l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women.

2018-06
The Journal of nutrition 148(6)
- Amanda M Henderson
- Rika E Aleliunas
- Su Peng Loh
- Geok Lin Khor
- Sarah Harvey-Leeson
- Melissa B Glier
- David D Kitts
- Tim J Green
- Angela M Devlin

PubMed: 29878267
DOI: 10.1093/jn/nxy057

Study Design

Type: Randomized Controlled Trial (RCT)
Sample size: n = 142
Population: healthy Malaysian women (n = 142, aged 20-45 y)
Methods: 12-wk, randomized, placebo-controlled intervention trial; daily 1 mg folic acid, 1.13 mg l-5-MTHF, or placebo
Blinding: Double-blind
Duration: 12 wk

Large Human Trial

Background

Folic acid fortification of grains is mandated in many countries to prevent neural tube defects. Concerns regarding excessive intakes of folic acid have been raised. A synthetic analog of the circulating form of folate, l-5-methyltetrahydrofolate (l-5-MTHF), may be a potential alternative.

Objective

The objective of this study was to determine the effects of folic acid or l-5-MTHF supplementation on blood folate concentrations, methyl nutrient metabolites, and DNA methylation in women living in Malaysia, where there is no mandatory fortification policy.

Methods

In a 12-wk, randomized, placebo-controlled intervention trial, healthy Malaysian women (n = 142, aged 20-45 y) were randomly assigned to receive 1 of the following supplements daily: 1 mg (2.27 μmol) folic acid, 1.13 mg (2.27 μmol) l-5-MTHF, or a placebo. The primary outcomes were plasma and RBC folate and vitamin B-12 concentrations. Secondary outcomes included plasma total homocysteine, total cysteine, methionine, betaine, and choline concentrations and monocyte long interspersed nuclear element-1 (LINE-1) methylation.

Results

The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk. The l-5-MTHF group had higher RBC folate (1951 ± 496 nmol/L; P = 0.003) and plasma folate [52.0 nmol/L (42.7, 73.1 nmol/L); P = 0.023] at 12 wk than did the folic acid group [RBC folate, 1498 ± 580 nmol/L; plasma folate, 40.1 nmol/L (24.9, 52.7 nmol/L)]. The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups. No differences in plasma vitamin B-12, total cysteine, methionine, betaine, and choline and monocyte LINE-1 methylation were observed.

Conclusion

These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. This trial was registered at clinicaltrials.gov as NCT01584050.

Research Insights

L-Methylfolate→Altered Monocyte LINE-1 Methylation
No differences in monocyte LINE-1 methylation were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Decreased Plasma Total Homocysteine Level
The l-5-MTHF group had 15% ... lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk.
Effect
Beneficial
Effect size
Moderate
Dose
1.13 mg/day
L-Methylfolate→Increased Betaine Level
No differences in plasma betaine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Increased Blood Folate Concentration
The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk.
Effect
Beneficial
Effect size
Moderate
Dose
1 mg (2.27 μmol)/day
L-Methylfolate→Increased Choline Level
No differences in plasma choline ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Increased DNA Methylation
No differences in ... monocyte LINE-1 methylation were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
L-Methylfolate→Increased Folate Level
The l-5-MTHF group had higher (P < 0.001) plasma folate [median (25th, 75th percentiles): 52.0 nmol/L (42.7, 73.1 nmol/L)] ... compared with ... placebo group at 12 wk.
Effect
Beneficial
Effect size
Large
Dose
1.13 mg/day
L-Methylfolate→Increased Methionine Level
No differences in plasma ... methionine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
L-Methylfolate→Increased Plasma Methionine Level
No differences in plasma methionine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Increased Plasma Total Cysteine Concentration
No differences in plasma total cysteine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Increased Red Blood Cell Folate Concentration
The l-5-MTHF group had higher (P < 0.001) RBC folate (mean ± SD: 1951 ± 496 nmol/L) ... compared with ... placebo group at 12 wk.
Effect
Beneficial
Effect size
Large
Dose
1.13 mg/day
L-Methylfolate→Increased Vitamin B-12 Level
No differences in plasma vitamin B-12 ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
L-Methylfolate→Reduced Cysteine Level
No differences in plasma ... total cysteine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
L-Methylfolate→Reduced Homocysteine Level
The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups.
Effect
Beneficial
Effect size
Moderate
Dose
1 mg (2.27 μmol)/day
L-Methylfolate→Reduced Vitamin B-12 Level
No differences in plasma vitamin B-12 ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Altered Monocyte LINE-1 Methylation
No differences in monocyte LINE-1 methylation were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Decreased Plasma Total Homocysteine Level
The l-5-MTHF group had 15% ... lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk.
Effect
Beneficial
Effect size
Moderate
Dose
1.13 mg/day
Vitamin B9→Increased Betaine Level
No differences in plasma betaine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Increased Blood Folate Concentration
The folic acid and l-5-MTHF groups had higher (P < 0.001) RBC folate (mean ± SD: 1498 ± 580 and 1951 ± 496 nmol/L, respectively) and plasma folate [median (25th, 75th percentiles): 40.1 nmol/L (24.9, 52.7 nmol/L) and 52.0 nmol/L (42.7, 73.1 nmol/L), respectively] concentrations compared with RBC folate (958 ± 345 nmol/L) and plasma folate [12.6 nmol/L (8.80, 17.0 nmol/L)] concentrations in the placebo group at 12 wk.
Effect
Beneficial
Effect size
Moderate
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Increased Choline Level
No differences in plasma choline ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Increased DNA Methylation
No differences in ... monocyte LINE-1 methylation were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Increased Folate Level
The l-5-MTHF group had higher (P < 0.001) plasma folate [median (25th, 75th percentiles): 52.0 nmol/L (42.7, 73.1 nmol/L)] ... compared with ... placebo group at 12 wk.
Effect
Beneficial
Effect size
Large
Dose
1.13 mg/day
Vitamin B9→Increased Methionine Level
No differences in plasma ... methionine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Increased Plasma Methionine Level
No differences in plasma methionine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Increased Plasma Total Cysteine Concentration
No differences in plasma total cysteine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Increased Red Blood Cell Folate Concentration
The l-5-MTHF group had higher (P < 0.001) RBC folate (mean ± SD: 1951 ± 496 nmol/L) ... compared with ... placebo group at 12 wk.
Effect
Beneficial
Effect size
Large
Dose
1.13 mg/day
Vitamin B9→Increased Vitamin B-12 Level
No differences in plasma vitamin B-12 ... were observed.
Effect
Neutral
Effect size
Small
Dose
1.13 mg/day
Vitamin B9→Reduced Cysteine Level
No differences in plasma ... total cysteine ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Reduced Homocysteine Level
The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P < 0.001) plasma total homocysteine concentrations than did the placebo group at 12 wk; there were no differences between the folic acid and l-5-MTHF groups.
Effect
Beneficial
Effect size
Moderate
Dose
1 mg (2.27 μmol)/day
Vitamin B9→Reduced Vitamin B-12 Level
No differences in plasma vitamin B-12 ... were observed.
Effect
Neutral
Effect size
Small
Dose
1 mg (2.27 μmol)/day