富含多酚的绿色地中海饮食可增强表观遗传调控潜力：DIRECT PLUS 随机对照试验。

A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial.

机构信息

Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, Leipzig 04103, Germany.

The Health & Nutrition Innovative International Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101 Beer-Sheva, Israel; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

出版信息

Metabolism. 2023 Aug;145:155594. doi: 10.1016/j.metabol.2023.155594. Epub 2023 May 24.

DOI:10.1016/j.metabol.2023.155594

PMID:37236302

Abstract

BACKGROUND

The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements.

METHODS

Our study included 260 participants (baseline BMI = 31.2 kg/m, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies.

RESULTS

A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction.

CONCLUSIONS

The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual's epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism.

摘要

背景

多酚丰富的饮食在体内调节表观基因组的能力在一定程度上尚不清楚。鉴于富含多酚且减少红/加工肉类（绿色-MED）的地中海饮食（MED）具有有益的代谢作用，正如之前 18 个月的 DIRECT PLUS 随机对照试验所证明的那样，我们分析了绿色-MED 饮食对甲基组和转录组水平的影响，以突出观察到的代谢改善的潜在分子机制。

方法

我们的研究包括 DIRECT PLUS 试验的 260 名参与者（基线 BMI = 31.2kg/m，年龄 = 5 岁），最初随机分为干预组之一：A. 健康饮食指南（HDG），B. MED（通过核桃额外提供 440mg 多酚），C. 绿色-MED（通过核桃、绿茶和 Mankai：绿色浮萍奶昔额外提供 1240mg 多酚）。使用 Illumina EPIC 和 RNA 测序技术，在基线和完成 18 个月干预后，分析所有研究对象的血液甲基组和转录组。

结果

与 MED（177）和 HDG（377）饮食组相比，绿色-MED 组中共有 1573 个差异甲基化区域（DMR；错误发现率（FDR）<5%）。这对应于与 MED（7）和 HDG（738）相比，绿色-MED 干预组中 1753 个差异表达基因（DEG；FDR<5%）。一致地，在接受绿色-MED 干预的受试者中，转录变化的表观遗传调节基因数量最多（6%）。对接受绿色-MED 干预的参与者的转录和表型变化进行加权聚类网络分析，确定了与血清叶酸变化相关的候选基因（均 P<1×10），并突出了一个包含 KIR3DS1 基因座的模块，该模块与多酚变化呈负相关（例如，P<1×10），但与 MRI 评估的浅层皮下脂肪面积、体重和腰围 18 个月变化呈正相关（均 P<0.05）。其中，该模块包括半胱氨酸-β-合酶基因 Cystathionine Beta-Synthase，在降低同型半胱氨酸方面发挥主要作用。