿肠道微生物组组成 与生长至24个月的生命相关。 职业和学习目标是1）获得流行病学的基础和高级技能， 生物统计学，2）发展多组学研究的进行和解释的核心能力，以及3） 加强纵向队列研究和临床转化试验的技能。通过完成这些学习 目标，并通过实现研究计划中的具体目标，申请人将很好地- 有能力获得竞争性外部资金，以实施未来的研究，评估产妇- 母乳-婴儿三联征与营养和生长结果。 研究影响：这项工作将确定母乳中被破坏并导致深远影响的关键元素 关于婴儿健康。关于母体代谢组学和婴儿肠道微生物组学特征的新数据 将为潜在的干预目标提供信息。

PROJECT SUMMARY More than one million HIV exposed uninfected (HEU) children are born annually, with the majority in sub-Saharan Africa. HEU infants are at an increased risk of poor linear growth, infectious morbidity, and mortality compared to their HIV unexposed uninfected peers. Breastfeeding reduces but does not eliminate poor health outcomes in HEU infants, despite improving maternal health with antiretroviral treatment. The biological mechanisms for vulnerabilities in breastfed HEU infants remain unclear. There are significant gaps in our understanding of how HIV infection affects breastmilk composition and the role of breastmilk composition in the development of poor growth among HEU infants. It is biologically plausible that systemic metabolic dysfunction associated with maternal HIV infection may alter metabolite levels in breastmilk and thereby affect infant outcomes. We hypothesize that HIV will alter the maternal plasma and breastmilk metabolome and that these alterations will be associated with the infant gut microbiome and infant growth. We propose to leverage the Tunza Mwana Kenyan birth cohort (NICHD 5R01HD096999) including lactating women living with and without HIV and their infants. Utilizing existing maternal plasma and breastmilk samples from 60 cohort participants (30 with HIV and 30 without HIV) and prospective infant growth monitoring, we will expand this unique cohort performing targeted metabolomics and machine learning to characterize metabolic relationships between the mother-breastmilk-infant triad and to identify metabolomic profiles in plasma and breastmilk associated with the infant gut microbiome composition and growth. Specific Aims are to 1) determine how maternal plasma metabolites correlate with breastmilk metabolites, and how plasma and breastmilk metabolites are associated with HIV in early (3 weeks) and later (6 months) lactation, 2) evaluate how breastmilk metabolites influence infant gut microbiome composition and diversity at 3 weeks and 6 months, 3) identify maternal plasma and breastmilk metabolites and infant gut microbiome compositions associated with growth to 24 months of life. Career and Learning Objectives are to 1) acquire foundational and advanced skills in epidemiology and biostatistics, 2) develop core competency in the conduct and interpretation of multi-omics studies, and 3) strengthen skills in longitudinal cohort studies and clinical-translational trials. By accomplishing these learning objectives and through the achievement of the specific aims in the research plan, the applicant will be well- positioned to attain competitive external funding to implement future studies assessing the maternal- breastmilk-infant triad and nutrition and growth outcomes. Study Impact: This work will identify key elements in breastmilk that are disrupted and lead to profound effects on infant health. New data generated on maternal metabolomic and infant gut microbiome profiles associated with infant growth will inform potential targets for intervention.