The Mediterranean diet is an eating pattern emphasizing plant-based foods, healthy unsaturated fats, lean proteins, and whole grains, while limiting red meat, added sugars, and processed foods.
Research highlights that the Mediterranean diet and its variants have been associated with a wide range of health benefits, including improvements in cardiometabolic health.
The Green Mediterranean (Green-MED) diet is a modified version that places even greater emphasis on plant-based foods, particularly those rich in polyphenols and plant-based protein.
Now, the results of an international clinical intervention study suggest that the dietary plan could influence gene function and may help compensate for certain inherited genetic alterations in folate metabolism.
The findings, published in Clinical Nutrition, show that the Green-MED diet increased folate levels, a B vitamin involved in DNA regulation and cellular health. Additionally, it was also linked to improvements in several markers of cardiometabolic health.
The findings are based on data from the DIRECT-PLUS randomized controlled trial, which investigated whether a more plant-focused, polyphenol-rich version of the Mediterranean diet could improve metabolic health and body-fat distribution better than standard healthy dietary plans.
The investigators found that people following the Green-MED diet had significantly higher blood folate levels than those in comparative groups following either a traditional Mediterranean diet or standard healthy dietary recommendations.
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Notably, higher folate concentrations were associated with improvements in several health measures, including:
Folate plays a central role in a vital biochemical network known as one-carbon metabolism. This describes a series of biochemical reactions that help cells build and repair DNA and provide the methyl groups used to regulate gene activity without altering the underlying genetic code.
“When this pathway functions efficiently, it supports cardiovascular and metabolic health. In contrast, impaired folate metabolism has been associated with elevated homocysteine, endothelial dysfunction, inflammation, and increased cardiometabolic risk,” Şebnem Ünlüişler, MSc, Genetic Engineer at London Regenerative Institute, explained to Medical News Today.
“This study reinforces that overall dietary patterns matter more than individual nutrients,” she said. “Rather than focusing only on folate supplementation, the findings suggest that a green Mediterranean diet can improve folate status and support key metabolic pathways by combining nutrient-rich foods with bioactive plant compounds.”
“For both clinicians and the general public, this is another reminder that dietary quality can have measurable biological effects beyond basic nutrition.”
— Şebnem Ünlüişler, MSc
In the study, the researchers were particularly interested in a common genetic variant in the MTHFR gene, rs1801133, which affects roughly 10-15% of individuals worldwide.
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People who inherit two copies of the higher-risk version of this variant, referred to as the TT genotype or C677T variation, often have reduced activity of an enzyme necessary for efficient folate metabolism. Evidence suggests that the MTHFR enzyme works at about 30% of its normal capacity in those with the TT genotype.
This can increase a person’s risk for cardiovascular and metabolic conditions, such as hypertension, heart attack, and metabolic dysfunction-associated steatotic liver disease (MASLD).
Additionally, this genotype can lead to elevated homocysteine levels, which are linked to a higher risk of several age-related health issues, such as Alzheimer’s disease and osteoporosis.
In the study, participants consumed a daily shake containing the aquatic plant mankai (Wolffia globosa), also known as duckweed. Mankai contains protein, fiber, minerals, essential amino acids, and naturally occurring folate.
Those carrying the TT genotype who consumed little mankai experienced an increase in cardiovascular risk scores over time. In contrast, those who closely followed the mankai-enriched Green-MED diet showed a substantial reduction in cardiovascular risk scores.
While the study was not designed to isolate the effects of mankai alone, the findings suggest that the plant may be an important contributor to the benefits seen with the Green-MED dietary pattern. According to the researchers, these findings suggest that dietary choices may partially offset some inherited metabolic risk.
“An easy way to think of the Green Mediterranean diet is the traditional Mediterranean diet with even more plants, specifically green tea, walnuts and a daily mankai shake,” said Michelle Routhenstein, MS, RD, CDCES, CDN, preventive cardiology dietitian.
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“This study added mankai, a type of duckweed, which has a mild flavor and can easily be added to smoothies, soups, or dips,” she told MNT.
“If it’s not available, don’t worry, the overall dietary pattern matters most. Focus on adding more folate-rich foods like spinach, kale, lentils, chickpeas, beans, and edamame to provide these beneficial nutrients. The goal is consistency, variety, and sustainability, not one specific food,” she added.
A notable finding from the study came from analyses of gene expression.
Researchers examined messenger RNA (mRNA) in blood samples and found that participants with the TT genotype showed increased activity in alternative folate-processing pathways after consuming higher amounts of plant-derived nutrients.
Specifically, genes involved in folate metabolism, including MTHFD2 and DHFR, became more active. The researchers believe these changes may help compensate for the reduced function of the MTHFR enzyme in those with the TT genotype.
The research team described folate as acting like an ‘epigenetic pencil’. They suggest that folate may influence cellular pathways through methylation processes that affect gene activity without altering DNA itself.
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Michelle Routhenstein, MS, RD, CDCES, CDN, a preventive cardiology dietitian and owner of Entirely Nourished, spoke to Medical News Today about the significance of this finding from a precision nutrition perspective.
“This study reinforces an important principle that I use in my private practice of targeted science-based nutrition. While our genes may influence our health, they are not set in stone and we can adapt our diet to help support our genetic makeup,” she said.
“MTHFR variants are common and it means that your body may process B vitamins less efficiently. This research suggests that a folate-rich Green Mediterranean diet may actually help improve folate status despite those genetic differences,” she explained.
“It is important to recognize that a well planned, nutrient-rich dietary pattern, rather than replying solely on supplements, can be an effective way to support methylation pathways, important for long-term cardiometabolic health.”
— Michelle Routhenstein, MS, RD, CDCES, CDN
Meanwhile, Ünlüişler noted that from a precision nutrition standpoint, these findings are exciting because they suggest that tailored diets could help offset the effects of lower MTHFR gene activity.
“MTHFR variants, particularly C677T, are common across many populations and can reduce the conversion of folate to its biologically active form, thus affecting methylation capacity and homocysteine metabolism. Although these genetic variants are often viewed as fixed risk factors, this study shows that their functional impact may be modifiable using targeted dietary patterns,” she explained.
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“It reinforces an important principle of precision nutrition: our genes influence our nutritional needs, but they do not necessarily determine our health outcomes. Personalised dietary strategies may therefore provide meaningful benefits even for individuals with reduced MTHFR function, supporting a more practical and evidence-based approach to nutrition.”
— Şebnem Ünlüişler, MSc
Although the results are promising, the study cannot prove that folate or mankai alone caused the observed improvements.
The intervention involved multiple dietary changes occurring simultaneously. Therefore, it is difficult to determine which specific components were responsible for the effects. Additionally, gene-expression changes were measured in blood samples and may not necessarily reflect what occurs in other tissues throughout the body.
Further research will be necessary to confirm the findings and determine whether similar benefits can be achieved across broader, more diverse populations.
However, the study still adds to growing evidence that nutrition may influence health not only through traditional metabolic pathways but also by affecting the biological mechanisms that regulate gene activity.
While more research is needed, the findings support the emerging field of precision nutrition, which aims to tailor dietary recommendations to an individual’s biological and genetic profile.
