Folate and choline: does it take two to tango in early programming of disease?

Background: The early life period marks a critical time during which the health trajectory of offspring can be shaped by external influences including maternal nutrition. Folate and choline are water-soluble micronutrients important for fetal development and involved in one-carbon metabolism. Intakes above and below the recommendations commonly occur for both of these nutrients including over-consumption of synthetic folic acid due to widespread vitamin supplement uses and discretionary fortification practices, whereas choline is under-consumed by a majority of the populations including pregnant women. Despite these intake patterns, long-term impact on offspring health is largely unknown. Moreover, limited attention has been on the combined effects of folate and choline despite being metabolically interrelated as methyl nutrients. This review summarizes evidence from animal models and human studies investigating the role of inadequate or supplemental maternal intakes of folic acid, choline and combined effects of folic acid and choline as modulators of health and disease in offspring. With the recent rise in the prevalence of obesity and metabolic diseases, our primary measures of interest were metabolic outcomes. Summary: Studies examining the role of maternal folate and/or choline in metabolic phenotypes of offspring have mostly been conducted in animal models with a limited number of reports that consider folate and choline together. Interdependent relationship between folate and choline has been demonstrated in studies where a deficiency in one leads to metabolic aberrations in another. Both deficient and excess maternal intakes of folic acid (in varying doses) have been shown to increase risk of obesity and characteristics of the metabolic syndrome in offspring but these findings were restricted to animal studies. Potential metabolic benefits of choline have been suggested in the presence of obesogenic environment but human data were sparse. An imbalanced intake of high folic acid and inadequate choline in the gestational diet created adverse consequences consistent with the obesogenic phenotypes whereas narrowing this imbalance with high choline blocked these effects. Mechanisms by which maternal folate and/or choline influence offspring outcomes may involve epigenetic modification of gene expression with DNA methylation that can be altered globally and gene-specifically. However, the effects of epigenetic programming were inconsistent, as compensatory changes in metabolic products may occur and other contributors including the gut microbiota may provide additional insights into the mechanisms. Key Messages: Folate and/or choline can impact offspring long-term health, with metabolic consequences that may arise from imbalances between folic acid and choline intakes. However, there is a paucity of mechanistic understanding as various contributors influence programming effects including those beyond epigenetics. As folate and choline are metabolically interrelated, future studies need to consider both nutrients to better elucidate metabolic programming of health and disease