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Friday, March 10, 2017

Folate status of gut microbiome affects lifespan

The first genes extending lifespan were identified in the nematode Caenorhabditis elegans [1], and several of the metabolic pathways they are involved in are conserved in other species, including flies, mice and humans. Some of the pioneering studies on aging in C. elegans made use of RNA interference (RNAi) to manipulate gene expression, a strategy that is easily applied in C. elegans by feeding the worms on Escherichia coli strains expressing the relevant RNA sequence.

However, it is becoming increasingly clear that the E. coli diet itself can have profound affects on C. elegans lifespan, and the degree of bacterial colonization within the worm gut has been shown to correlate inversely with worm lifespan [2]. In a recent paper in BMC Biology, Virk et al. [3] capitalize on a serendipitous finding - they show that a C. elegans lifespan extension phenotype originally attributed to an RNAi clone targeting the ugt-27 gene is actually due to a spontaneous mutation present in the host E. coli strain. The authors then use classic nutritional selection experiments and identify the mutation as an IS1 insertion element within the E. coli aroD gene. AroD is a dehydratase required for the production of shikimate (SHK; Figure 1), which is in turn a precursor of chorismate, a precursor of a wide variety of aromatic compounds in E. coli. Thus, the aroD mutation affects production of Phe, Tyr, and Trp (essential aromatic amino acids), menaquinol (vitamin K2), enterobactin (involved in E. coli iron uptake), coenzyme Q (an essential lipid component of the respiratory chain) and folates (vitamin B9). Virk et al. convincingly demonstrate that the lifespan extension in C. elegans can be returned to normal when the diet of E. coli aroD- is supplemented with either SHK or the folate precursor, pABA (Figure 1), but not when it is supplemented with the other aromatic products of this pathway. Because pABA supplementation abrogates the lifespan extension of C. elegans fed the aroD- E. coli diet, Virk et al. focus their attention on folate metabolism.

Folate supplementation, sulfa drugs, and human aging

Like C. elegans, mammals are unable to synthesize folate and acquire the metabolite through diet and gut microflora production. Since 1998, the US Food and Drug Administration has required folate supplementation in all cereal grains, which has resulted in higher blood folate content of the adult, non-supplement using population [9]. Recently, a study on the gut microflora of 531 human subjects across a wide range of ages, ethnicities, and geography showed that microbes residing in babies are enriched in genes involved in de novo folate biosynthesis, whereas the microbes residing in adult subjects were enriched in genes that metabolize dietary folate and THF [10]. However, because folate supplementation regulations and diet differ in the sampling population, there is insufficient data to assess whether the changes in microbial folate biosynthesis gene expression are linked to dietary folate. Interestingly, Virk et al. note that sulfa drugs have been reported to inhibit microbiome folate synthesis and extend lifespan in rats [1]. While the mechanism remains to be determined regarding how genetic or pharmacological knockdown of folate in E. coli can enhance C. elegans lifespan, Virk et al. have raised the intriguing possibility that manipulation of the folate status of gut microflora may impact lifespan in other species.


The use of folate-producing strains can be regarded as a new perspective on the specific uses of probiotics. Within the genus Lactobacillus, the strains belonging to the species L. plantarum are expected to produce folate in the presence of preformed pABA, while the other species cannot be regarded as folate producers. Therefore, the application of lactobacilli as folate-producing probiotics seems to be precluded, even though selected strains of L. plantarum deserve to be used in animal trials to provide evidence of their ability to produce folate in vivo. Unlike lactobacilli, several folate‑producing Bifidobacterium strains have been selected, but the release of high amounts of vitamin does not seem to be widespread within the genus. Animal trials confirmed that the administration of folate-producing bifidobacteria positively affected the plasmatic folate level, indicating that the vitamin is produced in vivo by the probiotic strains, and absorbed. In a human trial, the administration of the same strains resulted in a significant increase of folate concentration in feces. Even though the effect on plasmatic levels has not been investigated so far, folate-producing bifidobacteria may provide a complementary endogenous source of the vitamin and may contribute to prevent folate deficiency, which is often associated with premalignant changes in the colonic epithelia.


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