Green Mediterranean diet reshapes DNA methylation, boosts metabolism

A study published in the journal Metabolism describes the effect of a polyphenol-rich Mediterranean diet on epigenetic regulation.

Study: A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Image Credit: Antonina Vlasova / Shutterstock


Chronic low-grade inflammation is considered a major hallmark of various metabolic diseases, including obesity. Therefore, lifestyle interventions, such as a healthy diet and physical activity, are vital in managing body weight and reducing morbidity and mortality risks related to metabolic diseases.

Plant-based polyphenols with high antioxidant properties are known to have beneficial effects on metabolism. Mechanistically, polyphenols inhibit key epigenetic regulators, such as DNA-methyltransferases (DNMTs) or methylenetetrahydrofolate reductase (MTHFR), to modulate one-carbon metabolism and methylation processes. Moreover, folic acid and B vitamins as methyl donors play crucial roles in regulating DNA and histone methylases.

The Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT PLUS) has been conducted for 18 months to evaluate the metabolic impact of healthy dietary guidelines (HDG), the Mediterranean (MED) diet, and a modified MED diet enriched with polyphenols (green-MED).

The findings of this randomized controlled trial have revealed that both MED diets have a moderate impact on weight loss and a strong impact on hepatic fat reduction. Specifically, the green-MED, which contains high amounts of walnuts and Mankai (duckweed or watermeal), has been found to cause the highest reduction in waist circumference, low-density lipoprotein-cholesterol serum level, diastolic blood pressure, C- reactive protein, and visceral adipose tissue. Both walnut and Mankai are rich sources of folate and B vitamins.

In the current study, scientists have explored whether green-MED diet-mediated metabolic improvements observed in the trial are associated with its impact on genome-wide DNA methylation and mRNA expression patterns.

Study design

The study population included 260 participants (average age: 51 years; body mass index: 31 Kg/m2) from the DIRECT PLUS trial. They were randomly categorized into three intervention groups, including the HDG, MED diet, and green-MED diet groups. While the MED diet included 440 mg of polyphenols additionally provided by walnuts, the green-MED diet included 1240 mg of polyphenols additionally provided by walnuts, green tea, and Mankai.

Blood samples collected from the participants were analyzed for genome-wide DNA methylation and mRNA expression patterns at baseline and after the completion of the 18-month intervention period.  

Important observations

The analysis of genome-wide DNA methylation patterns before and after the dietary interventions identified 1,573 differentially methylated regions in the green-MED group, 377 in the HDG group, and 174 in the MED group. These findings corresponded to 1753 differentially expressed genes in the green-MED group, 738 in the HDG group, and only 7 in the MED group.

The consumption of a polyphenol-rich green-MED diet for 18 months resulted in significantly higher levels of folic acid and vitamin B-12 in the serum compared to other dietary interventions. The increased levels of folic acid and vitamin B-12 observed in the MED group participants at baseline could be attributed to lower levels of epigenetic changes observed in this group after the dietary intervention.  

The high amounts of walnuts, green tea, and Mankai in the green-MED diet showed a direct association with the increased levels of one-carbon precursors (folic acid and vitamin B-12) in participants consuming this particular diet. These observations collectively indicate that green-MED diet-mediated changes in DNA methylation patterns are associated with increased serum levels of folic acid and vitamin B-12.

In addition to having a substantial effect on one-carbon precursors associated with de novo methylation processes, a polyphenol-rich green-MED diet showed a direct effect on the methylation and transcription of genes encoding epigenetic modulators, including lysine demethylase 2B, lysine demethylase 5B, and histone lysine methyltransferase.

Weighted Cluster Network Analysis

The study conducted a Weighted Cluster Network analysis to identify key drivers of phenotypic changes associated with green-MED diet consumption. Three main modules containing most of the differentially methylated region genes were identified. Of these modules, one was significantly associated with C-reactive protein, folic acid, interleukin 6 (IL-6), and change in deep-subcutaneous adipose tissue area; one was associated with waist circumference; and one was associated with waist circumference and body weight change.

In the first module, the mRNA expression of the KIR3DS1 gene showed a negative association with changes in polyphenols but a positive association with changes in superficial-subcutaneous adipose tissue area, body weight, and waist circumference. KIR3DS1 is a killer cell immunoglobulin-like receptor associated with autoimmune diseases.   

This module also included the differentially methylated region gene Cystathionine Beta-Synthase, an enzyme responsible for reducing homocysteine levels. The mRNA expression of this gene was associated with changes in polyphenols.       

Study significance

The study highlights that a polyphenol-rich MED diet can significantly regulate DNA methylation patterns by increasing key epigenetic drivers such as folic acid and vitamin B-12. Furthermore, polyphenols present in the diet have high potency in regulating one-carbon metabolism with consequences in autoimmune responses.


Hoffmann A. 2023. A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Metabolism.

Posted in: Men's Health News | Medical Research News | Women's Health News

Tags: Adipose, Antioxidant, Blood, Blood Pressure, Body Mass Index, Cell, Cholesterol, Chronic, C-Reactive Protein, Diet, DNA, DNA Methylation, Enzyme, Folic Acid, Gene, Genes, Genome, Green Tea, Homocysteine, Immunoglobulin, Inflammation, Interleukin, Lipoprotein, Lysine, Metabolism, Mortality, Obesity, Physical Activity, Polyphenol, Protein, Receptor, Tea, Transcription, Vitamin B, Vitamins, Walnut, Weight Loss

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Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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