Details zur Publikation

Kategorie Textpublikation
Referenztyp Zeitschriften
DOI 10.1016/j.metabol.2023.155594
Lizenz creative commons licence
Titel (primär) A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial
Autor Hoffmann, A.; Meir, A.Y.; Hagemann, T.; Czechowski, P.; Müller, L.; Engelmann, B.; Haange, S.-B. ORCID logo ; Rolle-Kampczyk, U.; Tsaban, G.; Zelicha, H.; Rinott, E.; Kaplan, A.; Shelef, I.; Stumvoll, M.; Blüher, M.; Liang, L.; Ceglarek, U.; Isermann, B.; von Bergen, M.; Kovacs, P.; Keller, M.; Shai, I.
Quelle Metabolism-Clinical and Experimental
Erscheinungsjahr 2023
Department MOLSYB
Band/Volume 145
Seite von art. 155594
Sprache englisch
Topic T9 Healthy Planet
Keywords Randomized controlled trial (RCT); Cross-omics; mRNA expression; DNA methylation; Polyphenols; Lifestyle; Folate; Obesity


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.


Our study included 260 participants (baseline BMI = 31.2 kg/m2, 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.


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 × 10−3) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10−4), 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.


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.



dauerhafte UFZ-Verlinkung
Hoffmann, A., Meir, A.Y., Hagemann, T., Czechowski, P., Müller, L., Engelmann, B., Haange, S.-B., Rolle-Kampczyk, U., Tsaban, G., Zelicha, H., Rinott, E., Kaplan, A., Shelef, I., Stumvoll, M., Blüher, M., Liang, L., Ceglarek, U., Isermann, B., von Bergen, M., Kovacs, P., Keller, M., Shai, I. (2023):
A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial
Metab.-Clin. Exp. 145 , art. 155594 10.1016/j.metabol.2023.155594