Abstract
BackgroundTo prevent folate deficiencies, many countries supplement various foodstuffs with folic acid. This compound is a synthetic oxidised folate that differs from naturally occurring reduced folates in its metabolism and uptake. Notably, safety reviews of folic acid supplementation have not considered interactions with gut bacteria. Here, we use the Caenorhabditis elegans – Escherichia coli animal– microbe model to examine a possible bacterial route for folic acid uptake. It has been assumed that supplements are taken up directly by the worm, especially because E. coli is unable to take up folates. However, E. coli, like many other bacteria, can transport the folate breakdown product, para-aminobenzoate-glutamate (PABA-glu), via AbgT and use it for bacterial folate synthesis. This pathway may impact host health because inhibition of bacterial folate synthesis increases C. elegans lifespan.ResultsFolic acid supplementation was found to rescue a C. elegans developmental folate-deficient mutant; however, a much higher concentration was required compared to folinic acid, a reduced folate. Unlike folinic acid, the effectiveness of folic acid supplementation was dependent on the E. coli gene, abgT, suggesting a bacterial route with PABA-glu uptake by E. coli as a first step. Surprisingly, we found up to 4% PABA-glu in folic acid preparations, including in a commercial supplement. Via breakdown to PABA-glu, folic acid increases E. coli folate synthesis. This pathway restores folate synthesis in a bacterial mutant defective in PABA synthesis, reversing the ability of this mutant to increase C. elegans lifespan.ConclusionsFolic acid supplementation in C. elegans occurs chiefly indirectly via bacterial uptake of breakdown products via E. coli AbgT, and can impact C. elegans development and longevity. Examining how folic acid supplementation affects bacterial folate synthesis in the human gut may help us to better understand the safety of folic acid supplementation.
Highlights
IntroductionMany countries supplement various foodstuffs with folic acid
To prevent folate deficiencies, many countries supplement various foodstuffs with folic acid
E. coli is required for folic acid supplementation to prevent a C. elegans folate deficiency In order to examine if E. coli is required for folic acid to prevent developmental defects in our C. elegans folate deficiency model, we tested whether the E. coli abgT genotype influenced the outcome of supplementation
Summary
Many countries supplement various foodstuffs with folic acid. At each step of the folate cycle, an enzyme mediates a modification of the pterin ring of the bound folate, allowing the transfer of a chemical group containing one carbon atom (methyl, formyl, etc.) to or from the compound being synthesised [1] This cofactor role results in Animals cannot synthesise folates and must acquire them from their diet or gut microbes. There are concerns that folic acid supplementation may have adverse effects on health, especially in older people [4,5,6,7], and there are many unknowns about the efficacy of uptake and biological utilisation of folic acid [8] Despite these uncertainties, recent reviews of the evidence by Maynard et al BMC Biology (2018) 16:67 experts acting for government public health bodies have concluded that the risks are minimal and have recommended the fortification of flour or other food products as a beneficial intervention [3, 9, 10]
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