Introduction

Iron deficiency remains a widespread global health issue, affecting over two billion people worldwide [1]. It is estimated that about 40% of the population in developing countries and about 10% in developed countries suffer from iron deficiency [2]. This micronutrient plays a critical and universal role in numerous physiological processes, including protein and enzymatic functions, energy production, and is essential for fundamental biological mechanisms such as cellular growth and differentiation [3]. Iron deficiency impairs the function of multiple organ systems, most notably the central nervous, endocrine, and cardiovascular systems. It leads to the development of iron deficiency anemia (IDA) of varying severity, reduced physical performance, and a significant decline in quality of life [4]. In children, iron deficiency is particularly concerning due to its impact on growth and neurodevelopment [5, 6].

The principal causes of iron deficiency include inadequate dietary intake of iron-rich foods, increased physiological demand, and impaired absorption due to acquired or genetic factors. The literature addressing intestinal iron absorption presents conflicting views regarding the valence state of iron that is preferentially absorbed—whether ferrous (Fe²⁺) or ferric (Fe³⁺) [7–9]. However, numerous studies highlight the critical importance of the solubility of orally administered iron in the intestinal lumen as a key determinant of its bioavailability [10]. Moreover, iron valence is not as important as the ability of a person to absorb iron, the causes of iron metabolism disorders, as well as the features of the intestinal microbiota.

Iron metabolism and its role in gut microbiota

Recent studies have highlighted the complex interplay between iron bioavailability, absorption, and the activity of microorganisms in the large intestine, emphasizing the role of the gut microbiota in regulating iron homeostasis [11]. Only approximately 10% of dietary iron is absorbed by the human body, while the remaining 90% is excreted in feces, potentially influencing the microbial composition of the colon [12]. Depending on dietary intake, about 15% of ingested iron is absorbed in the duodenum, with the remainder passing into the colon, where it may serve as a nutrient source for commensal bacteria.

Colonic bacteria have evolved mechanisms to acquire iron, including the production of high-affinity iron-chelating molecules known as siderophores, as well as transferrin and lactoferrin receptors that facilitate the uptake of free iron in the gut lumen. Since iron is essential for the survival and proliferation of nearly all bacterial species [13], the amount of unabsorbed iron reaching the colon can significantly influence microbial population dynamics [14]. Thus, changes in systemic iron homeostasis can affect the iron content in the intestinal lumen and, consequently, the composition of the intestinal microbiota [15].

Experimental studies in mice have shown that iron regulatory protein 2 (Irp2) and mutated Hfe genes (involved in hereditary hemochromatosis) play significant roles in iron regulation. Compared to wild-type controls, mice with deletions in Irp2 or Hfe genes exhibited substantial changes in gut microbiota composition, underscoring the influence of host iron metabolism on microbial ecology [15]. Iron deficiency has been associated with an increased risk of intestinal infections due to its impact on microbiota structure [16]. Conversely, iron overload also exerts adverse effects. Jaeggi et al. [17] demonstrated that iron supplementation in infants led to a reduction in Bifidobacteria, an increase in Enterobacteriaceae (including pathogenic E. coli strains), and elevated fecal calprotectin levels, indicating intestinal inflammation. The virulence of many pathogens is closely linked to iron availability [18].

Several studies suggest that both iron deficiency and iron overload can contribute to colonic dysbiosis, inflammation, and the development of colorectal cancer [19–21]. Disruptions of the gut microbiota in hemochromatosis have been linked to altered ferroportin function. This iron-exporting protein, encoded by the SLC40A1 gene, is responsible for transporting iron from enterocytes and macrophages into the bloodstream. Mutations in SLC40A1 lead to a hemochromatosis phenotype characterized by hepatic iron overload and microbiota alterations [22–24]. An iron-rich gut environment favors the expansion of Proteobacteria, and studies conducted with children demonstrated that excess iron contributes to chronic inflammation and the proliferation of pathogenic bacteria [25].

Inflammatory bowel diseases (IBDs) can disrupt both iron absorption and gut microbiota balance. The resulting excess of iron in the intestinal lumen may contribute to the appearance of pathobionts—commensal bacteria that acquire pathogenic traits under dysbiotic conditions [26]. Lee et al. [27] further reported that in patients with IBDs and anemia, oral iron therapy produced distinct alterations in bacterial phylotypes and fecal metabolites compared to intravenous iron therapy. Notably, oral iron administration resulted in reduced levels of Faecalibacterium prausnitzii and Ruminococcus bromii [27]. F. prausnitzii is a well-recognized member of the healthy gut microbiota, known for its anti-inflammatory properties mediated by butyrate production [28, 29]. Similarly, R. bromii contributes to butyrate production through the fermentation of resistant starch [30]. A decrease in the abundance of these beneficial taxa is associated with sustained intestinal inflammation and may increase the risk of colorectal cancer [31]. These pathobionts are implicated in the etiology of both IBD and colorectal cancer [32]. However, not all studies confirm a universally negative effect of iron supplementation. For instance, an experimental study in rats revealed that iron-deficient rats had significantly lower concentrations of butyrate and propionate in the cecum (this may be due to lower levels of Roseburia spp. and the Eubacterium rectale group) and exhibited pronounced alterations in microbial composition [33]. In contrast, prolonged high-dose iron supplementation (50 mg Fe, 4 days per week for 266 days) did not induce intestinal inflammation, and the abundance of major microbial groups and short-chain fatty acid (SCFA) concentrations remained stable [34]. It can be assumed that in IBDs, IDA is associated not only with blood loss through stool, but also with impaired iron metabolism in the intestine, and concomitant changes in the microbiota confirm the effect of these pathogenetic patterns. Also, it is important that in patients with active IBDs, iron absorption is reduced, but in patients with IBDs in remission, it is normal [13]. Therefore, for prophylaxis of gut microbiota disorders in active IBDs, intravenous iron intake is preferred, and in IBDs in remission, oral iron can be administered. It is important to investigate the effect of iron deficiency and iron therapy on redox status, intestinal microbiota, and possible interactions between them because it also promotes negative effects in IBD patients [35].

Iron metabolism and the role of gut microbiota changes

While systemic iron levels can influence the composition of the intestinal microbiota, increasing evidence suggests that the microbiota itself actively participates in the regulation of iron absorption and homeostasis [36]. Studies in germ-free (axenic) mice have demonstrated the increase in the expression of divalent metal transporter 1 (DMT1) and duodenal cytochrome B (DCYTB) in 8–10-fold, reduction in ferroportin expression in the duodenum by twofold, and decreased iron levels in enterocytes. Following colonization with commensal bacteria, iron accumulation in intestinal epithelial cells increased significantly [37].

A study conducted among young women in southern India found that lower iron status positively correlated with decreased levels of fecal Lactobacillus spp. [38]. This relationship may be attributed to the ability of lactic acid—produced by Lactobacillus species—to enhance the bioavailability of dietary iron [39]. Similarly, other research has shown that probiotic strains such as L. fermentum can promote intestinal iron absorption. This effect has been linked to the production of p-hydroxyphenyllactic acid by Lactobacilli, which facilitates the reduction of ferric (Fe³⁺) to ferrous (Fe²⁺) iron—a necessary step for absorption via DMT1 channels in enterocytes [40]. The ability of Lactobacillus-based probiotics to improve iron bioavailability underscores their potential as adjunctive tools in clinical nutrition and anemia management [39].

Furthermore, the pH of the colonic lumen is an important factor that influences iron absorption. Several gut microorganisms ferment galactooligosaccharides, which leads to acidification of the gut environment, which increases the solubility and absorption of iron. Therefore, dietary inclusion of acetic acid-producing probiotic products may contribute to improved iron absorption through this pH-lowering mechanism [41].

Iron imbalance and its correction: which ways and types of iron administration can we choose?

To correct iron deficiency, various strategies may be employed, including the use of iron-rich foods, dietary supplements, and, in severe cases, medical interventions such as blood transfusions or erythrocyte concentrate infusions [42]. It has been well established that vegetables, meat, and meat products serve as excellent dietary sources of iron, and that fermentation of these products can enhance iron bioavailability. However, a major challenge lies not in the source of iron itself, but in the chemical form of the iron and the pathway by which it is absorbed [43].

As mentioned above, oral administration of heme iron has been shown to alter gut microbial populations, leading to dysbiosis, particularly through the reduction of butyrate-producing taxa. This is of clinical significance, as butyrate is a key SCFA with anti-inflammatory and anticarcinogenic properties. A comparative mouse study demonstrated that oral iron supplementation exacerbated colitis and promoted adenoma formation to a greater extent than parenteral iron administration [44].

Thus, intravenous iron supplementation, by minimizing adverse microbiota alterations and intestinal inflammation, may represent a more favorable therapeutic option compared to oral iron administration.

It is actual and clinically promising to use the peptide-iron chelates (peptide-iron complex). To investigate the effects of peptide-iron chelates on gut microbiota composition and intestinal inflammation in a mouse model of IDA, animals were administered low, medium, and high doses of peptide-iron chelates and ferrous sulfate (FeSO₄) (1.0, 2.0, and 3.0 mg Fe/kg body weight, respectively) via oral gavage daily for four weeks [45]. Intake of peptide-iron chelates at various doses resulted in reduced inflammation and increased secretion of secretory immunoglobulin A [45]. In addition, these chelates mitigated inflammatory cell infiltration and oxidative stress in colonic tissue, thereby improving gut permeability.

16S rRNA gene sequencing demonstrated that treatment with peptide-iron chelates increased microbial diversity in the colon, reduced dysbiosis, and restored the Firmicutes-to-Bacteroides ratio. In contrast, administration of traditional FeSO₄ was associated with an increase in pathogenic bacteria (e.g., Helicobacter and Erysipelatoclostridium) and a decrease in beneficial taxa (e.g., Bifidobacterium and Blautia) [45, 46].

A related study explored the use of a pectin-iron complex as a delivery matrix for L. plantarum CIDCA 83114. The researchers evaluated the biostability of pectin-iron nanoparticles and estimated their biological activity. The results demonstrated that iron was non-toxic to the probiotic cells and did not influence bacterial viability. So, the probiotic strain can promote the dual utility for both iron delivery and bacterial stabilization. This approach presents a promising alternative for addressing iron deficiency [47]. Further innovation includes a novel formulation based on three compounds: iron oxide nanoparticles, pectin, and lactic acid bacteria. These components act synergistically to provide safe delivery of soluble iron to the gastrointestinal tract [47].

Another study focused on the synthesis of organic iron-binding compounds derived from polysaccharides. A complex composed of iron chloride-inulin-succinic anhydride-cysteine was developed, which exhibited favorable biodegradability in the presence of inulinase and strong mucoadhesive properties. These results demonstrated that such iron-binding complexes may be effective in the oral treatment of IDA or as components of iron-fortified functional foods [48].

Probiotics, other biotics, and iron imbalance correction

A balanced gut microbiota plays a critical role in optimizing iron absorption. Therefore, therapeutic strategies targeting the correction of intestinal dysbiosis—through the use of probiotics (life bacteria strains), prebiotics (compounds that stimulate the growth and activity of beneficial bacteria in the intestine), or synbiotics (probiotics and prebiotics)—are increasingly considered as part of comprehensive approaches to managing iron deficiency conditions [42, 49].

However, evidence on the efficacy of probiotic interventions in improving iron absorption remains inconsistent. A systematic review indicated that L. plantarum 299v may be effective for the prevention of IDA. This strain was shown to improve the absorption of non-heme dietary iron in healthy adult Europeans [39]. In contrast, Rosen et al. [50] reported that for pediatric patients, there is no significant improvement in serum ferritin levels after intake of L. plantarum 299v compared to a control group, suggesting strain-and context-specific variability in response.

In an animal study, the effects of multi-strain oral probiotic supplementation were evaluated in rats. This medicine contains a mixture of several probiotic strains: B. bifidum W23, B. lactis W51 and W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, and Lactococcus lactis strains W19 and W58, and was administered at low (2.5 × 10⁹ CFU) and high (1 × 10¹⁰ CFU) doses. The results demonstrated enhanced iron-binding capacity in the high-dose group relative to controls [51].

Several studies have also reported that the intake of prebiotics and/or synbiotics correlates with improved iron bioavailability. This effect is primarily attributed to the decrease of ferric iron (Fe³⁺) to its more absorbable ferrous form (Fe²⁺), facilitating uptake by enterocytes [52]. For instance, in a study using Sprague-Dawley rats, dietary supplementation with unrefined galacto-oligosaccharide prebiotics over a period of 3–4 weeks significantly enhanced the intestinal absorption of calcium, magnesium, and iron [53].

A study conducted in school-aged children (9–12 years) demonstrated that synbiotic supplementation may improve iron absorption. All participants were divided into two different groups: participants in one group received iron supplementation in the form of syrup (administered twice weekly), while the other group consumed a synbiotic formulation consisting of L. plantarum Dad 13 and fructooligosaccharides in milk (administered six times weekly) over a 3-month period. Overall, no statistically significant differences were observed between the groups in serum iron levels or gut microbiota composition. However, a higher abundance of E. coli was found in children who received only the iron syrup, whereas those who consumed the synbiotic mixture exhibited increased levels of Bifidobacterium spp. in their feces [49].

The effect of synbiotic intake on iron absorption was revealed in patients with type 2 diabetes mellitus, given the known association between metabolic disturbances and altered serum mineral levels. Synbiotic supplementation was shown to exert beneficial effects on iron absorption in both diabetic and non-diabetic individuals, with significant changes in serum iron bioavailability observed in both groups [54].

As previously discussed, oral iron supplementation can adversely affect the gut microbiota and promote intestinal inflammation. Increased luminal iron concentrations in the colon may reduce the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, while promoting the growth of enterobacteria, including enteropathogenic E. coli. Therefore, combining oral iron therapy with probiotic supplementation may help mitigate these negative outcomes [55, 56].

A summary of selected studies evaluating the efficacy and safety of probiotic-based interventions in the correction of iron deficiency states is presented in the accompanying Table 1.

As can be seen from Table 1, most studies show a positive effect of probiotic strains and prebiotics on iron metabolism. We can see that probiotics generally improve iron status by restoring disorders of the intestinal microbiota, which improves the absorption, bioavailability, and assimilation of iron. A large number of papers are devoted to the strain L. plantarum 299v. Perhaps, as a result of further research, data will be obtained that will allow the introduction of this strain, or other probiotic strains, into the treatment regimens of patients with impaired iron metabolism.

Conclusions

Both iron deficiency and iron overload in the gut during therapeutic interventions can negatively affect the composition and function of the intestinal microbiota. Conversely, beneficial members of the colonic microbiota play a key role in enhancing systemic iron absorption. Therefore, modulation of gut microbiota through targeted use of probiotics, prebiotics, and synbiotics represents a promising strategy in the comprehensive management of iron deficiency disorders. These interventions not only support microbiota restoration and reduction of intestinal inflammation, but may also offer novel therapeutic avenues for iron imbalance correction. It is essential to study the ability of probiotics to act as iron transporters, convert iron into an accessible form, or create metabolites that indirectly increase iron content and absorption in the intestine.

While a growing body of evidence supports the efficacy of probiotic-based interventions in correcting iron deficiency, additional well-controlled, large-scale clinical trials are necessary to conclusively validate the beneficial effects of probiotics, prebiotics, and synbiotics in this context.