Human-associated microorganisms—approximately 10¹⁴ species—including their genes and metabolites, are known as microbiota, and their configuration begins from the perinatal period ^[1][2][1,2]. In the case of intestinal microbiota, the interdependent relationship with the human gastrointestinal tract is established during the first 3 years of life, but several important factors (e.g., genetics, diet, stress) can influence microbiota composition and, subsequently, their powerful symbiosis with the human body [2]. The imbalance in the gut microbiota, known as dysbiosis, can lead to serious consequences: intestinal and extra-intestinal disorders such as allergic/autoimmune diseases, cardiovascular or neurological disorders, behavioral diseases, or cancer ^[1][2][3][1,2,3]. Therefore, prevention and therapeutic strategies that maintain a healthy gut environment and human well-being have become trendy.

The “probiotic paradox” is based on the observation that both live and dead probiotic cells can produce a biological response, suggesting that the consumption of non-viable microbial cells confers some health benefits for consumers [3]. These ideas have directed microbiota research towards the postbiotic concept. Another direction explored the contribution of gut microbiota in the biosynthesis, uptake, absorption, and bioavailability of micronutrients. Therefore, the present paper aims to present an overview of the developments in the area of postbiotics related to advances in research of micronutrient-enriched biomass, and gaps  in our knowledge are highlighted while proposing a new strategy for microbial therapy—mineral-enriched postbiotics. The possible beneficial effects of these products on the host, directly or through the gut microbiota, are described and discussed based on the existing evidence about relationships between postbiotics and minerals with the gut microbiome, and further directions are depicted.

2. The Health Benefit of Mineral-Enriched Biomass and Their Applications in Microbial Therapy to Maintain Eubiosis and Improve Mineral Bioavailability

Micronutrients are vitamins and minerals needed by the body in very small amounts. However, their impacts on the body’s health are critical, and deficiency in any of them can cause severe and even life-threatening conditions. Because humans cannot synthesize all essential micronutrients, they need to be acquired exogenously from diet or oral supplements or produced by intestinal microbiota, such as vitamins K and B group ^[4][41]. They perform a range of functions, including enabling the body to produce enzymes, hormones, and other substances needed for normal growth and development. Micronutrient deficiencies can cause visible and dangerous health conditions, but they can also lead to less clinically notable reductions in energy level, mental clarity, and overall capacity. Many of these deficiencies are preventable through nutrition education and consumption of a healthy diet containing diverse foods, as well as food fortification and supplementation, where needed.

2.1. The Impact of Micronutrients on Human Health

Micronutrients ensure the preservation of homeostasis with a key role in the response that the human body can have in case of interactions with the external environment or reduce the disease burden. Certain micronutrients (vitamins and/or carotenoid compounds) are strictly dependent on the concentration present in the body to be considered valid. Often, their low concentration makes their influence negligible in the proper functioning of physiological functions ^[5][42]. Usually, a significant intake of micronutrients is due to the consumption of foods enriched with vitamins or minerals (such as rice or flour) ^[6][7][43,44]). Supplementation of various foods with micronutrients in powder form has been a common way of administering vitamins or minerals to target groups of the population, especially in products suitable for the prevention or treatment of anemia ^[8][45]. A study based on the Multiple Source Method in the elderly showed that the intake of folic acid, calcium, vitamin B6, and vitamin B2 was insufficient. In contrast, sodium intake was increased in the above-mentioned age group ^[9][46]. The same study had several conclusions valid throughout Europe, in that socioeconomic status was directly correlated with the amount of micronutrients consumed by food. High consumption of vitamins A, B2, and C was directly associated with the socioeconomic status of the target group. What matters in the case of target groups with age-appropriate nutritional requirements and specific diseases is nutrition education ^[9][46]. This depends on the degree of education, economic development of the country, and awareness that increasing food consumption does not mean a good state of health. To have a correct nutritional yield, even at an advanced age, a balance must be taken into account between what researchwers consume, the general state of health, and the possibility of access to products with an appropriate degree of quality. Overall, social status, lifestyle, and eating habits influence the proper functioning of the body and the response researcherswe have in the case of interaction with a pathogen ^[10][47]. Not only vitamins are essential for the proper functioning of the immune response (e.g., vitamin C). Folic acid, calcium, magnesium, zinc, iron, copper, and selenium act independently and in direct relation to each other to support this essential function and maintain homeostasis. Moreover, the level of each micronutrient is a critical detail. The additional intake of these micronutrients currently solves the response to exogenous factors, and the way they are administered determines their bioavailability. Maintaining homeostasis has become an issue in recent years because micronutrients and other bioactive compounds play a role in stimulating the cells of the immune system, which plays an essential role in resistance to SARS-CoV-2, for example. Controlled administration is part of the current strategy for maintaining the functioning of the immune system ^[11][48]. Minerals (e.g., selenium and/or zinc) and bioactive extracts from curcumin, echinacea, and propolis have been partially recognized as having possible actions in combating and reducing the effects of SARS-CoV-2 infection ^[12][49]. These data mentioned an action on the angiotensin-converting enzyme, inhibition of papain-like protease or chymotrypsin-like protease, and action against RNA-dependent RNA polymerase involved in the coronavirus replication cycle. The effects are also recognized against some dysfunctions associated with a viral infection, for example, severe acute respiratory syndrome. The mode of action of these micronutrients is manifested through the anti-inflammatory, antioxidant, antiviral, or immunomodulatory properties. Starting from reducing inflammatory processes, micronutrients and bioactive substances are an affordable option that effectively supports the fight against COVID-19 ^[12][49].

2.2. Mineral-Enriched Biomass Obtaining and Advantages

A new perspective, less considered, is the use of essential minerals to enrich the biomass of yeast and/or bacteria. Such a process would be helpful because it leads to the development of innovative new generation products, such as mineral-enriched prebiotics and postbiotics. Thus, it is possible to supply the human body with a large quantity of minerals (such as calcium, magnesium, iron, zinc, and selenium) with high bioavailability for the organism, in addition to the complex and beneficial components from the pre/postbiotic composition. Fermentation incorporation is an essential step in obtaining these products. Moreover, the natural assimilation of minerals by microbes improves the value of biomass as microbes are naturally adsorbent for minerals and increase micronutrient bioavailability, while the process is eco-friendly and cost-effective ^[4][13][41,50]. An important criterion for selecting industrial microbial strains for mineral-enriched biomass production is their stress tolerance, including the stress produced by the elevated concentration of one or two mineral ions and various stresses from the intestinal tract. A study showed that Saccharomyces cerevisiae had a lower resistance than Kluyveromyces marxianus to the presence of free radical species, also encountered in the gut. This detail makes the fermentation yield optimal at high temperatures, which has led to an advantage that can be used in innovative fermentation processes ^[14][51]. Some lactic acid bacteria (LAB) have been reported to be able to resist high concentrations of inorganic selenium (200 mg/L) and reach the maximum bioaccumulation potential in a medium with 150 mg/L of Se ^[15][52]. In this condition, two Lactobacillus paracasei strains (ML13 and CH135) were able to bioaccumulate approximately 40 mg Se/g biomass. Optimization studies to produce Se-enriched Saccharomyces boulardii CCT 4308 probiotic biomass in a batch system noted that the best Se accumulation was observed at 100 μg/mL while the strain can tolerate 400 μg/mL, and a good strategy to avoid a metal toxic effect is the addition of selenium at the end of the logarithmic phase ^[16][53]. In this case, the best biomass production (14.52 g/L) was obtained after 12 h cultivation, and cells accumulated 3.2 mg Se/g biomass, a result comparable with the selenium bioaccumulation by some commercial probiotics. Natural mediums were used to grow Se-enriched yeasts, sugar molasses—a complex carbon source with small amounts of proteins, vitamins, and nitrogen compounds in the case of S. boulardii—and juices from germinated brown rice, beewort, and soybean sprouts in a ratio of 4:4:2 for S. cerevisiae, where different concentrations of sodium selenite were added ^[16][17][53,54]. S. cerevisiae grew with lower amounts of inorganic selenium (15 μg/mL Na₂SeO₃) but produced 8.5 g/L biomass, and total Se achieved 3.53 mg/L. The carbon sources clearly influence the bioaccumulation process in S. cerevisiae; when in a medium with beet and sugarcane molasses, a strain yielded 3.77 mg/g intracellular selenium, while in synthetic and industrial media, reported 2.72 mg/g and 2.46 mg/g Se accumulation, respectively ^[17][18][54,55]. Another work proved that S. cerevisiae strains are able to adapt to growing in the presence of four times higher concentrations of minerals such as selenium, but macromorphological changes in the yeast colonies and growth reduction were observed during the adaptation process ^[19][56]. Interestingly, an adapted Zn-enriched Lactobacillus plantarum strain showed stronger tolerance to stress produced by acid, bile salts, and hydrogen peroxide, while antioxidant properties increased significantly ^[20][57]. In this case, electron microscopy analysis showed that the ultrastructure of zinc-enriched strain changes, as well as the metabolites pattern, compared to the non-adapted control strain. Different from selenium accumulation, yeasts are able to accumulate a higher quantity of inorganic zinc than bacteria, as Zn is an essential element for S. cerevisiae growth. However, in the presence of excessive ZnSO₄, this element had inhibitory effects ^[21][58]. The total Zn accumulation gradually gets bigger until there is 30 mg/L of zinc sulfate in the medium, while the biomass increased by 24-fold. Similar results were reported with an S. cerevisiae strain isolated from industrial sewage that, in optimal conditions of 25 μg/mL of zinc, at pH 6 and after 24 h of incubation, showed the maximum growth and Zn uptake, while the protein content of the biomass was above 50% (w/w) ^[22][59]. Furthermore, cultivation conditions are important in the case of zinc absorption, as the pH-dependency of Zn uptake has been reported ^[22][23][59,60]. In the last years, commercial preparations with selenium, zinc, multi-vitamins, and probiotic strains have been available.

2.3. Minerals—Gut Microbiome Relationship and the Beneficial Effects of Mineral-Enriched Biomass on Human and Animal Health

In healthy humans, minerals that are not absorbed in the small intestine get to the colon and become available for the commensal gut microbiota. The main effect of these minerals is to act/modulate the microbiota in the gut, both in terms of the microbial fingerprint and especially through the metabolic processes that can directly affect human health ^[24][61]. Some of the secreted microbes’ metabolites will contribute to the host’s mineral status improving the uptake, absorption, and bioavailability of minerals ^[4][41]. The dynamic relationship between the modulation process of the microbiota and the bioavailability of micronutrients is a process of interest in microbial therapy, but also for characterization of functional foods and the realization of personalized feeding schemes ^[24][25][61,62]. Recent works in humans and different model organisms demonstrated that the mineral–gut microbiome relationship is bidirectional. On the one hand, there is a symbiotic relationship between intestinal microbiota and the host that influence eubiosis and mineral status of the host. Bacteria can produce enzymes that help release minerals from foods, such as phytase enzymes that induce plant phytic acid hydrolysis releasing minerals, such as calcium, phosphate, and magnesium ^[26][63]. Microbes in the gut use minerals for their growth and functioning, avoiding health impairment associated with dysbiosis and pathobiont overgrowth ^[4][41]. For instance, phosphorous supplementation increased the microbial diversity and levels of short-chain fatty acids (SCFA), microbial metabolites produced from polysaccharide fermentation in the colon ^[27][64]. SCFA plays an important role in neuro-immunoendocrine regulation in humans. Zinc deficiency decreases the biodiversity of gut microflora, negatively alters their function and gut-brain signaling and increases inflammatory markers in the host’s blood system ^[28][65]. Interestingly, clinical trials with iron supplementation negatively modulated gut microbiota, increasing the proportion of enteropathogen E. coli while LAB (bifidobacteria and lactobacilli) relative abundance decreased ^[29][66]. The presence of various commensal bacteria in the gut and some end-products of microbial fermentations, such as SCFA, seem to favor mineral absorption. A study showed that an increase in the presence of SCFA-producing species, such as Bifidobacterium sp. or Lactobacillus sp., was correlated with the increase in the calcium absorption that influences the bone density and strength in humans and animals ^[30][67]. Furthermore, it has been shown that iron absorption is influenced by SCFA and bacterial siderophores facilitate the host uptake of iron ^[31][32][68,69]. Selenium supplementation induces changes in the composition of gut microflora that protect against intestinal dysfunction; at the same time, intestinal microflora improves the bioavailability of selenocompounds ^[33][70]. On the other hand, in the case of mineral limitations, gut microbes and the host become competitors; for instance, in selenium-limiting conditions, intestinal bacteria can remove Se and lower the selenoprotein level in the host and eventually impair the host immune response ^[33][70]. Overall, these findings demonstrate the importance of microbiota as a feasible target for improving host mineral bioavailability. It is, therefore, not surprising that probiotic supplementation was used in the treatment of mineral deficiency. In the last 10 years, in vivo studies and small clinical trials have demonstrated the association between gut microbiota, probiotics, and host mineral status ^[4][33][34][41,70,71]. However, large clinical trials are missing, and the existing data are mostly the result of in vitro research ^[35][72]. The few available clinical trials in humans demonstrated that probiotics with Lactobacillus spp. increased the magnesium bioavailability after cheese and vegetable milk consumption or non-dietary iron absorption ^[36][37][73,74]. A synbiotic containing Lactobacillus and Bifidobacterium species raised blood zinc levels ^[38][75]. In the case of mineral-enriched probiotic biomass, few works in different animal models suggested their beneficial effects on health. Yang et al., 2021 used Bacillus subtilis yb-114246, a strain with probiotic effect previously isolated from chickens and enriched with Se by adding sodium selenite into the culture medium, then supplemented the broiler chick diet ^[39][76]. The Se-enriched probiotic strain colonized the distant segments of the ileum as proved by fluorescence in situ hybridization FISH and real-time PCR and improved bacterial diversity, increasing the number of species from Actinobacteria, especially Lactobacillus, Peptococcus, Butyricicoccus, and Rominococcaceae species, that improved immunity, and higher body weight. Furthermore, the proportion of conditioned pathogens or pathogens (Salmonella, Shigella, Vibrio cholerare) significantly decreased. Diet supplemented with inorganic Se showed no significant increases in the final body weight of the broiled chickens, while chicks receiving a Se-enriched probiotic diet had higher weight compared to those fed only with the B. subtilis probiotic strain, proving the synergistic effect of minerals and probiotics. In another study in a murine model, a diet supplemented with Se/Zn-enriched Lactobacillus plantarum probiotic changes the gut microbial composition in a different way compared to a diet with inorganic Se/Zn supplements ^[40][77]. Mice diet supplementation with Se/Zn-probiotic increased the relative abundance of Adlercreutzia, while the abundance of Allobaculum decreased compared to results obtained with other mice groups ^[40][77]. Both Se/Zn-enriched diets induced the increase of Lactococcus spp., mostly in mice fed with inorganic Se/Zn, and Lactococcus lactis has been proved to uptake zinc and is capable of selenium biotransformation ^[40][41][77,78]. Some LAB, especially Lactobacillus strains, have been shown to accumulate intracellularly and then transform toxic selenite into selenium amino acids, such as selenocysteine found in the active site of important selenoproteins involved in the regulation of the redox signaling in all living organisms ^[40][77]. The most important selenoenzymes are glutathione peroxidases, thioredoxin reductase, or deiodinases, which are involved in different processes, including antioxidant function ^[33][70]. Similarly, zinc is required for the activation of many enzymes with antioxidant activity and has demonstrated Zn uptake by yeasts and lactic acid bacteria ^[20][22][57,59]. The selenium and zinc blood levels were the highest after Se/Zn-enriched L. plantarum diet, which increased the antioxidant defenses against oxidative stress ^[40][77]. Interestingly, the pattern of the selenocompounds in endogenous lactic acid bacteria isolated after inorganic Se/Zn supplementation was different compared with results obtained in experiments with Se/Zn-bioaccumulated probiotics. In a canine model, 2 g of Se/Zn-enriched probiotic (Lactobacillus and Candida utilis) diet increased the amount of lactic acid bacteria (Lactobacillus and Bifidobacterium) in the feces, while numbers of E. coli, Staphylococcus, and Enterococcus decreased ^[42][79]. Through a randomized controlled study, it has been shown that an increase in micronutrient intake reduces the influence of dysbiosis in degenerative diseases ^[43][80]. Considering the role of the intestinal microbiota in reducing inflammatory processes and modulating the intake of macro- and micronutrients, a direct relationship was identified between the impact of eating habits (regular consumption of fat and sugar), micronutrients (vitamins C, E, and D, carotenoid compounds, zinc) and omega-3 fatty acids. ReThisearchers  study concluded that these nutrients are essential for the intestinal microbiota, being directly related to the risk and progression of degenerative diseases, and bioavailability is a key factor. Dysbiosis is one of the main limiting factors supporting oxidative stress in the gut, identified as a contributing factor to developing various diseases and cancer ^[43][44][80,81].