Trial reportThe American journal of clinical nutrition2014
Folic acid handling by the human gut: implications for food fortification and supplementation.
Trial report in The American journal of clinical nutrition, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers, 4 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
68 citing papers in PubMed, 4 syntheses or guidelines pooled it, 136 citations in OpenAlex.
- Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review.Nutrients · 2026Pooled it
- Pooled it
- Pooled it
- Pooled it
- Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial.The American journal of clinical nutrition · 2025Trial
- Use of a Micronutrient Cocktail to Improve Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in Adults with Obesity: A Randomized, Double-Blinded Pilot Clinical Trial.Medicina (Kaunas, Lithuania) · 2024Trial
- Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid.Scientific reports · 2023Trial
- Trial
- Suitability and safety of L-5-methyltetrahydrofolate as a folate source in infant formula: A randomized-controlled trial.PloS one · 2019Trial
- Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial.European journal of nutrition · 2016Trial
- Developing an Environmentally Friendly Sequential Separation and Purification Process of Six Functional Components From Egg Yolk.Journal of food science · 2026Article
- Benefits of Lactic Acid Bacteria Folate Synthesis in Foods and Risks Associated with Deficiency - a Review.Probiotics and antimicrobial proteins · 2026Review
- Folate and global health: part 5. syntheses on neuropsychiatric disorders.Journal of global health · 2026Review
- Evaluation of Organically Versus Synthetically Derived Multivitamin and Mineral Supplementation on Circulatory Concentration in Healthy Humans: A Single-Blinded Randomized Intervention Study.Current developments in nutrition · 2026Article
- Association Between Folic Acid Use and Serum One-Carbon Metabolism-Related Metabolites in Maternal and Cord Blood of Japanese Pregnant Women.Metabolites · 2026Article
- Reference intervals for blood concentrations of folate-related biomarkers in early pregnancy among pregnant women in Qingdao.BMC pregnancy and childbirth · 2026Article
- Transgenerational Effects and Heritability of Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorder.International journal of molecular sciences · 2025Article
- 5-Formyltetrahydrofolate in a Cohort of Pregnant Women Following Folic Acid Supplementation.ACS omega · 2025Article
- Folate from probiotic bacteria and its therapeutic applications.Archives of microbiology · 2025Review
- Biological, dietetic and pharmacological properties of vitamin BNPJ science of food · 2025Review
8 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundCurrent thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.
objectiveWe tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.
designWe conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope-labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.
resultsFifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).
conclusionsThe human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.