A Randomized Pilot Trial to Evaluate the Bioavailability of Natural versus Synthetic Vitamin B Complexes in Healthy Humans and Their Effects on Homocysteine, Oxidative Stress, and Antioxidant Levels

Meinrad Lindschinger, Franz Tatzber, Wolfgang Schimetta, Irene Schmid, Barbara Lindschinger, Gerhard Cvirn, Olaf Stanger, Eugenia Lamont, Willibald Wonisch, Meinrad Lindschinger, Franz Tatzber, Wolfgang Schimetta, Irene Schmid, Barbara Lindschinger, Gerhard Cvirn, Olaf Stanger, Eugenia Lamont, Willibald Wonisch

Abstract

The vitamin B complex comprises 8 different water-soluble constituents that humans must sequester from the diet. This pilot study compared natural versus synthetic vitamin B complexes for their bioavailability, accumulation, and their impact on antioxidants, homocysteine levels, and oxidative stress. We conducted a double-blind randomized clinical trial with thirty healthy participants. They were randomly assigned to group N (natural) and group S (synthetic). Vitamin B was ingested daily for 6 weeks in the range of about 2.5 times above the recommended daily allowance. Blood samples were taken at baseline, 1.5 h, 4 h, 7 h (diurnal), 6 w (discontinuation of supplements), and 8 w (washout). Blood levels of thiamine (B1), riboflavin (B2), pyridoxine (B6), folic acid (B9), cobalamin (B12), homocysteine, total antioxidants, peroxidase activity, polyphenols, and total peroxides were determined. Compared to initial values, serum levels of each B vitamin increased at the end of the supplementation period: i.e., B1 (+23% N; +27% S), B2 (+14% N; +13% S), B6 (+101% N; +101% S), B9 (+86% N; +153% S), and B12 (+16% N) (p < 0.05). Homocysteine (-13% N) decreased, while peroxidase activity (+41% S) and antioxidant capacity increased (+26% N). Short-term effects were already observed after 1.5 h for B9 (+238% N; +246% S) and after 4 h for vitamin B2 (+7% N; +8% S), B6 (+59% N; +51% S), and peroxidase activity (+58% N; +58% S). During the washout period, serum levels of B vitamins decreased except for thiamine and peroxidase activity, which increased further. This clinical pilot study revealed comparable bioavailability for both natural and synthetic B vitamins but did not show statistically noticeable differences between groups despite some favourable tendencies within the natural vitamin group, i.e., sustained effects for cobalamin and endogenous peroxidase activity and a decrease in homocysteine and oxidative stress levels.

Conflict of interest statement

The authors declare they have no competing interests that might be perceived to influence the results and discussion reported in this article, except Wonisch W., who is affiliated with Omnignostica Ltd.

Copyright © 2019 Meinrad Lindschinger et al.

Figures

Figure 1
Figure 1
CONSORT flow diagram of healthy subjects supplemented daily with a natural or synthetic vitamin B complex for 6 weeks and a washout period for 2 weeks, according to the CONSORT 2010 Statement.
Figure 2
Figure 2
Study design. Time schedule for blood sampling (T1-T11) and supplementation with vitamin B complex (natural vs. synthetic) applicable to both study groups. The study was initiated with a three-week run-in phase before the first study day. After study onset, blood samples for information on the diurnal cycle were taken at baseline (T1), 1.5 hours after the first ingestion of the vitamin B complex (T2), 4 hours after the first ingestion (T3), and 7 hours after the first ingestion (T4). Supplementation was terminated after a period of 6 weeks (T5) followed by a 2-week washout period (T6), to complete the first phase of this crossover study. This timepoint was simultaneously the baseline for the second study phase. The vitamin B complex was crossed over in the two groups (natural vs. synhtetic and vice versa), and blood samples were taken after 1.5 hours after ingestion of the first substituted vitamin B complex (T7), then after 4 hours (T8) and 7 hours (T9). Supplementation in the second study phase was terminated after a period of 6 weeks (T10), followed by a washout period of another 6 weeks (T11) at the end point of the study. Due to carryover effects in the majority of biomarkers, crossover comparisons were generally dispensed with, resulting in a restriction to group comparisons in phase 1, as emphasized by dark arrows.
Figure 3
Figure 3
Serum thiamine levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 4
Figure 4
Serum riboflavin levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 5
Figure 5
Serum pyridoxine levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#), respectively.
Figure 6
Figure 6
Serum folic acid levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 7
Figure 7
Serum cobalamin levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 8
Figure 8
Serum homocysteine levels in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 9
Figure 9
Serum total antioxidants in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 10
Figure 10
Serum endogenous peroxidase activity in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).
Figure 11
Figure 11
Serum total peroxides in the follow-up for both subgroups supplemented with natural (filled circles) or synthetic (open circles) B vitamins. Blood sampling: T1 = baseline—immediately before the first supplement; T2 = 1.5 h—subsequent to the first supplementation; T3 = 4 h; T4 = 7 h; T5 = 6 weeks (end of supplementation); and T6 = 8 weeks (washout period) from baseline. Data are presented as mean values ± standard error. Significant differences (p < 0.05) were indicated at the respective timepoints for natural supplements (∗) and synthetic supplements (#).

References

    1. Kennedy D. O. B vitamins and the brain: mechanisms, dose and efficacy—a review. Nutrients. 2016;8(2):p. 68. doi: 10.3390/nu8020068.
    1. Kyme P., Thoennissen N. H., Tseng C. W., et al. C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice. Journal of Clinical Investigation. 2012;122(9):3316–3329. doi: 10.1172/JCI62070.
    1. Naurath H. J., Riezler R., Pütter S., Ubbink J. B. Does a single vitamin B-supplementation induce functional vitamin B-deficiency? Clinical Chemistry and Laboratory Medicine. 2001;39(8):768–771. doi: 10.1515/CCLM.2001.128.
    1. Dainin K., Ide R., Maeda A., Suyama K., Akagawa M. Pyridoxamine scavenges protein carbonyls and inhibits protein aggregation in oxidative stress-induced human HepG2 hepatocytes. Biochemical and Biophysical Research Communications. 2017;486(3):845–851. doi: 10.1016/j.bbrc.2017.03.147.
    1. Burton G. W., Traber M. G., Acuff R. V., et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. American Journal of Clinical Nutrition. 1998;67(4):669–684. doi: 10.1093/ajcn/67.4.669.
    1. Damiani E., Belaid C., Carloni P., Greci L. Comparison of antioxidant activity between aromatic indolinonic nitroxides and natural and synthetic antioxidants. Free Radical Research. 2009;37(7):731–741. doi: 10.1080/1071576031000102169.
    1. Jagtap S., Meganathan K., Wagh V., Winkler J., Hescheler J., Sachinidis A. Chemoprotective mechanism of the natural compounds, epigallocatechin- 3-O-gallate, quercetin and curcumin against cancer and cardiovascular diseases. Current Medicinal Chemistry. 2009;16(12):1451–1462. doi: 10.2174/092986709787909578.
    1. Carr A. C., Bozonet S. M., Pullar J. M., Simcock J. W., Vissers M. C. M. A randomized steady-state bioavailability study of synthetic versus natural (kiwifruit-derived) vitamin C. Nutrients. 2013;5(9):3684–3695. doi: 10.3390/nu5093684.
    1. Wolak N., Kowalska E., Kozik A., Rapala-Kozik M. Thiamine increases the resistance of baker’s yeast Saccharomyces cerevisiae against oxidative, osmotic and thermal stress, through mechanisms partly independent of thiamine diphosphate-bound enzymes. FEMS Yeast Research. 2014;14(8):1249–1262. doi: 10.1111/1567-1364.12218.
    1. Chang C. M., Yu C. C., Lu H. T., Chou Y. F., Huang R. F. S. Folate deprivation promotes mitochondrial oxidative decay: DNA large deletions, cytochrome c oxidase dysfunction, membrane depolarization and superoxide overproduction in rat liver. British Journal of Nutrition. 2007;97(5):855–863. doi: 10.1017/S0007114507666410.
    1. Stanger O., Wonisch W. Enzymatic and non-enzymatic antioxidative effects of folic acid and its reduced derivates. In: Stanger O., editor. Water Soluble Vitamins. Vol. 56. Dordrecht: Springer; 2012. pp. 131–161. (Subcellular Biochemistry).
    1. Bito T., Misaki T., Yabuta Y., Ishikawa T., Kawano T., Watanabe F. Vitamin B12 deficiency results in severe oxidative stress, leading to memory retention impairment in Caenorhabditis elegans. Redox Biology. 2017;11:21–29. doi: 10.1016/j.redox.2016.10.013.
    1. Hankey G. J., Ford A. H., Yi Q., et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013;44(8):2232–2239. doi: 10.1161/STROKEAHA.113.001886.
    1. Zou Y. X., Ruan M. H., Luan J., Feng X., Chen S., Chu Z. Y. Anti-aging effect of riboflavin via endogenous antioxidant in fruit fly Drosophila melanogaster. The Journal of Nutrition, Health & Aging. 2017;21(3):314–319. doi: 10.1007/s12603-016-0752-8.
    1. Esterbauer H., Gieseg S., Giessauf A., Ziouzenkova O., Ramos P. Free radicals and oxidative modification of LDL: role of natural antioxidants. In: Woodford F. P., Davignon J., Sniderman A., editors. Atherosclerosis X. Elsevier; 1995. pp. 203–208.
    1. Endo N., Nishiyama K., Okabe M., Matsumoto M., Kanouchi H., Oka T. Vitamin B6 suppresses apoptosis of NM-1 bovine endothelial cells induced by homocysteine and copper. Biochimica et Biophysica Acta (BBA) - General Subjects. 2007;1770(4):571–577. doi: 10.1016/j.bbagen.2006.11.009.
    1. Zelzer S., Tatzber F., Herrmann M., et al. Work intensity, low-grade inflammation, and oxidative status: a comparison between office and slaughterhouse workers. Oxidative Medicine and Cellular Longevity. 2018;2018:7. doi: 10.1155/2018/2737563.2737563
    1. Kim E. J., Lim S. Y., Lee H. J., et al. Low dietary intake of n-3 fatty acids, niacin, folate, and vitamin C in Korean patients with schizophrenia and the development of dietary guidelines for schizophrenia. Nutrition Research. 2017;45:10–18. doi: 10.1016/j.nutres.2017.07.001.
    1. Bird R. P. Chapter Four - the emerging role of vitamin B6 in inflammation and carcinogenesis. Advances in Food and Nutrition Research. 2018;83:151–194. doi: 10.1016/bs.afnr.2017.11.004.
    1. Saedisomeolia A., Ashoori M. Chapter Two - riboflavin in human health: a review of current evidences. Advances in Food and Nutrition Research. 2018;83:57–81. doi: 10.1016/bs.afnr.2017.11.002.
    1. Schulz K. F., Altman D. G., Moher D., for the CONSORT Group CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340, article c332 doi: 10.1136/bmj.c332.
    1. Tatzber F., Griebenow S., Wonisch W., Winkler R. Dual method for the determination of peroxidase activity and total peroxides-iodide leads to a significant increase of peroxidase activity in human sera. Analytical Biochemistry. 2003;316(2):147–153. doi: 10.1016/S0003-2697(02)00652-8.
    1. Wang L., Li H., Zhou Y., Jin L., Liu J. Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. European Journal of Nutrition. 2015;54(3):455–464. doi: 10.1007/s00394-014-0729-5.
    1. Wong E. K. C., Lee J. Y., Leong D. P., et al. Thiamine versus placebo in older heart failure patients: study protocol for a randomized controlled crossover feasibility trial (THIAMINE-HF) Pilot and Feasibility Studies. 2018;4(1):p. 149. doi: 10.1186/s40814-018-0342-0.
    1. Jannusch K., Jockwitz C., Bidmon H.-J., Moebus S., Amunts K., Caspers S. A complex interplay of vitamin B1 and B6 metabolism with cognition, brain structure, and functional connectivity in older adults. Frontiers in Neuroscience. 2017;11:p. 596. doi: 10.3389/fnins.2017.00596.
    1. Whitfield K. C., Bourassa M. W., Adamolekun B., et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Annals of the New York Academy of Sciences. 2018;1430(1):3–43. doi: 10.1111/nyas.13919.
    1. Allen B., Orfila C. The availability and nutritional adequacy of gluten-free bread and pasta. Nutrients. 2018;10(10, article 1370) doi: 10.3390/nu10101370.
    1. Holmberg M. J., Moskowitz A., Patel P. V., et al. Thiamine in septic shock patients with alcohol use disorders: an observational pilot study. Journal of Critical Care. 2018;43:61–64. doi: 10.1016/j.jcrc.2017.08.022.
    1. McMahon A., McNulty H., Hughes C. F., Strain J. J., Ward M. Novel approaches to investigate one-carbon metabolism and related B-vitamins in blood pressure. Nutrients. 2016;8(11):p. 720. doi: 10.3390/nu8110720.
    1. Chuang C. Z., Boyles A., Legardeur B., Lopez-S A., Su J., Japa S. Effects of riboflavin and folic acid supplementation on plasma homocysteine levels in healthy subjects. The American Journal of the Medical Sciences. 2006;331(2):65–71. doi: 10.1097/00000441-200602000-00011.
    1. Fernández-Bañares F., Giné J. J., Cabré E., et al. Factors associated with low values of biochemical vitamin parameters in healthy subjects. International Journal for Vitamin and Nutrition Research. 1994;64(1):68–74.
    1. Havivi E., Bar On H., Reshef A., Stein P., Raz I. Vitamins and trace metals status in non insulin dependent diabetes mellitus. International Journal for Vitamin and Nutrition Research. 1991;61(4):328–333.
    1. Parra M., Stahl S., Hellmann H. Vitamin B6 and its role in cell metabolism and physiology. Cell. 2018;7(7):p. 84. doi: 10.3390/cells7070084.
    1. Qin B., Xun P., Jacobs D. R., Jr., et al. Intake of niacin, folate, vitamin B-6, and vitamin B-12 through young adulthood and cognitive function in midlife: the Coronary Artery Risk Development in Young Adults (CARDIA) study. American Journal of Clinical Nutrition. 2017;106(4):1032–1040. doi: 10.3945/ajcn.117.157834.
    1. Endo N., Nishiyama K., Otsuka A., Kanouchi H., Taga M., Oka T. Antioxidant activity of vitamin B6 delays homocysteine-induced atherosclerosis in rats. British Journal of Nutrition. 2006;95(6):1088–1093. doi: 10.1079/BJN20061764.
    1. Martí-Carvajal A. J., Solà I., Lathyris D., Dayer M., Cochrane Heart Group Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database of Systematic Reviews. 2017;8 doi: 10.1002/14651858.CD006612.pub5.
    1. Tapola N. S., Karvonen H. M., Niskanen L. K., Sarkkinen E. S. Mineral water fortified with folic acid, vitamins B6, B12, D and calcium improves folate status and decreases plasma homocysteine concentration in men and women. European Journal of Clinical Nutrition. 2004;58(2):376–385. doi: 10.1038/sj.ejcn.1601795.
    1. Verlinde P. H. C. J., Oey I., Hendrickx M. E., van Loey A. M., Temme E. H. M. L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men. European Journal of Clinical Nutrition. 2008;62(10):1224–1230. doi: 10.1038/sj.ejcn.1602840.
    1. Stanger O., Semmelrock H. J., Wonisch W., Bös U., Pabst E., Wascher T. C. Effects of folate treatment and homocysteine lowering on resistance vessel reactivity in atherosclerotic subjects. Journal of Pharmacology and Experimental Therapeutics. 2002;303(1):158–162. doi: 10.1124/jpet.102.036715.
    1. Qin X., Li J., Spence J. D., et al. Folic acid therapy reduces the first stroke risk associated with hypercholesterolemia among hypertensive patients. Stroke. 2016;47(11):2805–2812. doi: 10.1161/STROKEAHA.116.014578.
    1. Ricks D. J., Rees C. A., Osborn K. A., et al. Peru’s national folic acid fortification program and its effect on neural tube defects in Lima. Revista Panamericana de Salud Pública. 2012;32(6):391–398. doi: 10.1590/S1020-49892012001400001.
    1. Cui S., Li W., Lv X., Wang P., Gao Y., Huang G. Folic acid supplementation delays atherosclerotic lesion development by modulating MCP1 and VEGF DNA methylation levels in vivo and in vitro. International Journal of Molecular Sciences. 2017;18(5):p. 990. doi: 10.3390/ijms18050990.
    1. Solini A., Santini E., Ferrannini E. Effect of short-term folic acid supplementation on insulin sensitivity and inflammatory markers in overweight subjects. International Journal of Obesity. 2006;30(8):1197–1202. doi: 10.1038/sj.ijo.0803265.
    1. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112(6):2214–2221. doi: 10.1182/blood-2008-03-040253.
    1. Rizzo G., Laganà A. S., Rapisarda A. M. C., et al. Vitamin B12 among vegetarians: status, assessment and supplementation. Nutrients. 2016;8(12):p. 767. doi: 10.3390/nu8120767.
    1. Matte J. J., Guay F., Girard C. L. Bioavailability of vitamin B12 in cows’ milk. British Journal of Nutrition. 2012;107(1):61–66. doi: 10.1017/S0007114511002364.
    1. Jud P., Hafner F., Verheyen N., et al. Age-dependent effects of homocysteine and dimethylarginines on cardiovascular mortality in claudicant patients with lower extremity arterial disease. Heart and Vessels. 2018;33(12):1453–1462. doi: 10.1007/s00380-018-1210-9.
    1. De Vries G. J., Lok A., Mocking R., Assies J., Schene A., Olff M. Altered one-carbon metabolism in posttraumatic stress disorder. Journal of Affective Disorders. 2015;184:277–285. doi: 10.1016/j.jad.2015.05.062.
    1. Stough C., Scholey A., Lloyd J., Spong J., Myers S., Downey L. A. The effect of 90 day administration of a high dose vitamin B-complex on work stress. Human Psychopharmacology: Clinical and Experimental. 2011;26(7):470–476. doi: 10.1002/hup.1229.
    1. Stanger O., Aigner I., Schimetta W., Wonisch W. Antioxidant supplementation attenuates oxidative stress in patients undergoing coronary artery bypass graft surgery. Tohoku Journal of Experimental Medicine. 2014;232(2):145–154. doi: 10.1620/tjem.232.145.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다