Martinez-Morata Irene, Wu Haotian, Galvez-Fernandez Marta, Ilievski Vesna, Bottiglieri Teodoro, Niedzwiecki Megan M, Goldsmith Jeff, Jones Dean P, Kioumourtzoglou Marianthi-Anna, Pierce Brandon, Walker Douglas I, Gamble Mary V
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States.
Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, United States.
J Nutr. 2024 Feb;154(2):670-679. doi: 10.1016/j.tjnut.2023.12.010. Epub 2023 Dec 12.
Folic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases the plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on the downstream metabolic effects of FA supplementation, including potential effects associated with UMFA.
We aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults.
Sixty participants were selected from the Folic Acid and Creatine Trial; half received 800 μg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, plasma 5mTHF, and plasma UMFA. Pathway analyses were conducted using Mummichog.
In penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and 2 fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid, and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation.
In addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation and UMFA. Further studies are needed to confirm these associations and assess their potential implications for human health.
This trial was registered at https://clinicaltrials.gov as NCT01050556.
叶酸（FA）是在补充剂和叶酸强化食品中发现的叶酸氧化形式。大多数叶酸被二氢叶酸还原酶还原为5-甲基四氢叶酸（5mTHF）；后者是食物中天然存在的叶酸形式。摄入叶酸会增加5mTHF和未代谢叶酸（UMFA）的血浆水平。关于叶酸补充的下游代谢影响，包括与UMFA相关的潜在影响，目前信息有限。
我们旨在评估叶酸补充的代谢影响，以及血浆5mTHF和UMFA与未接触过叶酸的孟加拉国成年人代谢组的关联。
从叶酸和肌酸试验中选取60名参与者；一半人每天服用800μg叶酸，持续12周，另一半人服用安慰剂。通过高分辨率质谱法测量血浆代谢组谱，包括170种已鉴定的代谢物和26541个代谢特征。采用惩罚回归方法评估目标代谢物与叶酸补充、血浆5mTHF和血浆UMFA的关联。使用Mummichog进行通路分析。
在已鉴定代谢物的惩罚模型中，叶酸补充与较高的胆碱水平相关。5mTHF浓度的变化与参与氨基酸代谢的代谢物（5-羟基吲哚乙酸、乙酰甲硫氨酸、肌酐、胍基乙酸、羟脯氨酸/N-乙酰丙氨酸）和2种脂肪酸（二十二碳六烯酸和亚油酸）呈正相关。5mTHF浓度的变化与乙酰谷氨酸、乙酰赖氨酸、肉碱、丙酰肉碱、肉桂酸、尿黑酸、花生四烯酸和尼古丁呈负相关。UMFA浓度与较低水平的花生四烯酸相关。所有模型中选择的代谢物共同与脂质、芳香族氨基酸代谢和尿素循环有关。对非靶向代谢特征的分析确定了与叶酸补充相关的其他通路。
除了重现与5mTHF相关的几种预期代谢变化外，我们还观察到与叶酸补充和UMFA相关的其他代谢物/通路。需要进一步研究来证实这些关联，并评估它们对人类健康的潜在影响。
