Quick summary: An international clinical trial reveals that a green Mediterranean diet enriched with Mankai and walnuts significantly boosts folate levels and triggers an adaptive reprogramming of alternative genes to compensate for inherited cardiovascular risks. Researchers found that this dietary intervention improves insulin sensitivity and reduces inflammatory markers alongside visceral and liver fat by stimulating critical biochemical pathways that regulate DNA maintenance. For public healthcare practice and public policy, these Nutri- Omics findings demonstrate the viability of precision nutrition as a targeted preventive strategy towards mitigating chronic cardiometabolic diseases and supporting healthy ageing.
A new international clinical study has shown how a specific plant-rich diet can influence gene expression and improve cardiometabolic health by increasing levels of folate, a key nutrient involved in essential cellular processes.
Published in Clinical Nutrition, the research identifies the molecular and transcriptomic mechanisms through which a dietary intervention may beneficially affect gene expression. Led by Iris Shai and Hila Zelicha Peer of Ben-Gurion University of the Negev, in collaboration with researchers from Leipzig University, the Leipzig Center of Metabolism (LieCeM), and Harvard University, the study suggests that certain plant-derived nutrients may act as an epigenetic pencil, helping to shape cellular health through nutrition.
Researchers found that adherence to the Green Mediterranean (Green-MED) diet resulted in a marked increase in circulating folate levels compared with both a traditional Mediterranean diet and standard healthy dietary guidelines. The rise appeared to stimulate one-carbon metabolism, a critical biochemical pathway involved in methylation processes that regulate gene expression, support DNA maintenance, and contribute to metabolic health.
Participants following the Green-MED diet, a polyphenol-rich eating pattern that includes green tea, walnuts, and a daily shake containing the aquatic plant Mankai (Wolffia globosa), while reducing red and processed meat consumption, experienced significantly higher serum folate concentrations. Laboratory analyses showed that these higher folate levels were strongly associated with improved insulin sensitivity, measured by HOMA-IR, lower levels of inflammatory markers such as IL-6, improvements in the triglyceride-to-HDL cholesterol ratio, and reductions in both visceral and liver fat.
The findings advance the emerging field of Nutri-Omics, demonstrating how precision nutrition may help offset inherited genetic predispositions. Researchers focused on a common variant of the MTHFR gene (rs1801133), which reduces the activity of a key enzyme involved in folate metabolism. Individuals carrying the high-risk TT genotype typically have lower folate levels throughout life.
The study found that TT carriers with low Mankai consumption experienced an increase in cardiovascular risk, as measured by the Framingham Risk Score. By contrast, TT carriers with high adherence to the Mankai-enriched Green-MED diet demonstrated a 7.74-point reduction in cardiovascular risk score, highlighting the potential interaction between dietary habits and inherited metabolic susceptibility.
One of the study’s most striking discoveries emerged from transcriptomic analysis. In response to increased intake of plant-derived nutrients, cells from TT carriers appeared to undergo adaptive biological reprogramming. Blood mRNA analysis revealed significant enrichment and increased expression of alternative folate-pathway genes, including MTHFD2 and DHFR, which compensated for reduced inherited enzyme activity and enabled more efficient utilisation of dietary folate.
The results provide a mechanistic explanation for several previously reported clinical outcomes from the DIRECT-PLUS trial, one of the world’s most comprehensive, rigorously controlled nutrition and imaging studies. Earlier research from the trial demonstrated regression of carotid atherosclerosis, reductions in aortic stiffness, improvements in glycaemic control, decreases in visceral adiposity and liver fat, and favourable effects on biomarkers associated with brain ageing. Collectively, the evidence suggests that targeted nutritional interventions may influence biological pathways linked to cardiometabolic health and healthy ageing.
At the centre of this metabolic transformation is Mankai, a nutrient-dense aquatic plant containing more than 45% protein, essential amino acids, fibre, minerals, and naturally occurring folate. The plant is particularly rich in bioavailable folate and provides a substantial proportion of the recommended daily intake. Participants with the highest Mankai consumption exhibited the strongest folate response and the most pronounced transcriptomic and clinical changes, suggesting it may play a central role in driving the biological effects observed during the intervention.
A key contribution to the study came from researchers at Leipzig University and the LieCeM, where Maria Keller and Peter Kovacs co-directed the nutrigenomic and transcriptomic investigations. Their work enabled the team to identify genotype-specific responses to the Green-MED diet and characterise the folate-dependent mechanisms underlying its health benefits.
Professor Shai said: “Our findings show that a diet rich in green plant-based foods may influence folate-related metabolic pathways associated with cardiometabolic health. The relationship we observed between folate levels, visceral fat reduction, and genetic responsiveness strengthens the scientific basis for personalised nutrition and advances the field of Nutri-Omics. These results suggest that folate may be considered not only a marker of deficiency, but also a biomarker reflecting dietary quality, cellular metabolic status, and the body’s capacity to activate protective metabolic and epigenetic mechanisms.”
Dr Zelicha Peer said: “Until now, folate has primarily been viewed through the lens of nutritional deficiency. Our findings suggest a broader role as a metabolic biomarker that reflects both the quality of plant-based nutrition and the body’s response to dietary intervention. The transcriptomic discoveries demonstrate that highly bioavailable plant-derived foods such as Mankai may directly influence cellular adaptability, help compensate for inherited metabolic challenges, and support long-term health.”
The international research team also included Dr Anat Yaskolka Meir, Dr Ehud Rinott, Dr Gal Tsaban, and Dr Alon Kaplan of Ben-Gurion University of the Negev; Dr Anne Hoffmann, Professor Matthias Blüher, Professor Uta Ceglarek, Professor Berend Isermann, and Professor Michael Stumvoll of Leipzig University and the Helmholtz Institute in Germany; Professor Ilan Shelef of Soroka University Medical Center; and Professor Frank Hu and Professor Meir Stampfer of Harvard University.
The research was supported by grants from the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (EXC-3105/1–533765739), the Israel Ministry of Health (grant 87472511), the Israel Ministry of Science and Technology (grant 3-13604), and the California Walnut Commission.