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Unlocking the Epigenetic Potential of a Polyphenol-rich Mediterranean Diet

Featured Publication, New Research Findings, HI-MAG,

Why “Eating Your Greens” Represents a Major Aspect of Lifestyle Driven Obesity Treatment


Researchers headed by Dr. Maria Keller (HI-MAG) and Prof. Iris Shai (Ben-Gurion University) investigated the underlying epigenetic effects of a so-called green-Mediterranean Diet (green MED) highly enriched in polyphenols with the addition of green tea and Mankai (a water lentil) and low in red or processed meat on the metabolism. They used a multi-omic approach, analyzing the blood methylome and transcriptome levels, as well as changes in urine polyphenols. The data was derived from participants involved in an 18-month Dietary Intervention Randomized Controlled Trial (RCT) called DIRECT PLUS, which compared participants living on a traditional MED to participants living on the adapted green MED. The results showed that the polyphenol-enriched green-MED diet significantly impacted the epigenome, particularly through the regulation of folate-related pathways involved in the one-carbon metabolism. These findings provide insights into the potential mechanisms by which plant-based dietary polyphenols can influence gene expression and metabolic improvements and may have implications for developing new dietary supplements and personalized weight-loss interventions in the future.

Even though the so-called Mediterranean Diet (MED), which is rich in polyphenols that are present for instance in berries, nuts, and olives, has beneficial effects on the metabolism, a potential underlying epigenetic regulatory capacity of polyphenols and other secondary plant components is commonly discussed for years and evidence from human randomized controlled trials is still lacking. Therefore, researchers from the Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) at Helmholtz Munich, the Medical Faculty at the University of Leipzig and the Ben-Gurion University of the Negev in Israel joined forces to investigate molecular mechanisms underlying the beneficial metabolic effects of a green-Mediterranean Diet (green MED).

The scientists aimed to understand epigenetic changes caused by this diet, because the study of gene activity and expression which are not accompanied by alterations of the underlying DNA sequence explores, how external factors, such as diet, stress, and environmental exposures, can modify gene expression patterns. Epigenetic modifications, such as DNA methylation and histone modifications, can influence gene function and have long-term effects on an individual's health and development. Understanding epigenetics has implications for fields such as medicine, genetics, and environmental science, as it provides insights into the complex interplay between genes and the environment.

The team has shown in previous studies that the green MED has various salutary effects ranging from reshaping the microbiome to halting brain atrophy, regressing hepatosteatosis and visceral adiposity and promoting dramatic proximal aortic de-stiffening.  In their new study, the researchers further successfully demonstrated that epigenetic key drivers such as folate mediate the polyphenol-enriched green-MED diet's prominent capacity to regulate the individual’s epigenome. These results are in line with the strong metabolic improvements as characterized by e.g. weight-loss and deep-subcutaneous adipose tissue reduction (MRI based).

For the first time in a human RCT, their work indicates direct effects of dietary polyphenols on methylome and transcriptome levels of genes encoding for enzymes of the one-carbon metabolism, which is a series of biochemical reactions involving the transfer of one-carbon units that are essential for DNA synthesis, amino acid metabolism, and the production of important molecules in the body.

“This study may also play a fundamental role in the development of new dietary supplements based on the identified polyphenols which were associated with transcriptional changes and therefore potentially mediating phenotypical improvements.”, highlights Maria Keller.

Iris Shai adds: “Considering the translational aspects of this study for the clinical work, these findings will be of inspiration for a broad community of scientists and physicians working in the field of metabolic disorders and will promote further efforts towards better understanding of the individual response to weight-loss interventions in obesity treatment.”


Original publication

Hoffmann et al. (2023): A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Metabolism. DOI:10.1016/j.metabol.2023.155594

About the scientists

Dr. Maria Keller Postdoctoral Researcher at the Helmholtz-Institute for Metabolic, Obesity and Vascular Research (HI-MAG) at Helmholtz Munich, the University of Leipzig and the University of Leipzig Medical Center

Prof. Dr. Iris Shai, professor of nutrition and epidemiology at Ben Gurion University in Beer-Sheva, Israel, and of nutrition at the Harvard T.H. Chan School of Public Health, Harvard University's public health school and an honorary professor at the University of Leipzig



More Information

About the Dietary Intervention Randomized Controlled Trial - DIRECT PLUS

The DIRECT-PLUS trial research team, led by Prof Iris Shai, was the first to introduce the concept of the green MED, a high in polyphenols diet. This modified MED is distinct from the traditional MED because of its more abundant dietary polyphenols (phytochemicals, secondary metabolites of plant compounds that offer various health benefits) and lower red or processed meat. On top of a daily intake of walnuts, participants under the green MED consumed three to four cups of green tea and one cup of Wolffia-globosa (Mankai) plant green shake of duckweed per day over 18 months. The aquatic green plant Mankai is high in bioavailable iron, B12, 200 kinds of polyphenols and protein, and is, therefore, a good substitute for meat.


Funding information

This study was supported by funding from the German Research Foundation SFB1052 "Mechanisms of Obesity" and by funding from the Free State of Saxony and Helmholtz Munich.

MA-Foto Maria Keller_IMG_E0369_ohne Hintergrund

Dr. Maria Keller