Can we microbe-manage our vitamin acquisition for better health?

Introduction

Vitamins are indispensable micronutrients that are needed for a myriad of metabolic and regulatory processes critical for all living organisms [1–3]. Because humans do not have the capacity to synthesize most of these essential nutrients themselves, they need to be obtained externally. Even though vitamins can be found in various foods, deficiencies still occur in developing and industrialized countries [4]. A rather unexpected source of vitamins is the microbiota present in the gastrointestinal (GI) tract. Most of these microbes can synthesize vitamins de novo and even produce them in excess, notably vitamin K and vitamins in the B group such as riboflavin, niacin, and cobalamin [5,6]. It has been estimated that they produce up to 30% of the recommended daily intake for the host; however, this depends on the microbiome composition and the host’s diet [7]. Moreover, microbes can work together to produce vitamins that can modulate the metabolic activity and composition of the human gut microbiome [8,9].

Interestingly, recent research has highlighted the importance of vitamins in the pathology of opportunistic pathogens that live as commensals in the human GI tract [10,11].

The advantages of vitamin production by gut microbiota

The human GI tract harbors a large and complex population of microorganisms that offers a range of physiological functions and are consequently imperative for the host’s health [1,2]. It has been shown that vitamins can beneficially modulate the microbiota in the GI tract by expanding the abundance of commensals, enlarging the microbial diversity, altering the amount of short-chain fatty acids, or modulating the barrier function or immune response [9]. Most of the human GI tract’s commensals can biosynthesize and secrete vitamin K and B group vitamins, but besides excess vitamin biosynthesis, the gut microbiota can also convert dietary vitamin A precursors into retinoic acid, a key regulator of gene expression [12,13]. This elevates the concentration of vitamin A metabolites, aids in maintaining immune homeostasis, and helps to prevent pathogen invasion (Fig 1) [13]. Furthermore, vitamins with antioxidant properties can affect infectious diseases, either directly or indirectly by tuning the immune system or the redox state [14,15].

[Figure omitted. See PDF.]

Fig 1. The role of gut microbiota in vitamin production.

Humans acquire vitamins through their diet and the microbiota in the large intestine, which can produce up to 30% of the recommended daily intake of vitamin K and the B group vitamins. The excreted vitamins can be used to cross-feed other species or can be absorbed by the host. Besides vitamin secretion, commensals in the GI tract can convert dietary vitamin A into active vitamin A metabolites, which are important for maintaining epithelial homeostasis and immune function. Created with BioRender.com. GI, gastrointestinal; IgA, immunoglobulin A; IL-17, interleukin 17; Th17, T-helper 17.

https://doi.org/10.1371/journal.ppat.1011361.g001

Vitamin cross-feeding: Teamwork makes the dream work

The microbial community of the GI tract relies on dynamic interactions among microbes that sustain a complex network of interconnected metabolisms [16]. Hundreds of metabolites are consumed, secreted, and shared in a phenomenon called cross-feeding, which leads to interspecies interactions, which can directly impact the human host [17,18].

According to genome annotation studies, 40% to 65% of human gut commensals produce at least one of the 8 vitamins belonging to the B group. While some organisms produced all 8, some had no de novo vitamin synthesis, which led to an interesting observation where pairs of organisms have complementary vitamin synthesis pathways [8]. This indicates that the gut microbes actively exchange vitamins among each other, suggesting that cooperation between species is necessary and may have led to the coevolution of certain species (Fig 1) [8]. An interesting example is vitamin B12 or cobalamin, a rather unusual vitamin as it is exclusively synthesized by microorganisms. The de novo synthesis is complicated and energetically demanding as it takes 30 enzymatic steps [19]. Therefore, some species salvage intermediates of the synthesis or the final cobalamin product from other species [20]. It has been shown that Clostridioides difficile, an opportunistic pathogen and common inhabitant of the human gut, down-regulates its cobalamin biosynthesis in the presence of Clostridium sardiniense. This indicates the cross-feeding of vitamin B12, which consequently influences community population dynamics. Interestingly, the combination of these organisms worsens the pathogen’s virulence in vivo partly by adapting the metabolism to one another, showing that commensals can alter the GI tract nutrient environment to modulate the virulence of pathogens [21].

The benefits of harboring opportunistic pathogens in the GI tract

The human GI tract is home to a variety of opportunistic pathogens such as Candida albicans that can cause invasive diseases with extremely high morbidity and mortality [22]. However, these pathogens are present in the GI tract of most people without causing any infection. This commensal state is underexplored, and it remains unclear what these potential pathogens are doing in the healthy GI tract. It seems likely that an opportunistic pathogen in the human GI tract would elicit some host benefit as a solely harmful pathogen would be subjected to a negative selection [23]. These benefits may provide an evolutionary pressure for establishing and maintaining opportunistic pathogens in the human gut. Rather remarkable about some pathogens is their excessive vitamin production. C. albicans, for example, secretes high levels of riboflavin, but it remains unclear why, as the physiological role for the overproduction is unknown [24]. It is conceivable that the produced vitamin can be absorbed by the host or other commensals and consequently provides a benefit for the human host.

Besides vitamin secretion, other advantages of harboring potential pathogens in the GI tract have been discussed before. It has been shown that these pathogens can train the immune system by stimulating the responsiveness of neutrophils and by providing protection against invasive infections (Fig 1) [23,25,26]. It is not surprising that opportunistic pathogens would offer some host benefits as they have coevolved for many years to form intricate and complex relationships [27]. In fact, these benefits most likely provide an evolutionary pressure for the establishment and maintenance of opportunistic pathogens as commensals in the gut.

Nurture your microbiota for more vitamins

Throughout the last century, mankind has raged a war against bacteria [28]. While antibiotic treatments help many people, major concerns are arising regarding drug resistance and the importance of the microbiome for human health. By eliminating part of our microbiota, we disarm our own defense lines and become more susceptible to other infections, e.g., fungal diseases. Recently, probiotics have become one of the most popular food supplements to the point where they have become a fast-growing multibillion-dollar industry [29]. Most probiotics contain species of the Bifidobacterium, Lactobacillus, or Saccharomyces genera, all capable of de novo synthesis of vitamins [30]. The elevated vitamin production of specific strains could be a novel promising application of probiotics as it can be helpful for both the host and other microbial species as the vitamin can be synthesized and delivered directly into the intestine [31,32]. This would be especially useful for water-soluble vitamins such as B vitamins, which cannot be stored in the body and consequently require a constant supply. Furthermore, it has been shown that a riboflavin-overproducing Lactobacillus strain can prevent mucositis, a mucosal inflammation and common side effect of cancer treatments [33].

Apart from probiotics, diets can also influence vitamin production. It has been shown that urinary riboflavin excretion was increased among people with higher carbohydrate and low-fat diets, suggesting that riboflavin secretion by the microbiota was enhanced in this condition [34].

Altogether, there are interesting applications for vitamin-overproducing strains as their antioxidant and anti-inflammatory properties can improve host health and the vitamin is protected from the harsh environment of the GI tract as it is secreted directly into the large intestine [31,33,35,36].

Vitamin fortification, beneficial or detrimental to human health?

In recent decades, the dietary patterns in high-income countries have shifted towards a higher calorie density and reduced nutritional value, which can lead to insufficient intake of certain micronutrients [37]. One strategy to enhance nutrient ingestion without increasing caloric intake is the fortification of food with vitamins, which has led to substantial health benefits [38,39]. Besides fortified foods, vitamins are also obtained from non-fortified foods and supplements, but the benefits of the latter are still debated in scientific research. While some studies suggest that vitamin supplements can increase gut microbial diversity and offer protection against infectious diseases, other research has shown that taking vitamins without medical justification does not reduce the risk of cardiovascular diseases or cancer and can even be harmful [40–47]. Excessive intake of fat-soluble vitamins (A, D, E, and K) can be particularly detrimental as these vitamins accumulate in adipose tissue, leading to adverse health effects. In contrast, water-soluble vitamins rarely accumulate in the body and are excreted by the kidneys. However, oral vitamin supplements typically provide high doses that surpass the recommended daily amount, which can alter the competitive or syntrophic interactions between gut microbes [48]. Studies with mice have demonstrated that vitamin B12 supplements promote colonization and pathogenesis of Citrobacter rodentium, a mice-specific pathogen, by altering the activities of Lachnospiraceae species. These findings emphasize that oversupplementation of vitamins can disrupt microbe–host interactions by altering microbial vitamin competition and sharing [48].

Vitamin biosynthesis as a drug target for new antibiotics

Vitamin biosynthetic pathways can be interesting drug targets as humans do not possess the enzymes for de novo synthesis while many microorganisms do. Therefore, host toxicity can be limited, which is especially interesting for pathogenic fungi where toxicity is a recurrent problem due to the high resemblance of pathways and subcellular structures, as fungi and humans are both eukaryotes. Especially the riboflavin (vitamin B2), pantothenic acid (vitamin B5), and folate (vitamin B9) biosynthesis pathways seem to be interesting drug targets as they are well conserved among fungi and essential for fungal growth [49]. Furthermore, vitamins are precursors for cofactors that are involved in a wide variety of metabolic processes. Their absence will trigger a wide inhibitory cascade of many metabolic processes. Additionally, the substrates and products of these enzymes are well known and have a high potential to be druggable [49].

Due to these promising aspects, researchers have investigated these pathways to inhibit microbes. Recently, roseoflavin, a riboflavin analogue, was found to inhibit the proliferation of the malaria parasite [50]. Also, riboflavin synthase was selected as a therapeutic target to inhibit gut microbes involved in the development of colorectal cancer [51].

An important factor to keep into account when targeting vitamin synthesis is the presence of the vitamins in the human gut. Some pathogens can take up external vitamins from the gut lumen, which can circumvent the drug’s mode of action.

Overall, microbial vitamin biosynthesis, and its effect on the host and commensal species, highlight the importance of the microbiota in supplying micronutrients. However, further insides regarding the molecular mechanisms of cross-talk between the microbiota and the human host are necessary to gain a deeper understanding of its role in human health and for the development of new therapeutic strategies.

Citation: Nysten J, Van Dijck P (2023) Can we microbe-manage our vitamin acquisition for better health? PLoS Pathog 19(5): e1011361. https://doi.org/10.1371/journal.ppat.1011361

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