The green Mediterranean diet remodels DNA methylation, stimulates metabolism

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

\"Study:Study: A green Mediterranean diet rich in polyphenols improves epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Image Credit: Antonina Vlasova / Shutterstock


Chronic low-grade inflammation is considered to be a major feature 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 the risks of morbidity and mortality related to metabolic diseases.

It is known that plant polyphenols with high antioxidant properties have beneficial effects on the metabolism. Mechanistically, polyphenols inhibit key epigenetic regulators, such as DNA methyltransferase (DNMT) or methylenetetrahydrofolate reductase (MTHFR), to modulate one-carbon metabolism and methylation processes. Furthermore, folic acid and B vitamins as methyl donors play crucial roles in the regulation of DNA and histone methylases.

The Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT PLUS) was conducted over 18 months to evaluate the metabolic impact of Healthy Dietary Guidelines (HDG), Mediterranean Diet (MED), and a modified MED diet enriched with polyphenols (green-MED ).

The results of this randomized controlled trial revealed that both MED diets have a moderate impact on weight loss and a strong impact on liver fat reduction. In particular, green-MED, which contains high amounts of nuts and Mankai (duckweed or water meal), was found to cause the greatest reduction in waist circumference, serum cholesterol level and lipoprotein a low density, diastolic blood pressure, C-reactive protein and visceral adipose tissue. Both walnut and Mankai are rich sources of folate and B vitamins.

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

Study design

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

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

Important remarks

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

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

The high amounts of nuts, green tea, and mankai in the green-MED diet showed a direct association with 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 folic acid and vitamin B-12 levels.

In addition to having a substantial effect on carbon precursors associated with de novo methylation processes, a green-MED diet rich in polyphenols has shown 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 consuming a green-MED diet. Three major modules containing the majority of differentially methylated region genes have been 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 change in body weight.

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 surface-subcutaneous adipose tissue area, body weight, and waist circumference. KIR3DS1 is an immunoglobulin-like receptor of killer cells associated with autoimmune diseases.

This module also included the differentially methylated region gene Cystathionine beta-synthase, an enzyme responsible for reducing homocysteine ​​levels. Expression of mRNA of this gene has been associated with changes in polyphenols.

Meaning of the study

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, the polyphenols present in the diet have a high potency in regulating the metabolism of a carbon with consequences in the autoimmune responses.


Hoffmann A. 2023. A green Mediterranean diet rich in polyphenols improves epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Metabolism.

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