Functional and health consequences of insufficiency of riboflavin and vitamin B6 in adults

Abstract

Riboflavin and vitamin B6 play crucial roles in various biological processes and regulatory pathways. Within one-carbon metabolism, riboflavin is an essential co-factor for the folate metabolising enzyme methylenetetrahydrofolate reductase(MTHFR). Homozygosity for the common C677T polymorphism in MTHFR (TT genotype) leads to reduced MTHFR activity and increased riboflavin requirements and is associated with an increased risk of hypertension. Previous randomised controlled trials (RCTs), conducted at this centre, demonstrated that supplementation with riboflavin reduced blood pressure (BP) in homozygous adults. Riboflavin is also required to generate pyridoxal 5’-phosphate (PLP), the active form of vitamin B6 in tissues, however few studies have focused on this metabolic interaction or on the health consequences of insufficient riboflavin on vitamin B6 status in adults. The overall aim of this thesis was to investigate functional and health consequences of suboptimal riboflavin and vitamin B6 status in adult cohorts. 

A narrative review (Chapter 2) of the literature investigated the evidence and biological mechanism underpinning the role of one-carbon metabolism in cardiovascular health and disease and concluded that evidence, although conflicting, was strongest for stroke and that further studies were required to examine mechanisms underpinning the role of riboflavin in hypertension. In Chapter 3, a combined analysis of data from four RCTs, previously conducted at this centre, found that riboflavin supplementation resulted in a decrease (P<0.001) in mean EGRac values, from 1.34(1.32, 1.37) to 1.21 (1.19, 1.22), indicating optimisation of riboflavin status. Correspondingly, PLP increased (P = 0.027), an effect driven by those with suboptimal riboflavin status at baseline (EGRac >1.26) among whom PLP increased by5.2 nmol/L, from 44.9 (40.3, 49.4) to 50.1 (44.6, 55.6) nmol/L (P =.042), confirming the metabolic dependency of vitamin B6 status on riboflavin and its role as a limiting nutrient for vitamin B6 adequacy in humans. In Chapter 4, the impact of riboflavin intervention on vascular health and endothelial functioning in genetically at-risk adults (Intervene study) was investigated. Early results from this ongoing study showed the association between the MTHFR 677TT genotype, BP, resting heart rate and flow-mediated dilation (FMD) appeared to be more pronounced in younger participants. Preliminary analysis (blinded) provides an early indication that FMD in these genetically at-risk adults may benefit from riboflavin treatment. Finally, the effect of the MTHFR C677T polymorphism on MTHFR enzyme activity and protein levels, using an ex vivo approach, was investigated in Chapter 5, and a strong correlation between MTHFR enzyme activity and MTHFR protein levels was observed, with further studies planned to investigate whether stabilisation of this mutation occurs with riboflavin supplementation.

The findings of this thesis provide RCT data confirming the metabolic dependency of vitamin B6 status on riboflavin. Furthermore, early evidence from the Intervene study suggests that the poorer endothelial function associated with the MTHFR C677Tpolymorphism can be improved with riboflavin intervention. Overall, these novel findings have important implications for emerging dietary recommendations for both riboflavin and vitamin B6.

Thesis embargoed until 31st October 2026

Date of Award	Oct 2024
Original language	English
Supervisor	Catherine Hughes (Supervisor), Helene Mc Nulty (Supervisor) & Mary Ward (Supervisor)