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

母体血浆和母乳代谢组对婴儿肠道微生物组和生长的影响

• 批准号: 10754737
• 负责人: David Taylor Hendrixson
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754737
• 关键词: Achievement; Affect; Africa South of the Sahara; Age Months; Biological; Biometry; Birth; Breast Feeding; Child; Competence; Complex; Data; Development; Elements; Epidemiology; Essential Amino Acids; Funding; Future; Goals; Growth; HIV; HIV Infections; HIV-exposed uninfected infant; Human Milk; Immune system; Infant; Infant Health; Intervention; Knowledge; Lactation; Learning; Life; Lipids; Longitudinal cohort study; Machine Learning; Maternal Health; Mediating; Metabolic; Metabolic dysfunction; Methods; Modeling; Monitor; Morbidity - disease rate; Mothers; National Institute of Child Health and Human Development; Nitrogen; Obesity; Oligosaccharides; Outcome; Participant; Pathway interactions; Perinatal; Persons; Plasma; Positioning Attribute; Research; Research Personnel; Risk; Role; Sampling; Serum; Tryptophan; Woman; Work; acylcarnitine; antiretroviral therapy; career; cohort; experience; gut dysbiosis; gut microbiome; high risk; improved; infant adiposity; infant gut microbiome; infant nutrition; infant outcome; insight; lipidomics; longitudinal analysis; metabolome; metabolomics; microbiome; microbiome composition; mortality; multiple omics; nutrition; peer; poor health outcome; prospective; skills; translational clinical trial

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.

项目概要 每年有超过 100 万未感染艾滋病毒 (HEU) 的儿童出生，其中大多数生活在撒哈拉以南地区 非洲。与其他婴儿相比，HEU 婴儿线性生长不良、感染发病率和死亡率的风险更高 向未接触过艾滋病毒、未感染艾滋病毒的同龄人传播。母乳喂养可以减少但不能消除不良健康后果 HEU 婴儿，尽管通过抗逆转录病毒治疗改善了孕产妇健康。的生物学机制 母乳喂养的 HEU 婴儿的脆弱性仍不清楚。我们对如何做到这一点的理解存在重大差距 HIV感染影响母乳成分以及母乳成分在发育不良中的作用 HEU 婴儿的生长。从生物学角度来看，全身代谢功能障碍与以下因素相关是合理的： 母亲艾滋病毒感染可能会改变母乳中的代谢水平，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代谢组，并且这些改变将 与婴儿肠道微生物群和婴儿生长有关。 我们建议利用 Tunza Mwana 肯尼亚出生队列 (NICHD 5R01HD096999)，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 从 60 名队列参与者（30 名感染艾滋病毒和 30 名未感染艾滋病毒）和前瞻性婴儿生长监测中，我们将 扩展这个独特的队列，执行有针对性的代谢组学和机器学习来表征代谢 母乳-婴儿三联体之间的关系，并确定血浆和婴儿中的代谢组谱 母乳与婴儿肠道微生物组的组成和生长有关。 具体目标是 1) 确定母体血浆代谢物与母乳代谢物的相关性，以及 哺乳期早期（3 周）和后期（6 个月）血浆和母乳代谢物与 HIV 有何关联， 2) 评估母乳代谢物如何影响 3 周时婴儿肠道微生物组的组成和多样性 6 个月时，3) 识别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 个月的生命有关。 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) 培养进行和解释多组学研究的核心能力，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- 旨在获得有竞争力的外部资金，以开展评估孕产妇的未来研究 母乳-婴儿三联征以及营养和生长结果。 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谱相关的新数据 婴儿生长的情况将为潜在的干预目标提供信息。