A novel nutritional supplement to reduce plasma homocysteine in nonpregnant women: A randomised controlled trial in The Gambia

Abstract

Background Infant DNA methylation profiles are associated with their mother’s periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials. Methods and findings We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 μg folic acid, 5.2 μg vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (−29.5 to −17.1) and 15.5% (−21.2 to −9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (−15.8 to −1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine. Conclusions The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia. Trial registration Clinicaltrials.gov Reference NCT03431597 .

Effects of low-dose B vitamins plus betaine supplementation on lowering homocysteine concentrations among Chinese adults with hyperhomocysteinemia: a randomized, double-blind, controlled preliminary clinical trial

“…Betaine or other one-carbon sources are recommended to be considered to combine with B vitamins supplementation to ameliorate homocystinuria [ 46 ]. However, only one RCT conducted in nonpregnant women in Gambia has evaluated the efficacy of supplementation with B vitamins plus betaine for 12 weeks on lowering homocysteine concentrations [ 20 ]. They have reported that the novel supplement (daily supplementation: 800 μg folic acid, 2.8 mg vitamin B 6 , 5.2 μg vitamin B 12 and 4 g betaine) reduces plasma homocysteine concentration by 2.32 μmol/L compared with the baseline and is more effective than a traditional supplement containing 15 micronutrients without betaine [ 20 ].…”

“…However, only one RCT conducted in nonpregnant women in Gambia has evaluated the efficacy of supplementation with B vitamins plus betaine for 12 weeks on lowering homocysteine concentrations [ 20 ]. They have reported that the novel supplement (daily supplementation: 800 μg folic acid, 2.8 mg vitamin B 6 , 5.2 μg vitamin B 12 and 4 g betaine) reduces plasma homocysteine concentration by 2.32 μmol/L compared with the baseline and is more effective than a traditional supplement containing 15 micronutrients without betaine [ 20 ]. Results of this study indicate that the combination of B vitamins and betaine may be a more effective nutritional supplement to reduce homocysteine concentration.…”

“…A meta-analysis of five supplementation trials with betaine has reported that daily supplementation with at least 4 g betaine between 6 and 24 weeks reduces blood homocysteine concentration by 1.23 μmol/L [ 14 ]. A recent RCT in Gambia has demonstrated that a novel nutritional supplement combining B vitamins and betaine has enhanced efficacy in reducing blood homocysteine concentration compared to a conventional supplement of B vitamins without betaine [ 20 ]. This finding indicates that B vitamins administrated at a safer dosage plus betaine might be an alternative and effective strategy for the long-term management of evaluated homocysteine concentration.…”

Maternal stevioside supplementation improves intestinal immune function of chicken offspring potentially via modulating gut microbiota and down-regulating the promoter methylation level of suppressor of cytokine signaling 1 (SOCS1)

“…If these immune-regulatory effects can be transmitted to the next generation, the intestinal immune function of chicken offspring may be enhanced. Numerous studies have proven that a changed phenotype of the parents induced by epigenetic factors—including dietary components—could be partly inherited by the offspring ( Li et al., 2018 ; James et al., 2019 ; Wu et al., 2019a ). It is worth mentioning that, in the colonic cells, a derivative of stevioside could affect DNA methylation, which is an important kind of epigenetic modification ( Mokarram et al., 2017 ).…”