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Page 8 of 22 D’Aimmo et al. Microbiome Res Rep 2024;3:11 https://dx.doi.org/10.20517/mrr.2023.59

[51]
foods . Therefore, dietary adaptations to new environments and food availability may have played a crucial
role in human adaptation, including efficiency in folate uptake and metabolism, which is vital for human
and animal health. Due to the low folate content in most food derived from animal sources, the diet itself
was presumably insufficient to provide adequate amounts of folate. In this scenario, microbiota could have
had an important role in compensating for a diet poor in folate and other important micronutrients. Folate-
producing bifidobacteria may have played a key role in maintaining a sufficient folate status as an important
group of the human gut microbiota.

MICROBIAL BIOSYNTHESIS OF FOLATE AND GUT MICROBIOTA
The gut contains approximately 10 to 10 bacteria, roughly comparable to the average number of the
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[52]
human body’s cells . These microorganisms and their genetic material constitute the gut microbiome.
Most gut microbiota are anaerobic bacteria, a few hundred species per host . Bacillota, Bacteroidota, and
[53]
Actinobacteriota represent > 90% of the microbial diversity, followed by a smaller proportion of
Pseudomonadota, Fusobacteriota, and Verrucomicrobiota .
[54]
The exact timing when the gut microbiota reaches an adult-like intestinal microbiota (maturation) remains
unclear. Gut colonization begins in early life and is affected by factors such as mode of delivery,
breastfeeding, and gestational age at birth. After that, everyone develops a more mature and unique
microbiota. However, even if the bacterial community of a mature gut is much more stable, it is not
completely static but rather a dynamic system affected by lifestyle, genetic , age, nutrition , medications,
[55]
[56]
and environment .
[57]
Metagenomic studies found that COGs (Clusters of Orthologous Groups), involved in synthesizing
[58]
B vitamins, including folate , are enriched in the human distal gut microbiome. Bacteria can produce
mono- and poly-glutamylated folate. The most common ones are polyglutamylated, such as THF,
5-methyl-THF, and 10-formyl-THF. All these forms are easily processed and absorbed by the intestinal
[59]
epithelium of mammalian cells [60,61] .
The physiological surroundings, such as digestive enzymes, gut motility, acidity levels, transporters, and
proteins, impact the absorption process of vitamin B in the gut. The human gut expresses two folate uptake
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systems. One is the proton-coupled folate transporter (hPCFT, derived from the SLC46A1 gene), and the
other is the reduced folate carrier (hRFC, derived from the SLC19A1 gene). The hPCFT protein operates in
the proximal small intestine at pH 5.5 to 6.0. On the other hand, the hRFC works better at a more neutral
pH of 7.0 to 7.4 and, therefore, plays a role in uptaking folate in the distal tract of the gut under more
alkaline pH conditions . Vitamins produced by microorganisms are primarily absorbed in the colon, while
[62]
vitamins supplemented with the diet are principally absorbed in the small intestine .
[63]
The gut microbiota of mammals plays a central role in maintaining the homeostasis of folate . Some
[64]
bacteria can synthesize vitamin B , while others can consume it. In addition, microorganisms can take up
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folate from the environment and use it in the same reactions as humans. Furthermore, another factor to
consider is the amount of folate released back into the lumen when the microbiota dies and lyses. This
amount, along with the balance between producers and consumers, determines the folate homeostasis in the
host.

Genome analysis revealed that most lactobacilli lack the genes for the biosynthesis of pABA and are
predicted or shown to be auxotrophic for folate . As a result, Lacticaseibacillus rhamnosus is traditionally
[65]
used to quantify folate in, for instance, food samples by microbiological assays (relying on the dependence