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.

摘要 心血管疾病（CVD）是死亡的主要原因，占全球所有死亡的三分之一以上。 CVD是由动脉粥样硬化引起的，动脉粥样硬化是一种复杂的慢性炎症性疾病， 动脉壁的炎症和脂质积聚。动脉粥样硬化开始于生命早期， 在成年早期普遍存在。因此，有广泛的共识，心血管疾病的预防应尽早开始， 不利的轨迹可能是最容易改变的--可能早在婴儿期。流行病学资料显示 母乳喂养的婴儿在以后的生活中患心血管疾病的风险较低，然而， 人类母乳和有助于母乳喂养有益效果的潜在机制仍然存在， 未知在乳糖和脂质之后，人乳低聚糖（HMO），一组复杂的碳水化合物， 是母乳中含量第三多的成分HMO-直接或间接通过 塑造婴儿肠道微生物组-可以影响婴儿炎症和脂质代谢，这两个关键因素 动脉粥样硬化和心血管疾病事实上，我们的初步数据显示，接受HMO 3 '-唾液酸乳糖的小鼠 （3 'SL）在母乳喂养期间用母鼠的乳汁喂养的小鼠具有显著较低的血浆甘油三酯， 胆固醇水平和发展较少动脉粥样硬化以后的生活。在这里，我们的目标是探索这些 观察到的有益效果从小鼠转化到人类。根据HMO成分变化的发现， 女性之间，并已与几个婴儿的健康和疾病的结果，我们建议测试 HMO量和组成与CVD和代谢的早期临床前标志物相关的假设 风险，以及从出生到幼儿期的炎症标志物。我们将利用 Barwon婴儿研究（BIS）是最全面的出生前心脏代谢和 炎症表型，应用最先进的技术来测量HMO组成， 生物库母乳和婴儿血浆样本，并测试HMO浓度是否与婴儿 脂质组学、代谢和心血管表型（AIM 1）以及婴儿炎症标志物（AIM 2）。 从成功完成拟议项目中获得的知识将增加现有的临床前数据 建立了因果关系。总之，这些结果将大大增强我们对母乳喂养的理解， 婴儿以后患CVD的风险较低，并形成早期生活干预的基础。这是非常及时的，因为 像3 'SL这样的HMO现在在生物工程微生物中合成，并随时准备成为新的，廉价的，可扩展的 和安全的选择，以帮助预防心血管疾病的早期生活时，不利的轨迹可能是最可修改的， 解决心血管疾病的健康和经济成本的巨大和不断增加。

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