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

摘要 心血管疾病(CVD)是导致死亡的主要原因，占全球死亡人数的三分之一以上。 心血管疾病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，由 动脉壁受到炎症和脂质堆积的影响。动脉粥样硬化开始于生命早期，本质上是 在成年初期就普遍存在。因此，人们达成了广泛的共识，即预防心血管疾病应及早开始。 不利的轨迹可能是最易改变的--可能早在婴儿期就有。流行病学数据显示 母乳喂养的婴儿在晚年患心血管疾病的风险较低，然而， 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。在乳糖和类脂之后，人类乳寡糖(HMOS)，一组复杂的碳水化合物， 是人类母乳中含量第三丰富的成分。医疗保健组织--直接或间接通过 塑造婴儿肠道微生物群-可以影响婴儿炎症和脂肪代谢，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‘-唾液酸乳糖注射的小鼠 (3‘SL)母乳在哺乳期显著降低血浆甘油三酯和 胆固醇水平，并在晚年较少出现动脉粥样硬化。在这里，我们的目标是探索这些 观察到的有益效果从老鼠转移到人类。基于HMO组成不同的发现 在女性之间，与几个婴儿的健康和疾病结局有关，我们建议测试 假设HMO的数量和组成与心血管疾病和代谢的早期临床前标记物有关 风险，以及从出生到儿童早期的炎症标志物。我们将充分利用 巴旺婴儿研究(BIS)，最全面的出生前心脏代谢和心脏代谢队列研究之一 全球炎症表型，应用最先进的技术测量HMO成分 生物库母乳和婴儿血浆样本，并测试HMO浓度是否与婴儿有关 脂类、代谢和心血管表型(AIM 1)以及婴儿炎症标志物(AIM 2)。 从拟议项目的成功完成中获得的知识将增加现有的临床前数据 建立了因果关系。总而言之，这些结果将极大地增强我们对母乳喂养的理解 婴儿患晚期心血管疾病的风险较低，这是早期生活干预的基础。这是特别及时的，因为 像3‘SL这样的HMO现在是在生物工程微生物中合成的，随时准备成为新的、廉价的、可扩展的 和安全的选择，帮助预防生命早期的心血管疾病，此时不利的轨迹可能最易改变和帮助 应对心血管疾病造成的巨大且不断增加的健康和经济成本。

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.