Exploring Associations between Human Milk Oligosaccharides and Atherosclerosis Risk Factors in Infancy and Early Childhood

探索母乳低聚糖与婴儿期和幼儿期动脉粥样硬化危险因素之间的关联

• 批准号: 10491367
• 负责人: Lars Bode
• 金额: $ 17.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491367
• 关键词: 4 year old; Accounting; Acute; Address; Affect; American Heart Association; Asthma; Atherosclerosis; Biomedical Engineering; Birth; Blood Circulation; Body Composition; Breast Feeding; Breastfed infant; C-reactive protein; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cessation of life; Child; Childhood; Cholesterol; Chronic; Clinical; Cognition; Cohort Studies; Colon; Communicable Diseases; Complex; Consensus; Data; Development; Disease; Disease Outcome; Disease model; Early Intervention; Elderly; Growth; Health Care Costs; Human; Human Milk; Hypersensitivity; Immune; Infant; Infant Development; Infant Health; Inflammation; Inflammatory; Innate Immune Response; Intervention; Knowledge; Lactation; Lactose; Life; Ligands; Linear Regressions; Link; Lipids; Mammals; Measures; Metabolic; Metadata; Microbe; Milk; Modeling; Mothers; Mus; Myocardial Infarction; Oligosaccharides; Outcome; Phenotype; Plasma; Principal Component Analysis; Resources; Risk; Risk Factors; Risk Marker; Sampling; Shapes; Small Intestines; Solid; Stroke; Structure; Technology; Testing; Time; Toll-like receptors; Translating; Translations; Triglycerides; Woman; atherosclerosis risk; base; biobank; cardiometabolism; cardiovascular disorder prevention; cardiovascular disorder risk; disorder risk; early childhood; economic cost; emerging adult; epidemiologic data; gut microbiome; infancy; infant gut microbiome; inflammatory marker; inter-individual variation; lipid metabolism; lipidomics; metabolomics; microbiome; mortality; mouse model; neurodevelopment; pre-clinical; prebiotics; prevent

ABSTRACT Cardiovascular disease (CVD) is the leading cause of mortality, accounting for over a third of all deaths globally. CVD is caused by atherosclerosis, a complex chronic inflammatory disorder that results from chronic damage to the arterial wall by inflammation and lipid accumulation. Atherosclerosis begins in early life and is essentially universal by early adulthood. Thus, there is broad consensus that CVD prevention should begin early when adverse trajectories may be most modifiable – potentially as early as during infancy. Epidemiological data show that breastfed infants are at lower risk of developing CVD later in life, however, the protective components in human breastmilk and underlying mechanisms that contribute to the beneficial effects of breastfeeding remain unknown. After lactose and lipids, human milk oligosaccharides (HMOs), a group of complex carbohydrates, are the third most abundant component of human breastmilk. HMOs – either directly, or indirectly through shaping the infant gut microbiome – can impact infant inflammation and lipid metabolism, the two key contributors to atherosclerosis and CVD. In fact, our preliminary data shows that mice that received the HMO 3’-sialyllactose (3’SL) with the dam’s milk during the breastfeeding period had significantly lower plasma triglyceride and cholesterol levels and developed less atherosclerosis later in life. Here, we aim to explore whether these observed beneficial effects translate from mice to humans. Based on the finding that HMO composition varies between women and has been associated with several infant health and disease outcomes, we propose to test the hypothesis that HMO amount and composition associate with early preclinical markers of CVD and metabolic risk, and markers of inflammation from birth to early childhood. We will leverage the extraordinary resources of the Barwon Infant Study (BIS), one of the most comprehensive pre-birth cohort studies of cardiometabolic and inflammatory phenotypes in the world, apply state-of-the-art technology to measure HMO composition in biobanked breastmilk and infant plasma samples, and test whether HMO concentrations associate with infant lipidomic, metabolic, and cardiovascular phenotypes (AIM 1) as well as infant markers of inflammation (AIM 2). Knowledge gained from the successful completion of the proposed project will add to the existing preclinical data that established causal relationships. Together, the results will greatly enhance our understanding why breastfed infants are at lower risk of later CVD and form the basis for early life interventions. This is particularly timely as HMOs like 3’SL are now synthesized in bioengineered microbes and stand ready as new, inexpensive, scalable and safe options to help prevent CVD early in life when adverse trajectories may be most modifiable and help address the substantial and increasing health and economic costs of CVD.

抽象的 心血管疾病（CVD）是死亡率的主要原因，占全球所有死亡人数的三分之一。 CVD是由动脉粥样硬化引起的，这是一种复杂 通过炎症和脂质积累的动脉壁。动脉粥样硬化始于早期，本质上是 成年初期。那就是广泛的共识，即CVD预防应早期开始 不良轨迹可能是最可修改的 - 可能最早在婴儿期。流行病学数据显示 但是，母乳喂养的婴儿在以后的生活中患CVD的风险较低，但是，受保护的成分 人类母乳和有助于母乳喂养有益影响的潜在机制仍然存在 未知。乳糖和脂质后，人乳寡糖（HMOS），一组复杂的碳氢化物， 是人类母乳中第三大的成分。 HMO-直接或间接通过 塑造婴儿肠道微生物组 - 可以影响婴儿注射和脂质代谢，这两个关键因素 进行动脉粥样硬化和CVD。实际上，我们的初步数据表明，接收HMO 3'-透明度的小鼠 （3'sl）在母乳喂养期间，水坝的牛奶的血浆甘油三酸酯和 胆固醇水平并在以后的生活中降低了动脉粥样硬化。在这里，我们旨在探索这些是否 观察到的有益作用从小鼠转化为人类。基于HMO组成各种的发现 在妇女之间，与几个婴儿的健康和疾病结局有关，我们建议测试 HMO数量和成分与CVD和代谢的早期临床前标记有关的假设 从出生到幼儿的风险和炎症标记。我们将利用非凡资源 Barwon婴儿研究（BIS）是心脏代谢和最全面的出生前队列研究之一 世界上炎症表​​型，应用最先进的技术来测量HMO组成 生物领域的母乳和婴儿血浆样品，并测试HMO浓度是否与婴儿相关 脂质组，代谢和心血管表型（AIM 1）以及感染的婴儿标记（AIM 2）。 从拟议项目的成功完成中获得的知识将添加到现有的临床前数据中 建立了因果关系。共同的结果将大大增强我们的理解 婴儿患CVD的风险较低，并构成了早期生命干预的基础。这特别及时 像3’SL这样的HMO现在已在生物工程的微生物中合成，并准备为新的，便宜，可扩展的 以及在广告轨迹可能是最可修改并提供帮助时，可以帮助防止CVD早期CVD的安全选择 解决CVD的健康和经济成本的大量和日益增长的问题。

项目成果

Age-dependent associations of human milk oligosaccharides with body size and composition up to 4 years of age.

母乳低聚糖与 4 岁以下体型和成分的年龄相关性。

• DOI: 10.1016/j.ajcnut.2023.02.016
• 发表时间: 2023
• 期刊: The American journal of clinical nutrition
• 作者: Mansell,Toby;Furst,Annalee;O'Hely,Martin;Chang,Melinda;Ponsonby,Anne-Louise;Vuillermin,Peter;Tang,MimiLk;Burgner,David;Saffery,Richard;Bode,Lars;BarwonInfantStudyInvestigatorGroup
• 通讯作者: BarwonInfantStudyInvestigatorGroup