A recent study published in the journal Metabolism has revealed the impact of a polyphenol-rich Mediterranean diet on the regulation of epigenetics.
Background: Chronic low-grade inflammation is recognized as a significant characteristic of various metabolic disorders, including obesity. Therefore, lifestyle interventions like adopting a healthy diet and engaging in physical activity are crucial for managing body weight and reducing the risks associated with metabolic diseases.
Plant-based polyphenols, which possess strong antioxidant properties, are known to have positive effects on metabolism. On a mechanistic level, polyphenols inhibit key regulators of epigenetics, such as DNA-methyltransferases (DNMTs) and methylenetetrahydrofolate reductase (MTHFR), thereby influencing one-carbon metabolism and methylation processes. Additionally, methyl donors like folic acid and B vitamins play essential roles in the regulation of DNA and histone methylases.
The Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT PLUS) was conducted over a period of 18 months to assess the metabolic effects of different dietary approaches: healthy dietary guidelines (HDG), the Mediterranean (MED) diet, and a modified MED diet enriched with polyphenols known as the green-MED diet.
The results of this randomized controlled trial have shown that both MED diets have a moderate impact on weight loss and a significant impact on reducing hepatic fat. Specifically, the green-MED diet, which includes high quantities of walnuts and Mankai (duckweed or watermeal), has demonstrated the most pronounced reductions in waist circumference, serum levels of low-density lipoprotein-cholesterol, diastolic blood pressure, C-reactive protein, and visceral adipose tissue. Both walnuts and Mankai are abundant sources of folate and B vitamins.
In the present study, researchers aimed to investigate whether the metabolic improvements observed with the green-MED diet in the trial were associated with changes in genome-wide DNA methylation patterns and mRNA expression.
The study was conducted on a sample of 260 participants (average age: 51 years; body mass index: 31 Kg/m2) enrolled in the DIRECT PLUS trial. The participants were randomly assigned to one of three intervention groups: HDG, MED diet, and green-MED diet. The MED diet included an additional 440 mg of polyphenols from walnuts, while the green-MED diet included an additional 1240 mg of polyphenols from walnuts, green tea, and Mankai.
Blood samples were collected from the participants at the beginning of the study and after the 18-month intervention period. These samples were then analyzed to investigate the genome-wide DNA methylation patterns and mRNA expression changes associated with the different dietary interventions.
Significant findings
The analysis of genome-wide DNA methylation patterns revealed noteworthy observations. In the green-MED group, 1,573 regions showed differential methylation before and after the dietary interventions, while the HDG group had 377 regions and the MED group had 174 regions. Additionally, gene expression analysis identified 1,753 differentially expressed genes in the green-MED group, 738 in the HDG group, and only 7 in the MED group, indicating substantial changes in gene expression associated with the green-MED diet.
The consumption of a polyphenol-rich green-MED diet for 18 months resulted in significantly higher serum levels of folic acid and vitamin B-12 compared to other dietary interventions. Participants in the MED group exhibited lower levels of epigenetic changes at baseline, which may be attributed to the increased levels of folic acid and vitamin B-12 observed after the dietary intervention.
The presence of abundant quantities of walnuts, green tea, and Mankai in the green-MED diet demonstrated a direct correlation with elevated levels of one-carbon precursors (folic acid and vitamin B-12) in participants following this specific diet. These findings suggest that changes in DNA methylation patterns associated with the green-MED diet are linked to increased serum levels of folic acid and vitamin B-12.
Moreover, the polyphenol-rich green-MED diet exhibited a direct impact on the methylation and transcription of genes encoding key epigenetic regulators, such as lysine demethylase 2B, lysine demethylase 5B, and histone lysine methyltransferase. This highlights the potential role of the green-MED diet in modulating epigenetic processes related to gene regulation.
Weighted Cluster Network Analysis
To investigate the underlying drivers of phenotypic changes linked to the consumption of the green-MED diet, a Weighted Cluster Network analysis was conducted. This analysis revealed the presence of three main modules that contained the majority of differentially methylated region genes.
Among these modules, one module showed a significant association with C-reactive protein, folic acid, interleukin 6 (IL-6), and changes in deep-subcutaneous adipose tissue area. Another module was associated with waist circumference, while a third module was associated with both waist circumference and body weight changes.
Within the first module, the mRNA expression of the KIR3DS1 gene exhibited a negative correlation with changes in polyphenols but a positive correlation 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.
Additionally, this module included the differentially methylated region gene Cystathionine Beta-Synthase, an enzyme responsible for reducing homocysteine levels. The mRNA expression of this gene was found to be associated with changes in polyphenols.
Significance of the Study
This study underscores the significance of a polyphenol-rich Mediterranean (MED) diet in the regulation of DNA methylation patterns, primarily through the elevation of essential epigenetic drivers like folic acid and vitamin B-12. Additionally, the potent polyphenols found in this diet play a crucial role in modulating one-carbon metabolism, which has implications for autoimmune responses.
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