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D’Aimmo et al. Microbiome Res Rep 2024;3:11 https://dx.doi.org/10.20517/mrr.2023.59 Page 17 of 22

Therefore, microbial metabolic engineering, which involves the modification of metabolic pathways
through genetic manipulation, represents a potent tool for enhancing the production of valuable
compounds in microorganisms beyond their inherent capabilities. These customized microbial cell
factories, referred to as engineered microbes, have been effectively generated to overproduce various
vitamins like B , B , and C [106-108] . However, it is worth noting that folates continue to be synthesized
12
2
chemically, as previously mentioned. Nevertheless, numerous metabolic engineering strategies have
emerged in both prokaryotic and eukaryotic microorganisms, paving the way for a more sustainable
approach to vitamin B production in the near future.
9
Ultimately, to achieve biotechnological folate production and biofortification of fermented foods, two
essential factors must be considered: (i) robust biomass production of microorganisms and (ii) an
appropriate technical process. The microorganism used should have the ability to produce folate efficiently
in a biological reactor, fermented foods, or the gut microbiota and must possess suitable properties to
complete that. The latter approach is particularly attractive since folate probiotics can significantly enhance
folate uptake by the host animal, as discussed above. The technological process must promote the
production and accumulation of folate in the chosen bioreactor or food product.

CONCLUSIONS
The global prevalence of folate deficiency varies largely between countries and surveys. Meta-analysis of
relevant studies suggests > 20% in low-income countries and < 5% in high-income countries. Deficiency
increases the risk for various negative health consequences, such as birth defects and anemia.

The growing awareness of the complexity and importance of the human gut microbiota for health and
disease motivates further studies targeting specific questions. This review addressed whether bifidobacteria
may contribute to a healthy folate status. The present review shows that fundamental research within this
field will lead to crucial insights such as recognizing a “good folate gut microbiota” vs. a “not so good”.

There are many open questions to be asked in the coming research. Many of those require a metagenomic
sequencing of the gut microbiota composition and an assessment of folate status in animals and humans.
How does it correlate? We would like to propose the following questions: (i) does a folate-rich diet select a
different gut microbiota compared to a folate-poor diet? If yes, (ii) can a gut microbiota with a large fraction
of high folate-producing bacteria compensate for a folate-poor diet to some extent? (iii) Can we significantly
improve the human folate status in those needed by selected bifidobacteria as probiotics and/or in
fermented foods? If yes, (iv) would it depend on the individual gut microbiota present? In other words,
could we learn how to recognize a gut microbiota likely to respond well to certain “folate probiotics”?

The bifidobacteria folate biosynthesis machinery and related genetics and physiological and bioprocessing
studies on folate production were reviewed. The differences between species and strains are large, as is the
impact of cultivation conditions on specific folate content. Advancing comprehension in this field will
contribute to the formulation of bio-based strategies aimed at enhancing folate levels in disadvantaged
population groups. This motivates further R&D to develop naturally high-folate fermented foods and
probiotics as alternatives to traditional fortification with synthetic folic acid.

DECLARATIONS
Authors’ contributions
Conceived and designed the work: Mattarelli P, D’Aimmo MR, Andlid T, Luiselli D, Scarafile D,
Modesto M