Folate (vitamin B9)

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_access

Primary abstract

experimental_model

Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency.

limitations

This was not aspartame feeding, and does not show aspartame causes folate depletion.

nutrient_topic

Aspartame collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Aspartame

plain_language

Downstream handling depends on nutrient state and exposure route.

primary_references

Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Aspartame: digestion, taste, metabolite dependencies and experimental signaling (2026-09-20) · lines 154–160

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. · source_derived_draft · unverified_draft

## aspartame-folate-methanol-context Downstream handling depends on nutrient state and exposure route. Four cynomolgus monkeys had higher labeled blood formate after 900 ppm methanol inhalation when folate-deficient than before depletion, while tracer-derived concentrations remained below endogenous formate. Model: Two-hour lung-only labeled-methanol exposure; repeated after diet-induced folate deficiency. Limitations: This was not aspartame feeding, and does not show aspartame causes folate depletion. Evidence access: Primary abstract Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys. · 1994 · https://pubmed.ncbi.nlm.nih.gov/7940538/ · DOI 10.1006/taap.1994.1202

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Folate and B12 meet at methionine synthase; this experiment manipulated folate intake.

experimental_model

Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.

exposure

Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.

limitations

A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

A shortage made a connected methionine-recycling marker rise.

primary_references

[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1408–1419

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft

### fol-depletion-homocysteine Controlled depletion lowered plasma folate and significantly raised plasma homocysteine in eight postmenopausal women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A shortage made a connected methionine-recycling marker rise. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: A concentration is not direct enzyme flux; B12 status, kidney function and other inputs also affect this marker. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. cross_nutrient: Folate and B12 meet at methionine synthase; this experiment manipulated folate intake. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion.

exposure

Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet.

limitations

No specific oncogene activation, tumor formation or whole-body methylation failure was measured.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The methylation readout changed with folate intake in these blood cells.

primary_references

[fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

tissue_or_cell_type

Human lymphocytes

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1421–1431

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. · source_derived_draft · unverified_draft

### fol-depletion-lymphocyte-methylation Lymphocyte DNA hypomethylation developed during the depletion periods and reversed during folate repletion of 286–516 micrograms/day. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The methylation readout changed with folate intake in these blood cells. organism: Homo sapiens tissue_or_cell_type: Human lymphocytes experimental_model: Eight healthy postmenopausal women aged 49–63 in a metabolic unit, sequential depletion/repletion. limitations: No specific oncogene activation, tumor formation or whole-body methylation failure was measured. exposure: Five weeks 56 micrograms/day folate, four weeks 111, then three weeks 286–516 using folic acid added to a low-folate diet. [fol-jacob1998] Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women (1998). https://pubmed.ncbi.nlm.nih.gov/9649607/ DOI: 10.1093/jn/128.7.1204

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Thirty-three women aged 60–85 in depletion, thirty in four repletion groups.

exposure

Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations.

limitations

The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The assay found more available sites for adding methyl groups to the extracted DNA.

primary_references

[fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

tissue_or_cell_type

Human leukocyte DNA, ex-vivo assay

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1445–1455

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. · source_derived_draft · unverified_draft

### fol-elderly-dna-methyl-acceptance In vitro incorporation of labeled SAM methyl groups into extracted leukocyte DNA increased after depletion (P=0.0025), consistent with lower pre-existing methylation. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The assay found more available sites for adding methyl groups to the extracted DNA. organism: Homo sapiens tissue_or_cell_type: Human leukocyte DNA, ex-vivo assay experimental_model: Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. limitations: The assay interpretation is distinct from measuring intracellular SAM or methylation at specific genes. exposure: Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations. [fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Thirty-three women aged 60–85 in depletion, thirty in four repletion groups.

exposure

Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations.

limitations

Different age, intake and assay design from the eight-woman study; no claim of an unexplained scientific contradiction.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Returning folate did not quickly normalize this particular readout.

primary_references

[fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

tissue_or_cell_type

Human leukocyte DNA, ex-vivo assay

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1457–1467

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. · source_derived_draft · unverified_draft

### fol-elderly-methylation-repletion-null No repletion group showed a significant change from postdepletion methyl-acceptance values over seven weeks. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Returning folate did not quickly normalize this particular readout. organism: Homo sapiens tissue_or_cell_type: Human leukocyte DNA, ex-vivo assay experimental_model: Thirty-three women aged 60–85 in depletion, thirty in four repletion groups. limitations: Different age, intake and assay design from the eight-woman study; no claim of an unexplained scientific contradiction. exposure: Seven weeks 118 micrograms/day folate, followed by seven weeks 200 or 415 micrograms/day with different food/supplement combinations. [fol-rampersaud2000] Genomic DNA methylation decreases in response to moderate folate depletion in elderly women (2000). https://pubmed.ncbi.nlm.nih.gov/11010943/ DOI: 10.1093/ajcn/72.4.998

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately.

exposure

Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei.

limitations

Enriched selection by micronucleus frequency and older assay methodology limit extrapolation. The full repair-to-break sequence was a mechanistic interpretation.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Insufficient folate was associated with more of an inappropriate DNA base in the measured samples.

primary_references

[fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

tissue_or_cell_type

Human blood-cell DNA

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1469–1479

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. · source_derived_draft · unverified_draft

### fol-low-status-blood-dna-uracil Folate-deficient participants had roughly eightfold higher measured blood DNA uracil than controls in the 1997 study. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Insufficient folate was associated with more of an inappropriate DNA base in the measured samples. organism: Homo sapiens tissue_or_cell_type: Human blood-cell DNA experimental_model: Selected splenectomized human volunteers: 22 at baseline, 19 supplementation completers; additional blood/marrow samples and Crohn case analyzed separately. limitations: Enriched selection by micronucleus frequency and older assay methodology limit extrapolation. The full repair-to-break sequence was a mechanistic interpretation. exposure: Folic acid 5 mg/day for eight weeks; blood DNA uracil and erythrocyte/reticulocyte micronuclei. [fol-blount1997] Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage (1997). https://pubmed.ncbi.nlm.nih.gov/9096386/ DOI: 10.1073/pnas.94.7.3290

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.

exposure

Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.

limitations

One subject, calorie restriction and multiple co-supplements; cannot calculate a population time-to-anemia distribution.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The red-cell disorder appeared after the blood folate changes.

primary_references

[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1517–1527

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft

### fol-severe-macrocytic-anemia Macrocytic anemia was documented after 469 days of restriction in the self-experiment. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The red-cell disorder appeared after the blood folate changes. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: One subject, calorie restriction and multiple co-supplements; cannot calculate a population time-to-anemia distribution. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.

exposure

Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.

limitations

Assay-dependent observations in a highly supplemented, initially replete individual with severe weight loss; these timings are not typical-person predictions. The paper gives inconsistent day counts for the RBC laboratory-limit crossing; both locations are retained.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Different blood compartments showed the shortage at different times.

primary_references

[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

tissue_or_cell_type

Human blood or whole-person clinical endpoints

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1505–1515

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft

### fol-severe-marker-sequence In the single-subject study, serum folate became abnormally low by day 219; RBC folate abnormality was reported at day 413 in the abstract/discussion and day 420 in the Results. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Different blood compartments showed the shortage at different times. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person clinical endpoints experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: Assay-dependent observations in a highly supplemented, initially replete individual with severe weight loss; these timings are not typical-person predictions. The paper gives inconsistent day counts for the RBC laboratory-limit crossing; both locations are retained. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations.

exposure

Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery.

limitations

Major energy restriction and weight loss confound isolated nutrient attribution. Other nutrients were supplemented; neither liver folate content nor a unique recovery dose was directly established.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The shortage eventually coincided with abnormal marrow-cell maturation and reversible blood-count changes.

primary_references

[fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

tissue_or_cell_type

Human bone marrow and peripheral blood

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1529–1539

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. · source_derived_draft · unverified_draft

### fol-severe-marrow-megaloblastosis Marrow examination at day 575 confirmed megaloblastic anemia; blood counts recovered during the subsequent replete-diet/supplement phase. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shortage eventually coincided with abnormal marrow-cell maturation and reversible blood-count changes. organism: Homo sapiens tissue_or_cell_type: Human bone marrow and peripheral blood experimental_model: Single initially folate-replete 58-year-old male self-experiment with serial blood assays and marrow examinations. limitations: Major energy restriction and weight loss confound isolated nutrient attribution. Other nutrients were supplemented; neither liver folate content nor a unique recovery dose was directly established. exposure: Prolonged severe folate restriction, major energy restriction/weight loss, and multiple other nutrient supplements; replete diet plus folic acid during recovery. [fol-golding2014] Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops (2014). https://pubmed.ncbi.nlm.nih.gov/25332850/ DOI: 10.1186/2193-1801-3-442

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Folate and choline status are coupled.

experimental_model

Metabolic-unit depletion/repletion: 11 men, 10 women.

exposure

Men: 25 micrograms folate/238 mg choline daily; women: 56 micrograms/147 mg

limitations

No functional choline deficiency by measured transaminase/lipid endpoints.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

Folate restriction strained choline markers during low choline intake.

primary_references

[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

tissue_or_cell_type

Plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 693–704

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft

### folate-methyl-low-folate-choline Combined low-folate/low-choline feeding lowered plasma choline by 28% in men and 25% in women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Folate restriction strained choline markers during low choline intake. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: No functional choline deficiency by measured transaminase/lipid endpoints. exposure: Men: 25 micrograms folate/238 mg choline daily; women: 56 micrograms/147 mg cross_nutrient: Folate and choline status are coupled. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

Folate/choline restriction affects circulating phospholipid.

experimental_model

Metabolic-unit depletion/repletion: 11 men, 10 women.

limitations

Male cohort; concentration does not identify biosynthetic flux.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

A choline-containing lipid also declined.

primary_references

[jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

tissue_or_cell_type

Plasma

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 706–716

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolic-unit depletion/repletion: 11 men, 10 women. · source_derived_draft · unverified_draft

### folate-methyl-low-folate-pc Men on the combined low-folate/low-choline diet showed 26% lower plasma phosphatidylcholine. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A choline-containing lipid also declined. organism: Homo sapiens tissue_or_cell_type: Plasma experimental_model: Metabolic-unit depletion/repletion: 11 men, 10 women. limitations: Male cohort; concentration does not identify biosynthetic flux. cross_nutrient: Folate/choline restriction affects circulating phospholipid. [jacob-1999] Folate nutriture alters choline status of women and men fed low choline diets (1999). https://pubmed.ncbi.nlm.nih.gov/10082779/ DOI: 10.1093/jn/129.3.712

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Young MTHFR 677CC/TT women; controlled folate feeding.

limitations

Assay-specific trend, not demonstrated global hypomethylation.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

This result suggested but did not establish a methylation decrease.

primary_references

[shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003

tissue_or_cell_type

Blood-derived genomic DNA

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 789–798

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young MTHFR 677CC/TT women; controlled folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-young-dna-trend Seven weeks at 115 micrograms DFE/day produced a nonsignificant tendency toward increased DNA methyl acceptance (P=0.08). Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: This result suggested but did not establish a methylation decrease. organism: Homo sapiens tissue_or_cell_type: Blood-derived genomic DNA experimental_model: Young MTHFR 677CC/TT women; controlled folate feeding. limitations: Assay-specific trend, not demonstrated global hypomethylation. [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Young MTHFR 677CC/TT women; controlled folate feeding.

exposure

Seven weeks after depletion

limitations

Within-group significance alone does not establish a genotype interaction.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Homo sapiens

plain_language

The directly measured DNA-base response differed across genotype groups.

primary_references

[shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003

tissue_or_cell_type

Blood-derived genomic DNA

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 800–810

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Young MTHFR 677CC/TT women; controlled folate feeding. · source_derived_draft · unverified_draft

### folate-methyl-young-tt-repletion During 400 micrograms DFE/day repletion, DNA methylcytosine:total-cytosine increased significantly only in MTHFR 677TT women. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The directly measured DNA-base response differed across genotype groups. organism: Homo sapiens tissue_or_cell_type: Blood-derived genomic DNA experimental_model: Young MTHFR 677CC/TT women; controlled folate feeding. limitations: Within-group significance alone does not establish a genotype interaction. exposure: Seven weeks after depletion [shelnutt-2004] Methylenetetrahydrofolate reductase 677C-->T polymorphism affects DNA methylation in response to controlled folate intake in young women (2004). https://pubmed.ncbi.nlm.nih.gov/15350988/ DOI: 10.1016/j.jnutbio.2004.04.003

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Dietary depletion and liver fractionation

exposure

Assay conditions described in the linked primary study.

limitations

Nuclear protection is conditional; it does not prove indefinite resistance to deficiency.

nutrient_topic

Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. · Folate (vitamin B9)

organism

Mus musculus

plain_language

The nucleus retained folate even when whole-cell stores fell.

primary_references

[field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Folate and folic acid: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1347–1357

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Dietary depletion and liver fractionation · source_derived_draft · unverified_draft

### mouse-folate-depletion-nuclear-retention Nuclear folate levels resisted depletion despite more than 50% lower total cellular folate in folate-depleted mouse liver. Condition category: nutrient_deficiency nutrient_topic: Folate and folic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The nucleus retained folate even when whole-cell stores fell. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Dietary depletion and liver fractionation limitations: Nuclear protection is conditional; it does not prove indefinite resistance to deficiency. exposure: Assay conditions described in the linked primary study. [field-2014] Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency (2014). https://pubmed.ncbi.nlm.nih.gov/25213861/ DOI: 10.1074/jbc.m114.599589

availability_state

nutrient_deficiency Imported condition classification; unverified.

experimental_model

Purified bovine/chicken DHFR and lymphoma-cell experiments; human DHFR interaction was modeled computationally.

limitations

Do not relabel the purified enzymes as human DHFR or infer that normal tea intake causes folate deficiency.

nutrient_topic

EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)

plain_language

Low folate made the cultured cells more sensitive.

primary_references

The antifolate activity of tea catechins. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781612/ · DOI 10.1158/0008-5472.can-04-3469

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 140–146

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Purified bovine/chicken DHFR and lymphoma-cell experiments; human DHFR interaction was modeled computationally. · source_derived_draft · unverified_draft

## egcg-folate-low Low folate made the cultured cells more sensitive. Folate depletion increased lymphoma-cell sensitivity to EGCG; the reported growth IC50 was 20 micromolar. Model: Purified bovine/chicken DHFR and lymphoma-cell experiments; human DHFR interaction was modeled computationally. Limitations: Do not relabel the purified enzymes as human DHFR or infer that normal tea intake causes folate deficiency. Evidence access: primary abstract. The antifolate activity of tea catechins. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781612/ · DOI 10.1158/0008-5472.can-04-3469

evidence_span

{"source_cache": "artifacts/copper-research/15325682.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a", "start_char": 0, "end_char": 1606, "text_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a"}

experimental_model

Long-duration high-copper feeding study

exposure

Nine men; prolonged high copper intake including 7 mg/day supplementation phase

limitations

Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake.

nutrient_topic

Copper research collection; topical membership is not evidence of a direct dietary effect. · Copper

organism

Human young men

plain_language

Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme.

primary_references

[copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

tissue_or_cell_type

Plasma homocysteine, folate, B12 and PLP

Copper: transport, cuproenzymes, deficiency, excess and nutrient interactions (2026-09-17) · lines 1183–1194

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Long-duration high-copper feeding study · source_derived_draft · unverified_draft

### copper-copper-homocysteine-folate High copper intake in nine men produced small decreases in plasma homocysteine and folate, without changes in B12 or PLP measures. Condition category: normal nutrient_topic: Copper research collection; topical membership is not evidence of a direct dietary effect. plain_language: Several vitamin-related blood markers shifted, but that does not identify a new copper-dependent methylation enzyme. organism: Human young men tissue_or_cell_type: Plasma homocysteine, folate, B12 and PLP experimental_model: Long-duration high-copper feeding study limitations: Small intervention with biomarker outcomes; it does not establish copper as a human methionine-synthase cofactor, B-vitamin depletion, or benefit from high copper intake. exposure: Nine men; prolonged high copper intake including 7 mg/day supplementation phase evidence_span: {"source_cache": "artifacts/copper-research/15325682.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a", "start_char": 0, "end_char": 1606, "text_sha256": "4b6a41a9645d006de2098c2ca83f5aaeab2f1d4d76608b1131dc47d0e2e4148a"} [copper-p15325682] Effect of long-term, high-copper intake on the concentrations of plasma homocysteine and B vitamins in young men. (2004). https://pubmed.ncbi.nlm.nih.gov/15325682/ DOI: 10.1016/j.nut.2004.05.011

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Zebrafish supplementation experiment.

limitations

Combination rescue is recorded without claiming clinical efficacy or statistical synergy in humans.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

A second nutrient changed the response to the first in this model.

primary_references

Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26821380/ · DOI 10.1371/journal.pgen.1005783

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 106–112

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Zebrafish supplementation experiment. · source_derived_draft · unverified_draft

## glycine-fish-glycine-folate A second nutrient changed the response to the first in this model. Adding folate with glycine restored hemoglobin in the tested zebrafish Slc25a38-deficiency model. Model: Zebrafish supplementation experiment. Limitations: Combination rescue is recorded without claiming clinical efficacy or statistical synergy in humans. Evidence access: Primary full text Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia. · 2016 · https://pubmed.ncbi.nlm.nih.gov/26821380/ · DOI 10.1371/journal.pgen.1005783

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Mouse developmental model and formate supplementation.

limitations

Does not establish treatment of human nonketotic hyperglycinemia or prove all disease features are formate-responsive.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

A downstream carbon donor bypassed part of the missing pathway.

primary_references

Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 138–144

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse developmental model and formate supplementation. · source_derived_draft · unverified_draft

## glycine-gldc-formate-bypass A downstream carbon donor bypassed part of the missing pathway. Formate treatment normalized folate profiles, restored embryonic growth and prevented neural-tube defects in the tested Gldc-deficient mice. Model: Mouse developmental model and formate supplementation. Limitations: Does not establish treatment of human nonketotic hyperglycinemia or prove all disease features are formate-responsive. Evidence access: Primary full text Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25736695/ · DOI 10.1038/ncomms7388

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human leukemia cells, knockout and metabolite-rescue experiment.

limitations

Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin.

nutrient_topic

Glycine collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Glycine

plain_language

Restoring a downstream one-carbon source worked where adding an amino acid did not.

primary_references

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

trigger_kind

machinery_impairment Imported condition classification; unverified.

Glycine: supply, one-carbon allocation, receptors and cross-nutrient mechanisms (2026-09-19) · lines 122–128

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human leukemia cells, knockout and metabolite-rescue experiment. · source_derived_draft · unverified_draft

## glycine-s38-formate-rescue Restoring a downstream one-carbon source worked where adding an amino acid did not. Formate at 1 mM rescued the low-B6 proliferation defect of SLC25A38-null K562 cells, while glycine, serine and folate did not under the tested conditions. Model: Human leukemia cells, knockout and metabolite-rescue experiment. Limitations: Culture rescue is not a nutritional recommendation; this growth endpoint differs from zebrafish hemoglobin. Evidence access: Primary full text SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation. · 2025 · https://pubmed.ncbi.nlm.nih.gov/39856062/ · DOI 10.1038/s41467-025-56130-3

availability_state

biomarker_context Imported condition classification; unverified.

cross_nutrient

Folate and B12 both participate in homocysteine remethylation.

experimental_model

Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients.

exposure

Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean.

limitations

Circulating concentration is not a direct MTR activity measurement.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself.

primary_references

[b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

tissue_or_cell_type

Human blood or whole-person endpoints

trigger_kind

biomarker_context Imported condition classification; unverified.

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1474–1485

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. · source_derived_draft · unverified_draft

### b12-deficiency-homocysteine-frequency Total homocysteine was elevated in 95.9% of the B12-deficiency episodes; it was also elevated in 91% of the folate-deficiency episodes. Condition category: biomarker_context nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: This marker is shared by connected nutrient pathways, so it cannot identify B12 deficiency by itself. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Selected clear-cut deficiency series: 434 B12 episodes in 406 patients and 123 folate episodes in 119 patients. limitations: Circulating concentration is not a direct MTR activity measurement. exposure: Serum MMA and total homocysteine assays; elevation defined above three standard deviations of the reference mean. cross_nutrient: Folate and B12 both participate in homocysteine remethylation. [b12-savage1994] Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies (1994). https://pubmed.ncbi.nlm.nih.gov/8154512/ DOI: 10.1016/0002-9343(94)90149-x

cross_nutrient

Preserves the B12/folate/homocysteine measurements without a universal depletion cascade.

experimental_model

Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes.

exposure

Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure.

limitations

End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking.

nutrient_topic

Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin B12 (cobalamins)

organism

Homo sapiens

plain_language

A B12 effect did not make the overall homocysteine trial result statistically significant.

primary_references

[b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Human blood or whole-person endpoints

Vitamin B12: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1636–1647

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. · source_derived_draft · unverified_draft

### b12-metformin-homocysteine-boundary The overall metformin-versus-placebo homocysteine change was +5% (95% CI -1% to 11%; P=0.091), although participants with low end-study B12 had higher homocysteine. Condition category: normal nutrient_topic: Vitamin B12 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A B12 effect did not make the overall homocysteine trial result statistically significant. organism: Homo sapiens tissue_or_cell_type: Human blood or whole-person endpoints experimental_model: Multicenter randomized placebo-controlled trial: 390 insulin-treated patients with type 2 diabetes. limitations: End-study B12 strata are not randomized mediators. The folate decrease lost significance after adjustment for BMI and smoking. exposure: Metformin 850 mg three times daily versus placebo for 4.3 years; historical experimental exposure. cross_nutrient: Preserves the B12/folate/homocysteine measurements without a universal depletion cascade. [b12-dejager2010] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"}

experimental_model

Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin

exposure

850 mg metformin three times daily for 4.3 years versus placebo

limitations

The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

A small folate fall was seen but did not survive adjustment.

primary_references

[metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

tissue_or_cell_type

Whole body

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1061–1072

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin · source_derived_draft · unverified_draft

### metformin-b12-folate-decrease Metformin was associated with a mean decrease in folate concentration of 5%, although after adjustment for body mass index and smoking no significant effect on folate remained. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: A small folate fall was seen but did not survive adjustment. organism: Human tissue_or_cell_type: Whole body experimental_model: Multicentre randomised placebo-controlled trial, 390 people with type 2 diabetes on insulin limitations: The strongest available human causal evidence for the B12 effect. It measured concentrations and deficiency incidence, not clinical deficiency syndromes. exposure: 850 mg metformin three times daily for 4.3 years versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/20488910.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922", "start_char": 0, "end_char": 2518, "text_sha256": "6c9e09d44fe1103e6927321e925e69e31c38d1a688fd2ac18ea96927098de922"} [metformin-p20488910] Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. (2010). https://pubmed.ncbi.nlm.nih.gov/20488910/ DOI: 10.1136/bmj.c2181

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}

experimental_model

Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks

exposure

Metformin added to insulin for 16 weeks versus placebo

limitations

Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

Both vitamins fall within months, not only after years.

primary_references

[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

tissue_or_cell_type

Whole body

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1178–1189

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft

### metformin-short-term-b12-folate Sixteen weeks of metformin reduced folate by 7% and vitamin B12 by 14% compared with placebo. Condition category: nutrient_deficiency nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: Both vitamins fall within months, not only after years. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"}

experimental_model

Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks

exposure

Metformin added to insulin for 16 weeks versus placebo

limitations

Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change.

nutrient_topic

Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. · Metformin

organism

Human

plain_language

The rise in that metabolite was accounted for by the two vitamins falling.

primary_references

[metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

tissue_or_cell_type

Whole body

trigger_kind

biomarker_context Imported condition classification; unverified.

Metformin: transport, molecular targets, gut mechanisms and nutrient interactions (2026-09-19) · lines 1191–1202

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks · source_derived_draft · unverified_draft

### metformin-short-term-homocysteine Metformin use was associated with a 4% increase in homocysteine, and the increase could be explained by the decreases in folate and vitamin B12. Condition category: biomarker_context nutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake. plain_language: The rise in that metabolite was accounted for by the two vitamins falling. organism: Human tissue_or_cell_type: Whole body experimental_model: Placebo-controlled randomised trial of 390 people with type 2 diabetes over 16 weeks limitations: Short-duration randomised evidence that the folate and B12 changes precede a measurable homocysteine change. exposure: Metformin added to insulin for 16 weeks versus placebo evidence_span: {"source_cache": "artifacts/metformin-research/14535967.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a", "start_char": 0, "end_char": 1640, "text_sha256": "ef4341dbaf004103ac5bc1df34e7286abd679d4b7a072c26655550135221123a"} [metformin-p14535967] Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. (2003). https://pubmed.ncbi.nlm.nih.gov/14535967/ DOI: 10.1046/j.1365-2796.2003.01213.x

dose

Purified hydroxytyrosol 45 mg/day

duration

8 weeks

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_scope

literature_reviewed; model-specific source-derived curation

experimental_model

Fourteen volunteers with mild hyperlipidemia

limitations

A small baseline-comparison study cannot establish deficiency, iron depletion, or a causal nutrient interaction without controlled replication.

nutrient_topic

Hydroxytyrosol chapter; interacting nutrients, drugs, peptides and proteins retain their experimental settings. · Hydroxytyrosol

organism

Fourteen volunteers with mild hyperlipidemia

plain_language

During the same 45 mg/day trial, serum and red-cell folate and serum ferritin fell at weeks 4 and 8, while serum iron remained stable.

primary_references

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial. (2017). https://pubmed.ncbi.nlm.nih.gov/28063380/ DOI: 10.1016/j.redox.2016.12.014

route

Oral

tissue

Nutrient and iron-status markers

Hydroxytyrosol: mechanism of action and interactions (2026-09-20) · lines 110–119

Original AI-assisted source-specific curation with primary-study citations, model, exposure, route, duration, negative findings and limitations preserved. Not publisher full text. · supports · Fourteen volunteers with mild hyperlipidemia · source_derived_draft · unverified_draft

## hydroxytyrosol-folate-ferritin During the same 45 mg/day trial, serum and red-cell folate and serum ferritin fell at weeks 4 and 8, while serum iron remained stable. Model/species: Fourteen volunteers with mild hyperlipidemia Tissue/system: Nutrient and iron-status markers Exposure: Purified hydroxytyrosol 45 mg/day Route: Oral Duration: 8 weeks Limits: A small baseline-comparison study cannot establish deficiency, iron depletion, or a causal nutrient interaction without controlled replication. Primary reference: Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial. (2017). https://pubmed.ncbi.nlm.nih.gov/28063380/ DOI: 10.1016/j.redox.2016.12.014 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Women aged 18–40; all groups received extract; selected MTHFR and DHFR genotypes considered.

limitations

No extract-free control, pregnancy outcome or long-term depletion test. Abstract dose terminology is inconsistent; no pure-EGCG dose is inferred.

nutrient_topic

EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)

plain_language

This short human study did not reproduce folate depletion.

primary_references

Evaluating the Effect of Epigallocatechin Gallate (EGCG) in Reducing Folate Levels in Reproductive Aged Women by MTHFR and DHFR Genotype in Combination With Letrozole or Clomiphene. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40077973/ · DOI 10.1111/cts.70189

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 156–162

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Women aged 18–40; all groups received extract; selected MTHFR and DHFR genotypes considered. · source_derived_draft · unverified_draft

## egcg-human-folate This short human study did not reproduce folate depletion. In 39 women studied for 30 days, folate stayed in the normal range across EGCG-containing-extract groups, including groups receiving clomiphene or letrozole. Model: Women aged 18–40; all groups received extract; selected MTHFR and DHFR genotypes considered. Limitations: No extract-free control, pregnancy outcome or long-term depletion test. Abstract dose terminology is inconsistent; no pure-EGCG dose is inferred. Evidence access: primary abstract. Evaluating the Effect of Epigallocatechin Gallate (EGCG) in Reducing Folate Levels in Reproductive Aged Women by MTHFR and DHFR Genotype in Combination With Letrozole or Clomiphene. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40077973/ · DOI 10.1111/cts.70189

availability_state

nutrient_deficiency Imported condition classification; unverified.

evidence_span

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experimental_model

Review of folate transport systems in relation to alcoholism-induced malabsorption

exposure

Chronic ethanol ingestion against folate transport

limitations

A review, labelled as such, used for the enumeration of routes. The individual transport measurements are recorded from their own primary papers where available.

nutrient_topic

Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. · Ethanol

organism

Human and animal

plain_language

Alcohol attacks the vitamin at the doorway, in both gut and kidney.

primary_references

[alcohol-p19292860] New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development. (2009). https://pubmed.ncbi.nlm.nih.gov/19292860/ DOI: 10.1111/j.1742-4658.2009.06959.x

tissue_or_cell_type

Intestine, liver and kidney

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Alcohol: ethanol clearance, acetaldehyde, the channels it binds, organ injury and nutrient collisions (2026-09-21) · lines 683–694

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of folate transport systems in relation to alcoholism-induced malabsorption · source_derived_draft · unverified_draft

### alcohol-ethanol-folate-transport Ethanol reduces intestinal and renal uptake of folate by altering the binding and transport kinetics of folate transport systems and by reducing the expression of folate transporters, with ethanol ingestion described as the major contributor to folate deficiency. Condition category: nutrient_deficiency nutrient_topic: Alcohol research collection; topical membership is not evidence of a direct clinical effect, and ethanol is recorded separately from the acetaldehyde it becomes. plain_language: Alcohol attacks the vitamin at the doorway, in both gut and kidney. organism: Human and animal tissue_or_cell_type: Intestine, liver and kidney experimental_model: Review of folate transport systems in relation to alcoholism-induced malabsorption limitations: A review, labelled as such, used for the enumeration of routes. The individual transport measurements are recorded from their own primary papers where available. exposure: Chronic ethanol ingestion against folate transport evidence_span: {"source_cache": "artifacts/alcohol-research/19292860.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "596af06cee715270d990c6fd6f421a3cf4efe2448193da3e58a35d74c2949e30", "start_char": 0, "end_char": 2909, "text_sha256": "596af06cee715270d990c6fd6f421a3cf4efe2448193da3e58a35d74c2949e30"} [alcohol-p19292860] New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development. (2009). https://pubmed.ncbi.nlm.nih.gov/19292860/ DOI: 10.1111/j.1742-4658.2009.06959.x