Metabolomic and nutrigenetic effects of folic acid supplementation and unmetabolized folic acid

叶酸补充剂和未代谢叶酸的代谢组学和营养遗传效应

• 批准号: 10386872
• 负责人: Mary Gamble
• 金额: $ 61.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386872
• 关键词: Adverse effects; Bangladesh; Bayesian Modeling; Beverages; Biochemical Pathway; Carbon; Clinical; Collaborations; Country; DHFR gene; Data; Development; Dietary Intervention; Disease; Dose; Enzymes; Etiology; Folic Acid; Folic Acid Deficiency; Food; Funding; Future; Genes; Genotype; Goals; Gold; Health; Hormones; Human; Individual; Intake; Intervention Studies; Laws; Link; Lipids; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methyltransferase; Neural Tube Defects; Nutrient; Observational Study; Outcome; Pathway interactions; Pattern; Pattern Recognition; Persons; Phenotype; Placebos; Plasma; Policies; Population; Prevention; Process; Proteins; Randomized; Reaction; Recommendation; Research; Research Design; Resolution; Role; S-Adenosylmethionine; Safety; Sample Size; Sampling; Serum; Systems Biology; Testing; Time; Uncertainty; United States National Institutes of Health; Walkers; biobank; body system; data repository; design; double-blind placebo controlled trial; folic acid supplementation; fortification; genetic variant; genome-wide; metabolic phenotype; metabolome; metabolomics; methyl group; multiple omics; novel; nucleotide metabolism; nutrition related genetics; programs; randomized placebo controlled trial; response; small molecule; systematic review; trial design

Folate is a key regulator of one-carbon metabolism (OCM), a biochemical pathway that provides methyl groups for numerous reactions including hundreds of essential methyltransferase enzymes. Food fortification with folic acid (FA), a synthetic inactive form of folate more stable than the natural form in food (5-methyltetrahydrofolate (5mTHF)), is mandated by law in 87 countries, including the US. People vary in their ability to metabolize FA to 5mTHF, resulting in unmetabolized FA (UMFA), which is present in serum of >95% of the US population. While adequate folate intake is essential for human health, the widespread presence of UMFA in serum has raised questions regarding potential unanticipated adverse effects. Expert panels systematically reviewing the safety of high FA intake concluded there is strong evidence on the benefits of FA, e.g. for neural tube defect prevention, but uncertainty for non-NTD outcomes. Many feel that there is a critical need to identify alterations in metabolites and metabolic pathways associated with high FA intake. The metabolome offers a robust approach to do so as it integrates meaningful changes in a broad spectrum of key regulatory processes. The goal of this proposal is to leverage a wealth of data and banked samples from a recently completed randomized, double-blind, placebo-controlled trial (RCT) of FA supplementation (FACT, n=610) in Bangladesh. Unlike the US, Bangladesh is a FA-naïve population, as foods are not fortified with FA. We propose to incorporate new studies that will use novel high-resolution metabolomics (HRM). Untargeted metabolomics is the quantitative measurement of small-molecule metabolites that captures an unbiased snap-shot of the activity of all metabolically active organ systems involved in the development of almost all metabolic disorders. The FACT study design includes supplementation with FA (400 or 800 µg/d x 12 or 24 weeks), and a “wash-out” period following FA cessation. This study design permits us to identify and validate novel metabolites and pathways altered by FA supplementation (Aim 1) and UMFA (Aim 2) and to determine the stability or reversibility of those effects over time. In collaboration with Dr. Walker, leader of the high-resolution metabolomics facility at Mt. Sinai, we will combine FACT’s rigorous RCT approach – the gold standard design to determine causality – with HRM that interrogates greater than 80% of metabolic pathways. We will test the hypotheses that FA supplementation and/or UMFA influence unanticipated downstream metabolites and pathways, and identify those that may be linked to health outcomes. In Aim 3, in collaboration with geneticist, Dr. Pierce, we will evaluate how gene variants influence the effects of FA supplementation and UMFA on metabolomic outcomes. In Aim 4, with Dr. Kioumourtzoglou, we will use novel pattern recognition and hierarchical approaches to identify specific metabolic patterns that are impacted by FA supplementation and/or UMFA. The findings of this study may inform policy decisions regarding FA fortification programs and the forms and doses of folate sold in over-the-counter supplements and used in popular beverage products.

叶酸是单碳代谢（OCM）的关键调节剂，这是一种生化途径，为包括数百种必需甲基转移酶在内的众多反应提供甲基。叶酸（FA）的食物强化是一种比食物中的自然形式（5-甲基四氢叶酸（5mthf））更稳定的叶酸的合成形式，在包括美国在内的87个国家 /地区法律命令。人们将FA代谢为5MTHF的能力各不相同，从而导致未代谢的FA（UMFA），该FA（UMFA）以> 95％的美国人群的血清中存在。尽管足够的叶酸摄入对于人类健康至关重要，但血清中UMFA的宽度引发了有关潜在意外不良影响的问题。专家小组系统地回顾了高足总摄入量的安全性，得出的结论是有充分的证据表明FA的好处，例如用于预防神经管缺陷，但非NTD结局的不确定性。许多人认为，迫切需要确定代谢物和与高FA摄入相关的代谢途径的变化。代谢组提供了一种强大的方法，因为它在广泛的关键监管过程中整合了有意义的变化。该提案的目的是利用最近在孟加拉国的FA补充（事实，n = 610）的最近完成的随机，双盲，安慰剂对照试验（RCT）中的大量数据和库存样本。与美国不同，孟加拉国是不可用的人口，因为食品没有加强FA。我们建议纳入将使用新型高分辨率代谢组学（HRM）的新研究。未靶向的代谢组学是对小分子代谢产物的定量测量，可捕获几乎所有代谢性疾病开发的所有代谢活性器官系统的活性的无偏发射。事实研究的设计包括补充FA（400或800 µg/d x 12或24周），以及FA停止后的“洗涤”期。这项研究设计使我们能够识别和验证通过补充FA（AIM 1）和UMFA（AIM 2）改变的新型代谢产物和途径，并确定随时间推移这些影响的稳定性或可逆性。与西奈山高分辨率代谢组学设施的负责人Walker博士合作，我们将将事实的严格RCT方法（用于确定计算性的黄金标准设计）与HRM结合使用，将大于80％的代谢途径询问。我们将测试FA补充和/或UMFA影响意外的下游代谢物和途径的假设，并确定可能与健康结果有关的。在AIM 3中，与遗传学家Pierce博士合作，我们将评估基因变体如何影响补充FA和UMFA对代谢组结果的影响。在AIM 4中，使用Kioumourtzoglou博士，我们将使用新颖的模式识别和分层方法来识别受FA补充和/或UMFA影响的特定代谢模式。这项研究的结果可能会为有关FA防御计划的政策决策以及在非处方补品中出售的叶酸形式和剂量提供信息。