A Green Mediterranean Diet, Genetics, and Folate: What an 18-Month Trial Found

Folate does a lot of essential work in the body: building DNA, recycling homocysteine, supporting a developing fetus's neural tube. Most nutrition advice treats folate needs as one-size-fits-all. A new 18-month trial suggests that's not quite right. How well your body responds to a folate-rich diet may depend on a gene you were born with.

Photo: Colin Watts / Unsplash

What the research found

The DIRECT PLUS trial randomized 294 people, mostly men in their 50s with abdominal obesity, into three groups for 18 months: standard healthy-eating guidelines, a Mediterranean diet with daily walnuts, or a "green Mediterranean" version that added a daily green tea and Mankai shake (Mankai is a protein-rich aquatic plant, also called duckweed) while cutting back on red and processed meat [1]. Retention was strong: 89% of participants completed the full 18 months.

By the end, the green-Mediterranean group's blood folate rose by 1.2 ng/mL, compared with 0.41 ng/mL in the standard Mediterranean group and just 0.1 ng/mL in the healthy-guidelines group [1]. The more Mankai someone ate, the bigger the folate increase.

Then the researchers looked at genetics. About 12% of participants carried two copies of a common MTHFR gene variant (called TT, or C677T) that slows folate processing. These TT carriers started with lower folate and ended the trial with somewhat less benefit from the green-Mediterranean diet than people with the more common CC or CT versions of the gene [1]. That's not the whole story, though. TT carriers also showed increased activity in a backup folate-processing gene after the intervention, which suggests the diet may still be doing something useful for them, just through a different route.

The bigger picture

This is one study in a series from the same Israeli research team, and the earlier DIRECT PLUS papers give useful context. The identical green-Mediterranean diet, tracked in the same trial population, has separately been linked to reduced visceral fat [2], slower age-related brain shrinkage [3], and shifts in gut microbiome composition that appeared to help drive those metabolic benefits [4]. Folate looks like one thread in a more complex diet-gene-microbiome story, not an isolated finding.

One caveat belongs next to the excitement here: raising folate levels doesn't automatically translate into better cardiovascular outcomes. A large 2011 meta-analysis of homocysteine-lowering trials found no reduction in stroke risk in countries where food is already fortified with folic acid, which includes the United States [5]. So the real story in this trial is about visceral fat and metabolic risk markers responding to a specific dietary pattern, not about folate as a stand-alone number to chase.

It's also worth being honest about who this trial studied: participants were mostly middle-aged men with abdominal obesity in Israel. Whether the same gene-diet interaction holds for women, younger adults, or other populations isn't yet established.

The naturopathic lens

This is exactly the kind of research that supports nutrigenomics-informed, food-first care instead of one-size-fits-all supplementation advice. MTHFR variants come up constantly in my practice, and patients often arrive having read that a TT genotype means they need high-dose folic acid or specific methylated B vitamins. This trial adds a more nuanced data point: for this particular outcome, TT carriers got less mileage from the same food-based intervention than CC/CT carriers, even though their bodies appeared to compensate through an alternate pathway.

That's the whole-person view in practice. Your genes set the terrain, but food, gut health, and lifestyle are what move the needle within that terrain. A folate-rich, plant-forward, polyphenol-heavy eating pattern, built around vegetables, legumes, walnuts, and green tea, is a reasonable foundation for most patients regardless of MTHFR status. Genetic testing can help fine-tune the details from there, rather than replace the foundation.

What this means in practice

Mankai shakes aren't exactly available at the corner grocery store, so don't feel like you're missing the point if you skip that particular ingredient. What translates from this trial: leaning your plate toward vegetables and legumes, adding walnuts, swapping some red and processed meat for plant proteins, and including green tea if you enjoy it. If you know you carry an MTHFR variant, or you're curious whether you do, that's a good conversation to have with your provider, especially if you're planning a pregnancy or have a personal or family history of elevated homocysteine. Genetics can inform your plan. They don't have to run it.

References

1. Zelicha H, et al. Effect of green Mediterranean diet on serum folate and its interaction with genetic variation in folate metabolism: The DIRECT PLUS 18-month dietary randomized controlled trial. Clinical Nutrition. 2026.

2. Zelicha H, et al. The effect of high-polyphenol Mediterranean diet on visceral adiposity: the DIRECT PLUS randomized controlled trial. BMC Medicine. 2022.

3. Kaplan A, et al. The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the DIRECT PLUS trial. American Journal of Clinical Nutrition. 2022.

4. Rinott E, et al. The effects of the Green-Mediterranean diet on cardiometabolic health are linked to gut microbiome modifications: a randomized controlled trial. Genome Medicine. 2022.

5. Holmes MV, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet. 2011.

6. Original article: "Effect of Green Mediterranean Diet on Serum Folate and its Interaction with Genetic Variation in Folate Metabolism: The DIRECT PLUS 18-month Dietary Randomized Controlled Trial." Clinical Nutrition, 2026. https://www.clinicalnutritionjournal.com/article/S0261-5614(26)00128-7/fulltext

Disclaimer

This article is for general educational purposes only and is not a substitute for individualized medical advice, diagnosis, or treatment. Always talk with your own healthcare provider about any symptoms, medications, or changes to your care.

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The Mediterranean Diet Cookbook for Beginners: Meal Plans, Expert Guidance, and 100 Recipes to Get You Started — ~$11.69

Written by a registered dietitian, this is a straightforward entry point to the eating pattern the DIRECT PLUS researchers built their intervention around: vegetables, legumes, olive oil, and nuts at the center of the plate. The meal plans are useful if you want structure while you adjust what a normal week of eating looks like.

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If this resonates with what you're experiencing and you'd like to explore a naturopathic approach, book a consultation with our clinic.