TY - JOUR
T1 - A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential
T2 - the DIRECT PLUS randomized controlled trial
AU - Hoffmann, Anne
AU - Meir, Anat Yaskolka
AU - Hagemann, Tobias
AU - Czechowski, Paul
AU - Müller, Luise
AU - Engelmann, Beatrice
AU - Haange, Sven Bastiaan
AU - Rolle-Kampczyk, Ulrike
AU - Tsaban, Gal
AU - Zelicha, Hila
AU - Rinott, Ehud
AU - Kaplan, Alon
AU - Shelef, Ilan
AU - Stumvoll, Michael
AU - Blüher, Matthias
AU - Liang, Liming
AU - Ceglarek, Uta
AU - Isermann, Berend
AU - von Bergen, Martin
AU - Kovacs, Peter
AU - Keller, Maria
AU - Shai, Iris
N1 - Funding Information:
This work has been supported by the Free State of Saxony , Deutsches Zentrum für Diabetesforschung and grants from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation – Projektnummer 209933838 – SFB 1052; B03, B11, C01, Z04; SPP 1629 TO 718/2- 1). DIRECT PLUS was also supported by the Israel Ministry of Health grant 87472511 (to IrSh); Israel Ministry of Science and Technology grant 3-13604 (to IrSh); and the California Walnuts Commission (to Iris Shai). AYM is supported by the Council for Higher Education - Zuckerman support program for outstanding postdoctoral female researchers. MvB, BE, SBH and URK are grateful for the ProMetheus platform for proteomics and metabolomics funded by the UFZ . The information, content, and conclusions drawn in this work are those of the authors and should not be construed as the official position by, or policy of, the funding agencies, nor should any endorsements be inferred.
Publisher Copyright:
© 2023 The Authors
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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/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. 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 × 10−3) 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. 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.
AB - 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/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. 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 × 10−3) 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. 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.
KW - Cross-omics
KW - DNA methylation
KW - Folate
KW - Lifestyle
KW - mRNA expression
KW - Obesity
KW - Polyphenols
KW - Randomized controlled trial (RCT)
UR - http://www.scopus.com/inward/record.url?scp=85161485321&partnerID=8YFLogxK
U2 - 10.1016/j.metabol.2023.155594
DO - 10.1016/j.metabol.2023.155594
M3 - Article
C2 - 37236302
AN - SCOPUS:85161485321
SN - 0026-0495
VL - 145
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
M1 - 155594
ER -
