What is already known
Micronutrient deficiencies are a significant health concern in low- and middle-income countries, particularly affecting child development. Traditional methods like supplementation and fortification are not always effective and can have adverse effects, such as digestive issues with iron supplements. Beneficial gut bacteria can improve micronutrient availability by removing anti-nutritional compounds like phytates and polyphenols, or by producing vitamins. Gut bacteria, in conjunction with the intestinal mucosa, also protect against pathogens, reinforce the intestinal epithelium and enhance micronutrient absorption. However, the exact role of gut microbiota in micronutrient deficiencies is not well-understood, and bacterial metabolism depends on obtaining micronutrients from the gut environment, leading to competition or cooperation among resident bacteria to maintain micronutrient homeostasis. Consequently, the composition of gut microbiota can be influenced by micronutrient availability.
What this research adds
This review consolidates the existing information regarding the reciprocal interaction between micronutrients and gut microbiota, with a specific emphasis on iron, zinc, vitamin A, and folate (also known as vitamin B9). These particular deficiencies are public health concerns worldwide.
Conclusions
The interplay between micronutrients and the microbiome is a significant factor in determining the risk of vitamin and mineral deficiencies, which has implications for global public health.
Deficiencies in micronutrient, which encompass essential minerals and vitamins vital for metabolic processes, are a global public health issue, particularly affecting vulnerable groups in low- and middle-income countries. These deficiencies can lead to various adverse health outcomes, including anemia, stunted growth, and cognitive development issues in children. Iron, zinc, vitamin A, and folate (vitamin B9) deficiencies are the most common worldwide.
Efforts to combat these deficiencies include fortifying staple foods, but these strategies are not always effective due to poor acceptability and quality control. Micronutrient absorption primarily occurs in the small intestine through various mechanisms.
The human digestive tract houses a complex community of microorganisms, particularly bacteria, with their composition influenced by genetics and environmental factors, including diet. Gut microbiota plays a crucial role in human health and are associated with various diseases. While most research has focused on macronutrients, bacteria also require micronutrients for survival. For instance, some bacteria compete for external sources of iron, while others can synthesize vitamins like folate.
Although the host’s absorption mechanisms for most micronutrients are well understood, the impact of gut microbiota on micronutrient absorption and availability is less clear. Given the amount and variety of bacteria present along the digestive tract, it is necessary to consolidate current knowledge while highlighting the existing gaps in research within this field.
A recent review from Humblot and colleagues, published on Critical Reviews in Food Science and Nutrition Journal, provides an overview of the reciprocal relationship between the gut microbiota and micronutrients, with micronutrient intakes of the host influencing the composition of the gastrointestinal tract, while the gut microbiota can impact the availability of micronutrients, consequently affecting the host’s micronutrient status.
Micronutrients and host health
Micronutrients are essential for metabolism and overall human health. Despite efforts to increase micronutrient intake through supplementation, fortification, and dietary diversification, micronutrient deficiencies are still highly prevalent globally, affecting both industrialized and developing countries. Vulnerable groups such as children and women are particularly affected due to their higher nutritional requirements.
Clinical signs of micronutrient deficiencies are specific to each nutrient and typically manifest in advanced stages of deficiency. For example, iron deficiency, the most common form of micronutrient malnutrition, can lead to anemia, impaired immune function, reduced work capacity, and endocrine dysfunction. Factors contributing to iron deficiency include low intake of heme iron (which is more bioavailable than non-heme iron), diets rich in phytates and phenolic compounds that reduce iron absorption, and chronic inflammation.
Zinc deficiency, affecting over 1 billion people globally, is associated with growth problems in children (stunting) and weakened immune function, making children more susceptible to diseases like diarrhea, pneumonia, and possibly malaria. Zinc deficiency can also increase the risk of other micronutrient deficiencies.
Inadequate folate intake during pregnancy can result in neural tube defects in early embryonic development. In the general population, folate deficiency can lead to megaloblastic anemia and neurological symptoms similar to vitamin B12 deficiency. Over 20% of women of reproductive age in low- and middle-income countries are estimated to be folate deficient.
Finally, vitamin A deficiency not only causes eye issues and blindness but also compromises immune function and skin and epithelial integrity. To combat this deficiency, high-dose vitamin A supplements are administered every six months to children under 5 years of age in many low- and middle-income countries, although the effectiveness of this intervention is questioned.
Effect of iron on gut microbiota
It has been demonstrated a complex relationship between iron, bacterial growth, and the gut microbiota. Iron levels in the colon are believed to be high, far exceeding the minimum requirement for bacterial growth. However, the bioavailability of iron for bacteria depends on various factors, including the form of iron, iron speciation, pH levels, and oxygen levels. Different forms of iron are used in supplementation or fortification. Iron supplements contain more iron than the body can absorb, leading to a significant amount of unabsorbed iron remaining in the digestive tract.
Studies in humans have shown that iron supplementation or fortification can lead to an increase in potentially pathogenic bacteria and a decrease in beneficial species like those from the Lactobacillaceae family. Iron supplementation after antibiotic therapy also resulted in changes in the composition and function of gut bacteria. Iron is essential for pathogenic bacteria and the mammalian immune system can control iron availability for bacteria by producing iron-binding proteins like lactoferrin, a process known as “nutritional immunity.”
Research on the impact of iron supplementation on gut microbiota yields diverse results, making generalizations difficult. The only consistent results include a decrease in the Lactobacillaceae family and the phylum Actinobacteria during iron supplementation. The chemical form of iron used can also influence bacterial composition, and the effects of iron supplementation do not always directly oppose those of iron deficiency.
Effect of bacteria from the gut on iron bioavailability
Heme iron is more readily absorbed by both bacteria and humans compared to non-heme iron, as it is influenced by the composition of the food matrix and the physico-chemical conditions in the digestive tract. Non-heme iron in many food matrices is bound to inhibitors like polyphenols, fibers, or phytates. Bacterial enzymes can break down these inhibitors, improving iron absorption.
Bacteria can also generate short-chain fatty acids (SCFA) by fermenting indigestible carbohydrates from the diet. SCFA can lower the pH in the digestive tract, converting ferric iron to ferrous iron, thus enhancing its absorption by both bacteria and the host. Additionally, certain organic acids, such as lactic acid, are produced by various bacteria throughout the digestive tract. The acidification of the intestinal environment can also degrade complexes that bind to micronutrients, making iron absorption more efficient.
Innovative strategies to fight iron deficiencies
Due to low compliance and adverse effects of iron supplementation, like diarrhea or constipation, strategies to improve iron status include the use of probiotics, prebiotics, symbiotics, and postbiotics. For instance, a study found that taking the probiotic Lactiplantibacillus plantarum 299v, along with iron, ascorbic acid, and folic acid, was safe and improved iron status while attenuating the loss of iron stores.
Another approach involved the use of iron-free lactoferrin alongside ferrous sulfate, significantly increasing iron absorption. Lactoferrin may be useful in iron formulation for infants, since it enhances iron absorption while reducing potential adverse effects on the gut microbiota. Further possibilities for preventing and treating iron deficiency include the use of iron-enriched microorganisms, which can supply the host with large amount of minerals alongside probiotic benefits. Some experiments in anemic mice demonstrated improved hemoglobin concentrations through the consumption of yeasts grown in the presence of iron. However, human trials with cheese containing iron-enriched yeast were less efficient in absorption compared to cheese with iron sulfate alone, suggesting the need for further research in humans. Overall, the role of gut bacteria in regulating iron bioavailability for the host is clear as well as the complexity of interactions between host factors and bacteria in managing iron uptake, including the potential for sharing iron resources among commensal bacteria and with the host.
Zinc status and gut microbiota in human
Research on the impact of zinc status or supplementation on gut microbiota is limited, despite zinc’s essential role in numerous metabolic processes. A recent study revealed that while there was a comparable level of bacterial diversity in school-age children with and without zinc deficiency, those lacking zinc exhibited greater individual diversity. Notably, the zinc-deficient group had higher levels of certain bacteria, including Coprobacter, Acetivibrio, Paraprevotella, and Clostridium. These bacteria could potentially serve as biomarkers for diagnosing zinc deficiency in clinical settings, although further research is needed to confirm this finding.
Innovative strategies to fight zinc deficiencies
Zinc supplementation has been found to impact the composition and function of gut microbiota, leading to investigations into the combined administration of zinc and probiotics. In human pilot studies, zinc alone was found to be more effective than probiotics for treating children under 24 months. However, co-supplementation of zinc and Lactiplantibacillus plantarum IS-10506 in preschool children did not demonstrate greater efficiency than probiotics alone. Further research is needed to determine the potential benefits of co-administering zinc and probiotics in humans.
While studies on zinc status and host microbiota have primarily focused on pathological conditions, there is a need for deeper investigations, especially in humans, to better understand the relationship between gut bacteria and zin in a normal situation. Emerging tools like zinc-enriched probiotics offer promising alternatives for treating zinc deficiency, particularly considering that high-dose and long-term zinc supplementation may interfere with the absorption of iron and copper, potentially leading to their deficiencies.
Contribution of folate from bacteria to the host
Bacteria require folate for their growth, and some bacteria can synthesize it. While some bacteria can produce folate from environmental precursors, others must acquire it from the environment. Research suggests that bacterial folates synthesis contributes significantly to host folate status. Early studies found higher levels of folate in human fecal samples than dietary intake, implying folate synthesis by gut bacteria.
Genomic analysis of bacterial genomes showed that a substantial percentage contain folate biosynthesis genes. The gut microbiota serves as a significant folate source, and alterations in gut microbiota composition resulting from various factors like diet may influence folate needs.
Consumption of dietary fibers can alter gut microbiota composition, potentially leading to increased folate levels in colon and circulation. It was found that, despite slower folate absorption in the colon compared to the small intestine, labelled folates specifically targeting the colon were incorporated into host tissue. However, one study suggested that fecal microbiota’s folate production may not accurately predict human folate status.
Gut bacteria not only synthesize folate but can also convert folic acid into forms better absorbed by the host. There is also an interplay between different gut bacteria regarding folate production and use, as demonstrated in synthetic co-culture experiments.
The metabolic capacity of gut microbiota depends on both its composition and the host’s physiological characteristics. For instance, genes responsible for folate biosynthesis are more common in the gut microbiota of babies and young children compared to adults. Additionally, undernourished children exhibited lower abundance of genes related to B-vitamin metabolism in their microbiomes, and obese women with low folate status had reduced presence of B vitamin-producing bacteria.
Use of folate producing bacteria to enrich food
Numerous bacteria capable of producing folate have been identified and effectively utilized to enhance folate content of fermented foods. Some of these bacteria have also demonstrated the ability to enhance folate levels in rodents following folic acid-deficient diets.
Using folate-producing probiotics offers a potential avenue for improving folate status and regulating gut microbiota. Encouraging outcomes have emerged from in vitro studies, wherein the folate-producing bacterium Latilactobacillus sakei was found to elevate SCFAs and modify the fecal bacterial composition. Similarly, in rats, the consumption of fermented milk produced with a folate-producing Lactiplantibacillus plantarum not only restored normal folate levels but also significantly reshaped the composition of gut bacteria.
Interaction between microbiota composition and vitamin a absorption and metabolism
Vitamin A plays a vital role in immune regulation, cytokine production, and maintaining the gut barrier. It supports intestinal epithelial cell proliferation, differentiation, and resistance to pathogen invasion.
Dietary vitamin A exists as retinyl esters and pro-vitamin A carotenoids, present in animal food and vegetables, respectively. Absorption of these compounds occurs primarily in the upper half of small intestine. Vitamin A and carotenoids are fat-soluble compounds in our diet that need to be solubilized into micelles before they can be absorbed by enterocytes. This solubilization process begins with emulsification into small droplets in the stomach and duodenum, where vitamin A becomes part of micelles created with bile salts.
Carotenoids can passively diffuse into enterocytes, while retinoids rely on carrier-dependent proteins for absorption. Only free retinoid forms are absorbed, necessitating the hydrolysis of retinyl esters to retinol. The presence of bile salts produced by certain gut bacteria, like Lactobacillaceae, Bifidobacterium, Bacteroides, or Clostridium, can facilitate vitamin A solubilization and enhance its absorption, as bile salts are essential for the micellarization process.
Vitamin a status and gut microbiota: studies in human population
Carotenoid intake and status are linked to increased microbiota diversity and the abundance of beneficial bacteria. In pregnant women, carotenoid intake and plasma concentrations correlate with greater diversity in gut microbiota. The influence of vitamin A on gut microbiota composition can indirectly impact immune responses in the intestine. For instance, vitamin A has been shown to inhibit norovirus replication, a common cause of acute gastroenteritis, both directly and indirectly through microbiome changes, particularly affecting Lactobacillaceae.
In patients with ulcerative colitis, vitamin A intake leads to significant shifts in microbiota composition. In children with autism, vitamin A supplementation increases Bacteroidales bacteria while reducing Bifidobacterium. Interestingly, a study involving 306 neonates in Bangladesh found that vitamin A supplementation increased Bifidobacterium levels in boys compared to a placebo, with no significant difference in girls. Furthermore, Actinobacteria relative abundance was positively associated with plasma retinol in girls in a concentration-dependent manner, but not in boys. Additionally, the relative abundance of Akkermansia, a mucosa-associated bacterium, was positively associated with plasma retinol in girls.
In summary, there is a lack of data on how micronutrients like iron, zinc, vitamin B9, and vitamin A impact the composition of gut microbes. However, the interplay between these micronutrients and the microbiome is likely a significant factor in determining the risk of vitamin and mineral deficiencies, which has implications for global public health.
Therefore, researchers and policymakers, including European institutions and national ministries, focusing on micronutrient deficiencies should consider the role of the human microbiota.
Furthermore, studies on micronutrient metabolism should expand their focus to include the overall composition of gut microbiota, rather than just pathogenic bacteria, as has been the case with iron. Collaborative efforts between microbial scientists, food scientists, and nutrition scientists could offer innovative approaches to combat micronutrient deficiencies.
While the effects of iron on the intestinal microbiota have been extensively studied due to the widespread prevalence of iron deficiency, further research into the effects of zinc, vitamin B9, and vitamin A, either alone or in combination, is necessary to better understand the intricate interaction between micronutrients, the microbiome, and the host.
