Folates, lifespan and the gut microbiome

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It is an increasingly well known – or at least, well quoted – fact that humans contain ten times more bacterial cells than human ones. The microbial population of the gut in particular is the focus of vigorously burgeoning research interest because of its possible importance in metabolic and inflammatory disease, as testified by a recent special section of Science dedicated to the topic.

It is already well known that antibiotics upset the balance of the intestinal microflora, but more subtle effects of drugs and diet that may influence or be influenced by the gut microbiome are among the many questions yet to be properly explored. In this context, an entirely adventitious discovery in the nematode worm Caenorhabditis elegans, reported in BMC Biology, may open new questions on the effects of diet, drugs and intestinal bugs on longevity.

The original aim of the experiments, in the laboratory of David Weinkove, was to identify genes affecting longevity by knocking them out with RNAi introduced into the E. coli on which laboratory worms are normally fed. The adventitious discovery was that the increased lifespan in the particular case now reported in BMC Biology has nothing to do with the gene under investigation, but is the consequence of a defect in folate biosynthesis in the E. coli carrying the RNAi.

In pursuit of the mechanism of this unlooked-for effect, Weinkove and his colleagues have succeeded in establishing that the folate status of the dietary E. coli is critical to the effect on worm longevity, though not how it works. Mysteriously, for example, replacing the folate precursor pABA in the worm’s diet reverses the increase in longevity, but replacing the folate end-product only partially reverses it.

Weinkove and colleagues cite a study in rats reporting that sulfonamides inhibit folate biosynthesis in gut microbes and prolong the life of the rats, suggesting that effects on folate status may not be confined to nematode worms, and in an accompanying commentary explaining the issues, and with helpful illustrations of the biochemical pathways involved, Theresa Nguyen and Catherine Clarke raise questions of the possible effects on humans of sulfonamide antibacterial drugs, which act by intercepting folate synthesis, and of dietary folate supplements in bread and cereals.

All this opens interesting avenues for further research. But until a lot more is known about the mechanism of these effects, it seems appropriate to say that it would be premature to conclude that if we want a long life we should avoid folate-supplemented breakfast cereals and embrace sulfonamide drugs.

Miranda Robertson