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Same Food, Different Outcome: How Biology Shapes the Effects of Food on Health (Oral Session 3)

(OR03-07-25) Effect of Green Mediterranean Diet on Serum Folate and Its Interaction With Genetic Variance in Folate Metabolism: The DIRECT PLUS 18-Month Dietary RCT

Saturday, May 31, 2025
11:12 AM – 11:24 AM ET
Location: S220 B-D
Emerging Leaders in Nutrition Science Poster Competition Nutrition Translation Award Competition for Early Career Investigators

    Presenting Author(s)

  • Hila Zelicha, RD PHD

    Post-Doctoral Fellow
    University of California, Los Angeles
    Los Angeles, California, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • MK

    Maria Keller

    University of Leipzig Medical Center, Germany

  • PK

    Peter Kovacs, Prof.

    University of Leipzig Medical Center, Germany

  • IS

    Iris Shai, PhD

    Ben-Gurion University of the Negev
    Negev, Tel Aviv, Israel

Objectives: We explored the effect of a green Mediterranean diet on serum folate levels and associations with cardiometabolic risk parameters over an 18-month intervention. We further investigated the interaction of genetic modification involved in folate metabolism with diet and serum folate.

Methods: In the 18-month DIRECT-PLUS trial, 294 participants were randomized to: basic healthy dietary guidelines (HDG), MED, or green-MED diets. Both isocaloric MED groups consumed walnuts (28g/day); the green-MED group also consumed green tea (3-4cups/day), Wolffia globose Mankai green-shake (500ml/day), and avoided red/processed meat. For 234 participants we genotyped rs1801133 single nucleotide polymorphism, a significant genetic variant for folate serum levels, and evaluated its effect on serum folate and mRNA level of the candidate genes encoding for key enzymes in folate metabolism.

Results: After 18 months of intervention, the green-MED diet significantly increased serum folate levels, as compared to the HDG and MED diet (p < 0.05, Multivariate models). Greater intake of Mankai plant played a significant marker for higher serum folate levels (p=0.003). An 18-month increase in serum folate was associated with improved HOMA-IR (β=-0.326; p< 0.001), reduced TG/HDLc ratio (β=-0.188; p=0.017), and decreased IL-6 levels (β=-0.151; p=0.024; multivariate models). Carriers of the rs1801133 TT genotype showed significantly lower serum folate levels at baseline (p=0.037) and after the intervention (p=0.045, dominant mode of inheritance). Carriers of the CC/CT genotype showed the highest increase in folate levels following the green-MED intervention (p=0.03). We further demonstrated that the TT-genotype carriers showed a reduced MTHFD2 mRNA levels at baseline (p=0.005), but an enriched transcription compared to CC/CT carriers after the intervention (p=0.001).

Conclusions: Serum folate could serve as a dietary biomarker for green plants intake as Mankai and its diet-induced elevation is associated with beneficial changes in cardiometabolic profile. rs1801133 genotype affects baseline folate levels and could be compensated by enriched dietary intake, likely by increasing MTHFD2 activity.

Funding Sources: DFG;Israel Ministry of Health;Israel Ministry of Science and Technology;California Walnuts Commission