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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:4135-4138, December 2003

Human Nutrition and Metabolism
Research Communication

Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women1,2

Margreet R. Olthof3, Trinette van Vliet*, Esther Boelsma* and Petra Verhoef

Wageningen Centre for Food Sciences and Wageningen University, Division of Human Nutrition and Epidemiology, Wageningen, the Netherlands; and * TNO Nutrition and Food Research, Zeist, the Netherlands

3To whom correspondence should be addressed. E-mail: margreet.olthof{at}wur.nl.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
High plasma homocysteine is a risk for cardiovascular disease and can be lowered through supplementation with 6 g/d of betaine. However, dietary intake of betaine is ~0.5–2 g/d. Therefore, we investigated whether betaine supplementation in the range of dietary intake lowers plasma homocysteine concentrations in healthy adults. Four groups of 19 healthy subjects ingested three doses of betaine or placebo daily for 6 wk. A methionine loading test was performed during run in, on d 1 of betaine supplementation, and after 2 and 6 wk of betaine supplementation. Fasting plasma homocysteine after 6-wk daily intakes of 1.5, 3 and 6 g of betaine was 12% (P < 0.01), 15% (P < 0.002) and 20% (P < 0.0001) less than in the placebo group, respectively. Furthermore, the increase in plasma homocysteine after methionine loading on the 1st d of betaine supplementation was 16% (P < 0.06), 23% (P < 0.008) and 35% (P < 0.0002) less than in the placebo group, respectively, and after 6 wk of supplementation was 23% (P < 0.02), 30% (P < 0.003) and 40% (P < 0.0002) less, respectively. Thus, doses of betaine in the range of dietary intake reduce fasting and postmethionine loading plasma homocysteine concentrations. A betaine-rich diet might therefore lower cardiovascular disease risk.

KEY WORDS: • betaine • homocysteine • methionine • intervention • human

A high plasma concentration of homocysteine is considered a risk factor for cardiovascular disease. Both fasting homocysteine and the increase in homocysteine concentrations after a methionine loading test are predictors of cardiovascular disease risk (1–3). Homocysteine concentrations can be lowered through increased remethylation of homocysteine into methionine. Betaine (trimethylglycine) or 5-methyltetrahydrofolate serve as methyl donors in this reaction. Alternatively, homocysteine can be degraded through vitamin B-6–dependent reactions. The effect of betaine supplementation on plasma homocysteine concentrations has mainly been investigated in clinical settings. Only doses of betaine >6 g/d lower plasma homocysteine in hyperhomocysteinemic patients with genetic defects in homocysteine metabolism (4–6) and hence lower doses of betaine have not been used in clinical settings (7). Studies in healthy volunteers showed that 6 g/d of betaine lowers fasting plasma homocysteine by 10–15%, and postmethionine loading homocysteine concentrations by 40% (8–10). Folic acid lowers fasting homocysteine more than betaine (11,12), but it does not lower homocysteine after a methionine load, whereas betaine does (9).

Dietary intake of betaine is estimated at 0.5–2 g/d (personal communication, Prof. Steven Zeisel, University of North Carolina at Chapel Hill). The main food sources of betaine are spinach, beets and wheat products (13). Our primary objective was to investigate the effects of betaine supplementation at doses in the range of dietary intake on fasting and postmethionine loading plasma homocysteine concentrations in healthy adults. Furthermore, we tested whether the effect of betaine on fasting and postmethionine plasma homocysteine concentrations requires an adaptation period. Therefore, we included homocysteine measurements on d 1 and after 2 wk of supplementation. Lastly, we expected that betaine supplementation would increase remethylation of homocysteine into methionine. Therefore, we also measured the effect of betaine supplementation on methionine concentrations.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
This study was conducted according to Good Clinical Practice guidelines at TNO Nutrition and Food Research (Zeist, the Netherlands). The protocol was approved by the local medical ethics committee. Subjects were recruited from the pool of volunteers registered at the institute and by advertisements in local newspapers. All gave written informed consent. Eligible subjects were healthy as assessed by a general health and lifestyle questionnaire, blood pressure measurement and blood analyses of hematology, homocysteine, B-vitamins, liver enzymes, creatinine, glucose and lipids. Plasma total homocysteine concentrations were <25 µmol/L. Participants had no history of cardiovascular disease and had not used vitamin B supplements more than once a week in the 3 mo before entering the study.


   Subjects and design.
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Of 132 eligible subjects, 76 (44 males and 32 females) with the highest plasma total homocysteine concentrations (range 8.4 to 22.2 µmol/L) were included in this double-blind placebo-controlled intervention study. However, the mean plasma homocysteine concentrations of the treatment groups were within normal range (Table 1). Subjects were stratified by gender, plasma homocysteine concentration, blood pressure and smoking (yes or no), then randomly assigned to one of four treatment groups (n = 19 per group). During a run-in period of 7 d, all subjects ingested 3 g of placebo (lactose; BUFA B.V. Pharmaceutical Products, Uitgeest, the Netherlands) twice a day to familiarize themselves with the study procedures. After a fasting blood sample had been taken on d 8, the 6-wk treatment period began. The treatments consisted of 0.75 g of anhydrous betaine (BUFA B.V.) mixed with 2.25 g of placebo, 1.5 g of betaine mixed with 1.5 g of placebo, 3 g of betaine or 3 g of placebo. Twice a day (i.e., after breakfast and after the evening meal), supplements were dissolved in a glass of water and ingested. Thus, all treatments consisted of 6 g of powder and the daily treatment dose was 1.5 g of betaine with 4.5 g of placebo, 3 g of betaine with 3 g of placebo, 6 g of betaine or 6 g of placebo. Subjects ingested the supplements twice daily so that results could be compared with our previous study (9) and because ingestion of betaine twice a day is the optimal regimen for maximal lowering of homocysteine (14). Betaine has a bitter taste, whereas lactose is sweet. To preserve the blinding of study results, 1 mg of quinine (chinine hydrochloridum, BUFA B.V. Pharmaceutical Products) was added per 3 g of lactose during the run-in period.


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  		TABLE 1 Fasting plasma homocysteine concentrations in healthy adults before and after 2 and 6 wk of betaine supplementation1

 
A methionine-loading test was performed on four different days during the study, i.e., during the run-in period (d 3), on the 1st d of the treatment period (d 8), after 2 wk of treatment (d 22) and after 6 wk of treatment (d 50). On d 3, 8, 22 and 50 a fasting blood sample was collected from each subject; subjects then ingested 100 mg of L-methionine (Methioninum apyrogeen; BUFA B.V. Pharmaceutical Products) per kg of body mass dissolved in a glass of orange juice (~150 mL). The methionine load was ingested with a standardized low protein breakfast, and with half the daily dose of supplement dissolved in water. A blood sample was collected at 6 h after the methionine load. A lunch without restrictions was served afterwards. The standardized breakfast consisted of several slices of low protein bread with diet margarine, jam, colored sprinkles and/or honey. One cup (~150 mL) of coffee or tea was allowed with the standardized breakfast, but the amount had to be the same on all four measurement days. Throughout the study subjects were asked not to consume liver products more than twice a week, and not to consume >2 eggs per week because eggs and liver are major sources of betaine and of choline, the dietary precursor for betaine.


   Blood collection.
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 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Venous blood was taken from the anticubital vein in the forearm after an overnight fast on d 3, 8, 22, 45 and 50. In addition, blood samples were obtained 6 h following methionine loading on d 3, 8, 22 and 50.

For the analysis of total homocysteine, blood was collected in vacutainer tubes containing EDTA, and for methionine analysis blood was collected in vacutainer tubes containing lithium-heparin. Samples were mixed and put on ice immediately after collection. Within 30 min samples were centrifuged for 10 min at 2000 x g at 4°C. Samples were coded to hide the identity and treatment of subjects, and were stored below -18°C. All samples obtained from one subject were analyzed in the same run.


   Biochemical analyses.
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Plasma homocysteine concentrations were measured in fasting blood samples collected on d 3, 8, 22, 45 and 50 and in nonfasting blood samples collected on d 3, 8, 22 and 50. The total homocysteine concentrations (sum of all oxidized and reduced forms of homocysteine) were measured by HPLC with fluorescence detection (15). Within- and between-run CV were 3.5 and 8.0%, respectively. Plasma methionine concentrations were measured in fasting and nonfasting subject blood samples collected on d 3 and 50. Plasma for methionine analysis was deproteinized with sulfosalicylic acid. The supernatant obtained after centrifugation was analyzed on an automated amino acid analyzer (Biotronik LC 5001, München, Germany) using ion exchange chromatography and postcolumn derivatization with ninhydrin. Within- and between-run CV were <2 and <4%, respectively.


   Statistical analysis.
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
RESULTS
 DISCUSSION
 LITERATURE CITED
 
All subjects completed the study. In the group treated with 3 g/d betaine, 1 subject did not attend d 8 due to logistic reasons. In the group treated with placebo, 1 subject did not attend blood sampling 6 h after methionine loading on d 22 due to illness. The data from these subjects were therefore not used in the statistical analyses for these days.

For each individual the change in plasma homocysteine and methionine concentrations was calculated by subtracting the value obtained during the run-in period from the values obtained during the treatment period (i.e., 1st d of betaine supplementation, after 2 wk and after 6 wk of betaine supplementation) (Tables 1, , 2, and 3). The means of all individual changes were calculated per treatment group and were compared with the General Linear Models procedure in SAS (ANOVA, SAS Software version 6.12; SAS Institute, Cary, NC). If ANOVA indicated a significant overall treatment effect (P <= 0.05), a Student’s t test was used to compare treatment means between betaine supplementation and placebo groups. The data from two volunteers in the 6-g/d betaine group, and one in the placebo group were considered to be outliers for statistical reasons only. However, when the analyses with and without the data of these subjects was performed the conclusions did not differ (data not shown). Therefore, we show the data of all subjects in the results. For plasma homocysteine analyses a one-sided significance level ({alpha} = 0.05) was used and 90% CI calculated, because increases in plasma homocysteine after betaine supplementation relative to placebo were not expected (8–10). For plasma methionine analyses a two-sided significance level ({alpha} = 0.05) was used and 95% CI calculated.


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  		TABLE 2 Increase in plasma homocysteine concentrations in healthy adults after methionine loading before, after a single dose, and after 2 and 6 wk of betaine supplementation1, 2

 

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  		TABLE 3 Plasma methionine concentrations in the fasting state and after methionine loading in healthy adults1

 

   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Fasting homocysteine.

Plasma homocysteine concentrations at baseline were similar among the groups which indicates successful randomization (Table 1). In the groups that ingested 1.5, 3 and 6 g/d of betaine for 6 wk fasting plasma homocysteine was 1.3 (12%), 1.6 (15%), and 2.2 µmol/L (20%) less than in the placebo group, respectively (P < 0.01) (Table 1). The reductions in plasma homocysteine after 2 wk of betaine supplementation were also significant (P < 0.01) and the magnitude of the effect was comparable to that after 6 wk of betaine supplementation.

Postmethionine homocysteine.

After subjects had ingested a single dose of 0.75, 1.5 and 3 g of betaine, the increase in homocysteine after a methionine load was 4.4 (16%; P = 0.06), 6.8 (23%; P = 0.008) and 10.4 µmol/L (35%; P = 0.0002) less than in the placebo group, respectively (Table 2). Six wk of betaine treatment reduced the increase in plasma homocysteine after methionine loading by 23, 30 and 40%, respectively (P < 0.03). The effects of betaine on postmethionine concentrations of homocysteine after 2 wk of supplementation were significant (P < 0.02) and comparable to those after 6 wk.

Plasma methionine.

In the group that ingested 6 g/d of betaine, methionine concentrations in fasting plasma and after methionine loading were higher than in the placebo group (P < 0.002, Table 3). The groups that ingested 1.5 and 3 g/d of betaine also had greater methionine concentrations than in the placebo group, but these changes were not significant (P = 0.35 and P = 0.52, respectively).


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
LITERATURE CITED
 
This is the first placebo-controlled study that shows that supplementation of betaine at doses as low as 1.5 g/d lowers plasma homocysteine concentrations in healthy adults. Furthermore, there seems to be an apparent dose-response relationship between betaine supplementation and plasma homocysteine concentrations (Tables 1, , 2).

Fasting plasma homocysteine was maximally lowered at 2 wk of betaine treatment and was maintained after 6 wk of supplementation. We did not test the differences between 2 and 6 wk due to insufficient statistical power. Furthermore, a single dose of 0.75 g betaine on the 1st d of supplementation reduced postmethionine increases in plasma homocysteine by 16% and minimal adaptation occurred after 6 wk of betaine supplementation. Our data support the hypothesis that betaine is quickly available as a methyl donor (16,17), which results in increased betaine-dependent remethylation of homocysteine into methionine. This hypothesis is substantiated by our finding that fasting and postmethionine load plasma methionine concentrations were increased by betaine supplementation (Table 3), as was also found by others (18). Betaine supplementation increases remethylation through increased betaine availability in the liver, increased activity of the enzyme betaine-homocysteine methyltransferase (BHMT), or both. Animal studies showed that BHMT activity is higher when animals are fed more methionine or more methyl donors such as betaine (19–22).

In rats and mice betaine administration increased remethylation and decreased the catabolism of homocysteine through the transsulfuration pathway within a few hours and returned to normal after 24 h (23). This is in line with the immediate effects of betaine on plasma homocysteine after a methionine load in humans (9).

Homocysteine lowering after supplementation of 6 g/d of betaine in this study is similar to the effect found in previous studies (9,10). The new finding that low doses of betaine in the range of dietary intake can substantially lower plasma homocysteine suggests that a diet rich in betaine may lower homocysteine. This is supported by the observation that plasma betaine concentrations are negatively correlated with plasma homocysteine in patients (22,24). Recent information on the content of betaine and choline in various foods will allow further investigation of the relationships among intake of these compounds, plasma homocysteine and disease risk (13). Choline is important because it is metabolized into betaine in the body and might thus have homocysteine-lowering effects as well (25).

A reduction in plasma homocysteine of 5 µmol/L is estimated to reduce the risk of cardiovascular disease by 20–30% (26,27). Based on the current study, a person who consumes a diet rich in betaine (~2 g/d of betaine) would have a 1.3 µmol/L (12%) lower plasma homocysteine concentration than a person who consumes a diet poor in betaine (0.5 g/d). The concurrent reduction in cardiovascular disease risk due to a betaine-rich diet would be ~5–8%. However, it is important to note that betaine supplementation might also increase serum cholesterol, which could diminish the health benefits (10).

Whether homocysteine lowering results in a lower risk of cardiovascular disease is still under debate, but evidence for a causal relationship is accumulating (27–30). Ongoing placebo-controlled intervention trials investigating the effects of homocysteine lowering by supplementation of a combination of B-vitamins on disease endpoints will be reported soon (31). However, these trials cannot separate the potential protective effect of B-vitamins themselves, in particular folic acid, from the subsequent homocysteine lowering. Comparing the effects on homocysteine lowering of B-vitamin supplementation with those of other metabolic pathways, such as betaine-dependent remethylation, might help determine causality. Thus, future studies should consider a two-by-two factorial design comparing betaine and B-vitamins as homocysteine lowering food components.

We conclude that doses of betaine in the range of dietary intake can substantially lower fasting plasma homocysteine. Furthermore, it is likely that betaine tempers increases in homocysteine concentrations after a meal. As new evidence continues to confirm that plasma homocysteine is a cause of cardiovascular disease, a diet rich in betaine might prove effective in lowering cardiovascular disease risk.


   ACKNOWLEDGMENTS
 
We thank the volunteers for their participation, all involved at TNO Nutrition and Food Research for their dedication and the laboratory staff at the division of Human Nutrition and Epidemiology, Wageningen University for homocysteine analyses.


   FOOTNOTES
 
1 Published as an abstract at the 8th International Congress on Phospholipids, 2002, Vienna, Austria [Olthof, M. R., van Vliet, T., Boelsma, E. & Verhoef, P. (2002) Effect of betaine on plasma homocysteine. A dose response study in healthy volunteers.], at the 3rd Conference on Hyperhomocysteinemia, Saarbrücken, Germany [Olthof, M. R., van Vliet, T., Boelsma, E. & Verhoef, P. (2003) Effect of betaine on plasma homocysteine. A dose response study in healthy volunteers. Clin. Chem. Lab. Med. 41: A32] and at the 4th International Conference on Homocysteine Metabolism, 2003, Basel, Switzerland [Olthof, M. R., van Vliet, T., Boelsma, E. & Verhoef, P. (2003) Effect of betaine on plasma homocysteine. A dose response study in healthy volunteers. J. Inherit. Metab. Dis. 26 (suppl): 12.]. Back

2 Funded by the Wageningen Centre for Food Sciences, an alliance of major Dutch food industries, University of Maastricht, TNO Nutrition and Food Research, and Wageningen University and Research Centre, with financial support by the Dutch government. Back

Manuscript received 17 July 2003. Initial review completed 6 August 2003. Revision accepted 25 September 2003.


   LITERATURE CITED
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 Subjects and design.
 Blood collection.
 Biochemical analyses.
 Statistical analysis.
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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S. E Chiuve, E. L Giovannucci, S. E Hankinson, S. H Zeisel, L. W Dougherty, W. C Willett, and E. B Rimm
The association between betaine and choline intakes and the plasma concentrations of homocysteine in women
Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1073 - 1081.
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P. I. Holm, S. Hustad, P. M. Ueland, S. E. Vollset, T. Grotmol, and J. Schneede
Modulation of the Homocysteine-Betaine Relationship by Methylenetetrahydrofolate Reductase 677 C->T Genotypes and B-Vitamin Status in a Large-Scale Epidemiological Study
J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1535 - 1541.
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M. Fisher, K. Lees, and J. D. Spence
Nutrition and Stroke Prevention
Stroke, September 1, 2006; 37(9): 2430 - 2435.
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N. K. Fukagawa
Sparing of Methionine Requirements: Evaluation of Human Data Takes Sulfur Amino Acids Beyond Protein
J. Nutr., June 1, 2006; 136(6): 1676S - 1681S.
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J. D. Spence
Homocysteine: Call Off the Funeral
Stroke, February 1, 2006; 37(2): 282 - 283.
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U. Schwab, A. Torronen, E. Meririnne, M. Saarinen, G. Alfthan, A. Aro, and M. Uusitupa
Orally Administered Betaine Has an Acute and Dose-Dependent Effect on Serum Betaine and Plasma Homocysteine Concentrations in Healthy Humans
J. Nutr., January 1, 2006; 136(1): 34 - 38.
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J. D. Spence, H. Bang, L. E. Chambless, and M. J. Stampfer
Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis
Stroke, November 1, 2005; 36(11): 2404 - 2409.
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S. H Zeisel
Choline, homocysteine, and pregnancy
Am. J. Clinical Nutrition, October 1, 2005; 82(4): 719 - 720.
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R. L. Jacobs, L. M. Stead, C. Devlin, I. Tabas, M. E. Brosnan, J. T. Brosnan, and D. E. Vance
Physiological Regulation of Phospholipid Methylation Alters Plasma Homocysteine in Mice
J. Biol. Chem., August 5, 2005; 280(31): 28299 - 28305.
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M. R Olthof, E. J Brink, M. B Katan, and P. Verhoef
Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men
Am. J. Clinical Nutrition, July 1, 2005; 82(1): 111 - 117.
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J. Robertson, F. Iemolo, S. P. Stabler, R. H. Allen, and J. D. Spence
Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products
Can. Med. Assoc. J., June 7, 2005; 172(12): 1569 - 1573.
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A. Melse-Boonstra, P. I Holm, P. M Ueland, M. Olthof, R. Clarke, and P. Verhoef
Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations
Am. J. Clinical Nutrition, June 1, 2005; 81(6): 1378 - 1382.
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 Arterioscler. Thromb. Vasc. Bio.Home page
P. I. Holm, P. M. Ueland, S. E. Vollset, O. Midttun, H. J. Blom, M. B.A.J. Keijzer, and M. den Heijer
Betaine and Folate Status as Cooperative Determinants of Plasma Homocysteine in Humans
Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 379 - 385.
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S. A. Craig
Betaine in human nutrition
Am. J. Clinical Nutrition, September 1, 2004; 80(3): 539 - 549.
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