Unmetabolized folic acid and organ fibrosis: Are they nefarious partners?

Abstract

Recent publications raise the possibility that folic acid (FA), specifically unmetabolized folic acid (UMFA), might promote the progression of organ fibrosis via signaling through folate receptors, leading to excessive extracellular matrix production by myofibroblasts and other cell types. Clinical research over the past two decades adds credence to this largely unexplored contention. FA is a synthetic form of folate, first made in 1945, that has been added to the food supply in the US since 1998 to decrease neural tube defects; subsequently, other countries have followed suit. Notably, synthetic FA, compared to natural dietary folates, is metabolized differently, and potentially activates cellular signaling pathways, leading to fibrosis progression. Although FA food supplementation programs have resulted in a roughly 2-fold increase in serum folate concentrations and a decrease in the prevalence of neural tube defects, other concerns have surfaced. As such, due to the incomplete metabolism of ingested FA, before it can enter cellular processes, most individuals exhibit concentrations of unmetabolized folic acid (UMFA) in the circulation. We hypothesize that it is UMFA, but not natural occurring food folates, which in part promotes the progression of organ fibrosis in many systems. We feel the issue is relevant since organ fibrosis is involved in nearly half of all mortality in industrialized nations. Finally, this proposed nexus of UMFA and organ fibrosis might have preventive and therapeutic implications, and more research is needed on the topic.