Response of the Gut Microbiome and Circulating Metabolome to Diet Intervention in Young Children: Ancillary Study to the Keeping Ideal Cardiovascular Health Family Intervention Trial (KIDFIT)

项目摘要/摘要 在25-54岁的美国成年人中，大多数死于心血管疾病(CVD)的人 饮食不太理想。虽然饮食是成人心血管疾病预防工作的重要目标，但对 儿童时期的饮食可能更有效。动物数据表明，早期饮食具有独特的调节潜力 生物系统，并持久地为儿童的生物长期健康或疾病编程。然而，尽管NHLBI 战略愿景目标1优先了解饮食如何调节生物系统，如微- 生物群和代谢组维持健康，只有有限的动物和观察到的成体数据存在。目标是 这一应用的目的是确定饮食模式干预对肠道微生物群的分子影响，以及 幼儿的循环代谢物。这一目标将通过对一项受资助的 一项临床试验测试了为期12个月的饮食方法停止高血压(DASH)饮食干预的效果。 对3-5岁儿童(n=140)的肥胖和其他CVH指标(如血压、血脂)的影响。vbl.使用 更多的参与者样本，深度表型和先进的生物信息学，拟议的工作将解决 三个具体目标。首先，它将测试DASH饮食干预对肠道微生物群的影响，包括 微生物分类群、群落以及代谢相关基因和转录本的丰富性。第二，它将定义 饮食和肠道微生物群与循环代谢物的关系。使用目标和非目标 将对代谢组学方法、血液代谢物、代谢物网络和代谢途径进行评估。 最后，以一种探索性的方式，它将探索饮食干预与随后的肥胖之间的联系 和CVH指标，通过肠道微生物组和血清代谢组。预期的结果是初步的 DASH饮食如何改变幼儿肠道微生物群和循环代谢组的模型，以及如何 这些改变与CVH的短期结局有关。这些试点数据可以在更大的样本中进行验证，并且 从而有助于最终开发新的、有针对性的早期饮食策略，以保存理想的CVH。 拟议的研究还将作为Amanda Marma Perak医学博士的培训平台，她的目标是 有一个独立的翻译研究计划，专注于了解CVH的早期决定因素 以及制定策略，以保护终生的CVH。一个由杰出科学家组成的团队将在一个 西北大学和鲁里儿童医院丰富的研究开发环境。定制 指导性、体验性和专业性发展活动将补充指导研究经验 确保佩拉克博士达到她的短期培训目标，首先获得系统生物学分子方面的专业知识 方法和翻译临床相关性的机械论见解，第二，临床试验的进行。这些 计划和资源将确保佩拉克博士在5年内成为一名分子流行病学家和儿科心脏病专家 谁可以领导多学科团队进行转化研究，通过流行病学评估获得新想法- 机制研究和临床应用，对儿科CVH的推广具有持续的影响。

PROJECT SUMMARY/ABSTRACT The majority of deaths from cardiovascular disease (CVD) in US adults ages 25-54 years are associated with suboptimal diet. While diet is an important target of CVD prevention efforts in adults, intervention on the childhood diet may be more effective. Animal data suggest that early-life diet has the unique potential to modulate biological systems and durably program a child’s biology for long-term health or disease. Yet, although NHLBI’s Strategic Vision Objective 1 prioritizes understanding how diet modulates biological systems such as the micro- biome and metabolome to sustain health, only limited animal and observational adult data exist. The objective of this application is to define the molecular effects of a dietary pattern intervention on the gut microbiome and circulating metabolome in young children. This objective will be attained through an ancillary study to a funded clinical trial that tests the effects of a 12-month Dietary Approaches to Stop Hypertension (DASH) diet interven- tion on adiposity and other CVH metrics (e.g., blood pressure, lipids) in 3- to 5-year old children (n=140). Using additional participant samples, deep phenotyping and advanced bioinformatics, the proposed work will address three specific aims. First, it will test the effect of the DASH diet intervention on the gut microbiome, including abundances of microbial taxa, communities, and metabolism-related genes and transcripts. Second, it will define the associations of diet and the gut microbiome with the circulating metabolome. Using targeted and nontargeted metabolomics approaches, blood metabolites, metabolite networks, and metabolic pathways will be evaluated. Finally, in an exploratory fashion, it will probe pathways linking the diet intervention with subsequent adiposity and CVH metrics, through the gut microbiome and serum metabolome. The expected outcome is a preliminary model of how the DASH diet alters the gut microbiome and circulating metabolome in young children, and how these alterations relate to short-term CVH outcomes. These pilot data can be validated in larger samples, and thereby contribute to eventual development of novel, targeted early-life dietary strategies to preserve ideal CVH. The proposed research will also be leveraged as a training platform for Amanda Marma Perak, MD, who aims to have an independent translational research program focused on understanding early-life determinants of CVH and developing strategies to preserve life-long CVH. A team of prominent scientists will provide mentorship in a rich research developmental environment at Northwestern University and Lurie Children’s Hospital. Customized didactic, experiential, and professional development activities will complement mentored research experience to ensure that Dr. Perak attains her short-term training goals to gain expertise in, first, systems biology molecular methods and translation of mechanistic insights for clinical relevance, and second, clinical trials conduct. These plans and resources will ensure that in 5 years, Dr. Perak is a molecular epidemiologist and pediatric cardiologist who can lead multidisciplinary teams in translational research, taking new ideas through epidemiologic evalua- tion, mechanistic study, and clinical application, with a sustained impact on the field of pediatric CVH promotion.