Maternal nutrition, seasonality and epigenetics: an exploration of one-carbon metabolism and a novel nutritional supplement design in The Gambia

A series of studies in rural Gambia established first-in-human evidence that periconceptional environment, including maternal methyl-donor nutritional status, predicts offspring DNA methylation. Methyl donor status is largely determined by the complex interlinking pathways of one-carbon metabolism. Women’s methyl donor status (‘methylation potential’) is higher in the Gambian rainy season than in the dry season. Compared to infants conceived in the rainy season, those conceived in the dry season have decreased methylation at metastable epialleles (MEs). MEs are genomic loci whose methylation states are established in the very early embryo prior to gastrulation. Dry season conceptions are also associated with methylation patterns suggestive of a loss of imprinting at the VTRNA2-1 gene, a putative tumour suppressor and regulator of innate immunity. The long-term goal is to design an intervention that shifts the maternal metabolome to improve regulation of the infant epigenome by providing micronutrients in the ratio and quantity necessary for optimal one-carbon metabolism all year round. To achieve this we first require a proof-of-concept trial showing that a nutritional supplement can address nutritional imbalances and increase methylation potential in non-pregnant women. This step provides the overall rationale for this thesis. The research in this thesis contributes three key areas to existing knowledge of nutritional epigenetics in The Gambia. Firstly, it characterises seasonal differences in plasma nutritional biomarkers in a new dataset, validating the findings from previous studies and extending the consideration to new metabolites. Secondly, it explores how maternal nutritional predictors of infant DNA methylation may change between seasons, highlighting the importance of considering seasonality and underlying nutritional status in nutritional epigenetic research. Thirdly, it describes the design of a novel drink powder supplement, tailored to the target population by analysing negative nutritional predictors of homocysteine (designed to increase methylation potential). A clinical trial tested this new supplement alongside an existing multiple micronutrient tablet (UNIMMAP) amongst non-pregnant women in rural Gambia. Both interventions proved to be promising candidates for future epigenetic trials, acting on metabolic pathways to increase methylation potential. Whilst the explicit targeting of DNA methylation profiles by nutritional interventions remains premature, accumulating evidence supports a focus on nutrition-sensitive epigenetic mechanisms as potential contributors to the developmental origins of health and disease.