Ferro e Microbiota

Journal of Trace Elements in Medicine and Biology 75 (2023) 127093
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Journal of Trace Elements in Medicine and Biology

journal homepage: www.elsevier.com/locate/jtemb
Iron in infectious diseases friend or foe?: The role of gut microbiota

Zinnet Şevval Aksoyalp a, 1, 2, Aybala Temel b, *, 1, 3, Betul Rabia Erdogan a, 1, 4
a
Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology, Izmir, Turkey
b
Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmaceutical Microbiology, Izmir, Turkey
A R T I C L E I N F O A B S T R A C T
Keywords: Iron is a trace element involved in metabolic functions for all organisms, from microorganisms to mammalians.
Gut microbiota Iron deficiency is a prevalent health problem that affects billions of people worldwide, and iron overload could
Commensal bacteria have some hazardous effect. The complex microbial community in the human body, also called microbiota,
Iron
influences the host immune defence against infections. An imbalance in gut microbiota, dysbiosis, changes the
Siderophores
Hepcidin
host’s susceptibility to infections by regulating the immune system. In recent years, the number of studies on the
Iron chelators relationship between infectious diseases and microbiota has increased. Gut microbiota is affected by different
parameters, including mode of delivery, hygiene habits, diet, drugs, and plasma iron levels during the lifetime.
Gut microbiota may influence iron levels in the body, and iron overload and deficiency can also affect gut
microbiota composition. Novel researches on microbiota shed light on the fact that the bidirectional interactions
between gut microbiota and iron play a role in the pathogenesis of many diseases, especially infections. A better
understanding of these interactions may help us to comprehend the pathogenesis of many infectious and
metabolic diseases affecting people worldwide and following the development of more effective preventive and/
or therapeutic strategies. In this review, we aimed to present the iron-mediated host-gut microbiota interactions,
susceptibility to bacterial infections, and iron-targeted therapy approaches for infections.
1. Introduction the human gut microbiota [7,8]. These commensal members of gut
microbiota have different effects on protecting the intestinal mucosa
Microbiota refers to an ecological community of commensals, sym integrity and providing resistance to the pathogen colonization [9]. An
bionts and pathogens living in different body parts, such as skin, respi imbalance in gut microbial composition, defined as ‘dysbiosis’, has been
ratory tract, gut, and vagina. Human microbiota exhibits significant associated with various diseases including, irritable bowel syndrome,
variations in interpersonal and different life periods [1]. Gut microbiota inflammatory bowel disease [10], gastric ulcer [11], colon cancer [12],
is a complex community of bacteria, viruses, and eukaryotes that colo obesity [13], autism [14], asthma [15], atopy [16], and hypertension
nize the gastrointestinal tract and help maintain the metabolic balance [17]. Dysbiosis changes the host’s susceptibility to infections by regu
of the human body [2,3]. Metabolic, protective, or structural functions lating innate and adaptive immune systems, through direct or indirect
of gut microbiota have been provided via different signaling pathways mechanisms [8]. Therefore, the studies focused on the relationship be
that include many molecules essential for host health, such as bile acids, tween infectious diseases and microbiota members have gained impor
polyamines, choline metabolites, and short-chain fatty acids (butyrate, tance in recent years [18]. Particularly, gastrointestinal tract infections
propionate, acetate) [4,5]. Synergistic and complicated interactions caused by Gram-negative enteropathogenic bacteria, recurrent Clos
between the host immune system and the gut microbiota play a role in tridium difficile infections and some viral infections have been investi
maintaining immunological homeostasis in healthy individuals [6]. gated in terms of their interactions with the gut microbiota [19].
Firmicutes (~49–76%), Bacteroidetes (~16–23%), Actinobacteria (<5%), In addition to the mode of delivery, age, diet, medications, hygiene
and Proteobacteria (<10%) are four major bacterial phyla dominating habits, antibiotic use, and geography, iron is also an important factor
* Corresponding author.
E-mail addresses: zinnetsevval.aksoyalp@ikcu.edu.tr (Z.Ş. Aksoyalp), aybala.temel@ikcu.edu.tr (A. Temel), betulrabia.erdogan@ikcu.edu.tr (B.R. Erdogan).
1
All authors contributed equally.
2
0000-0002-7822-3154.
3
0000-0003-1549-7219.
4
0000-0001-7377-4777.
https://doi.org/10.1016/j.jtemb.2022.127093
Received 9 April 2022; Received in revised form 13 September 2022; Accepted 5 October 2022
Available online 8 October 2022
0946-672X/© 2022 Elsevier GmbH. All rights reserved.
Z.Ş. Aksoyalp et al. Journal of Trace Elements in Medicine and Biology 75 (2023) 127093
affecting the composition and diversity of the gut microbiota (Fig. 1) [1, 31]. Bacteroides thuringiensis directly targets spore-forming species
20]. Iron is crucial for both microorganisms and the human body for Bacilli and C. difficile in intestines through its bacteriocin [5].
maintaining biological processes, such as enzymatic reactions, DNA B. thetaiotaomicron also induces the antimicrobial peptide expression
synthesis, and mitochondrial energy production in all living organisms against Gram-positive bacteria [32]. Bifidobacterium spp. is another
[21]. The human body needs iron as a primary constituent of haemo commensal bacteria that supports host immunity via several synthesized
globin and myoglobin, which are oxygen transport proteins, and iron compounds and secretions [33]. In vitro studies indicate that a variety of
also plays a role in generating reactive oxygen derivatives (Fig. 1) [22]. organic acids, enzymes, and peptides produced by Bifidobacterium spe
Thus, iron homeostasis is firmly controlled to prevent the harmful out cies directly inhibit the adhesion of enterohaemorrhagic E. coli and
comes of oxidative stress. Besides the survival of some gut microor C. difficile to enterocytes, thus reducing the risk of the intestinal infec
ganisms has been associated with iron levels [23]. The relationship tion [33–35]. Lactobacillus spp. adapts well to the gastrointestinal tract
between iron and the growth and virulence of various pathogens has and protects the intestinal lumen from the pathogens through protein
been investigated [24,25]. Moreover, the direct and indirect interactions aceous pili and secretions [36,37]. Lactobacillus delbrueckii ssp. may
between immune system cells and iron metabolism involve in the reduce the adherence and the cytotoxic effect of C. difficile in the human
pathogenesis of some infectious diseases. Therefore, iron deficiency, intestinal epithelial cell [38]. Lactobacillus spp. can trigger the host im
iron supplementation, or iron targeted therapy approaches have multi mune response by inducing Toll-like receptor-2 signaling [5]. Afore
directional effects on gut microbiota and susceptibility to infections. We mentioned effects of commensal microorganisms and their metabolites
aimed to discuss the relationship between iron, infection, and gut show that an imbalance in the gut affect the host health condition
microbiota and evaluate the iron-targeted therapies by a selective inevitably.
literature search on related topics in this review.
3. Gut microbiota and iron
2. The effects of gut microbiota on infections and immune
system Iron is a trace element for the growth and virulence of most micro
organisms (except for Borrelia burgdorferi and some Lactobacilli) in the
The Human Microbiome Project and various gut microbiome pro gut [20]. For example, iron is required for virulence and colonization of
jects, such as the International Human Microbiome Consortia, the Salmonella and E. coli [39]. The organism must strictly control the ab
British Gut Project, and the Human MetaGenome Consortium Japan sorption, consumption, storage, and recycling of iron [21]. The lower
investigated the host-microbe interactions in recent years [1]. The gut levels of free iron in circulation restrict the growth of pathogens [40].
commensal members have a critical effect on inhibiting the enter Iron exists in heme (organic iron) and non-heme forms (inorganic iron).
opathogens overgrowth in the gastrointestinal tract, which is described The heme is synthesized in the mitochondria of plants and vertebrates
as a ‘colonization resistance’ phenomenon [9]. Protective role of cells [41,42]. Pathogenic bacteria utilize heme as iron source because
commensal anaerobes against infectious diseases has been investigated heme contains the most amount of iron in the body proteins [39].
for over fifty years [26]. Several studies, including different animal Iron homeostasis is predominantly regulated by absorption rather
models, and pathogenic microorganisms also reported increased sus than iron excretion which is not controlled in the body [43]. In healthy
ceptibility to infections following antibiotic-mediated depletion of gut people, iron absorption is controlled by the physiological iron require
microbiota [5,9,27,28]. Vancomycin-resistant Enterococcus faecium, ment, dietary iron intake, iron bioavailability, and the regulation of iron
Gram-positive C. difficile, and Gram-negative bacilli belonging to absorption according to these factors, which is defined as ‘adaptation’
Enterobacteriaceae are the main exogenous pathogens whose coloniza [44]. Iron exists in heme (Fe2+, ferrous iron) and non-heme forms (Fe3+,
tion is prevented through commensals [5,28,29]. These pathogens are ferric iron) [41,42,45]. Pathogenic bacteria utilize heme as a source of
commonly responsible for life-threatening infections (bacteriemia, iron because heme contains the most amount of iron in the body pro
diarrhea, urinary tract infections, gastroenteritis), especially among teins. Iron absorption is dependent on the redox state. Heme and
hospitalized patients, and their intrinsic/acquired antibiotic resistance non-heme iron are absorbed by different pathways [22], and the heme
mechanisms make it challenging to eradicate the infections [5]. form is more easily absorbed [45]. Animal proteins and ascorbic acid
Commensal bacteria and their secreted molecules enhance mucosal increase the absorption of non-heme and heme iron, while a plant-based
immunity in the gut through direct (microbiota-mediated) and indirect diet that contains high phytic acid inhibits iron absorption [46].
(immune-mediated) mechanisms of colonization resistance [1]. Direct Absorbable iron is the ferrous (Fe2+) state iron or heme iron. Heme iron
mechanisms are bacteriocins, nutrient depletion and type VI secretion is catabolized to Fe2+ iron by the heme oxygenase 1 (HOX1) enzyme but
systems [5]. Indirect mechanisms are antimicrobial peptide production, the transfer mechanism of Fe2+ iron into the duodenum has not been
maintenance of the epithelial barrier, and modulation of bile acids [5]. fully elucidated [22]. Ferric (Fe3+) iron is an insoluble form at physio
Bacteroides fragilis and Bacteroides thetaiotaomicron, gut commensals, logical pH. It is reduced to Fe2+ iron with duodenal cytochrome b
defend the body, against Salmonella and Escherichia coli infections [30, (Dcytb) at low pH, then is absorbed by divalent metal transporter-1
Fig. 1. Factors affecting the gut microbiota and

the roles of iron in the body. Mode of delivery,
age, lifestyle, hygiene habits, drugs, and diet
affect the gut microbiota composition. Iron-
containing foods and drugs also affect gut
microbiota diversity. Iron is involved in both
several physicological functions (mitochondrial
energy production, oxygen transportation,
erythrocyte maturation) and pathological pro
cesses (production of reactive oxygen radicals
and induction of microbial growth/ virulence).
2
(DMT-1) [47]. DMT1 and Dcytb levels are upregulated by disease (Malaria, Helicobacter pylori infection, and hookworm infection),
hypoxia-inducible factor (HIF)− 2α signaling [47]. Ferroportin (FPN) digestive disorders, Celiac disease, dietary deficiency, and malabsorp
transfers the iron into the systemic circulation [48]. Circulating iron is tion [70–72]. Serum ferritin shows total iron storage in the body, and a
transported into cells by transferrin. Since transferrin can bind only Fe3+ lower ferritin level indicates iron deficiency [71]. Iron deficiency may
form, Fe2+ iron is oxidized to Fe3+ iron by ferroxidase enzymes, such as occur even if the ferritin level is high since ferritin is an acute phase
hephaestin in the intestine cells or ceruloplasmin in other tissues [49]. reactant, its level may increase in inflammation [71]. Decreased trans
Unutilized Fe3+ iron is stored in the form of ferritin and hemosiderin ferrin saturation index is another indicator for iron deficiency due to
[50]. In iron deficiency, iron absorption increases with the induction of increased transferrin expression [71].
HIF-2α signal and higher expression of DcytB, DMT1, and FPN [51,52]. Iron replacement therapy, either dietary intake or iron supplements,
Gut microbiota members and their metabolites affect the absorption is frequently administered in iron deficiency anaemia. Iron supplements
and bioavailability of iron. Dysbiosis is related to iron metabolism dis are administered by oral or intravenous (i.v.) route. Due to the low
orders [53] and may be rectified using prebiotics, probiotics, and syn absorption of oral iron, the duration of treatment is longer than i.v.
biotics [54]. These supplements have been shown either to increase iron treatment. Daily oral iron therapy is acutely caused to hepcidin upre
absorption and/or iron bioavailability by improving dysbiosis, mostly in gulation which is a negative regulator and limits intestinal iron ab
preclinical studies reflecting anaemia [55–57]. Moreover in healthy sorption [73]. An alternate-day regimen is advised to overcome this
subjects, lactic fermentation of vegetables with Lactobacillus plantarum situation [73]. The non-absorbed part of oral iron supplements from the
(probiotic), was found to augment iron uptake and bioavailability intestinal lumen reaches into the colon [24] and may facilitate the
through an increment in hydrated Fe3+ compared to fresh vegetables growth of pathogens [74]. Oral iron supplements cause gastrointestinal
[58]. Lactic acid fermentation of foods may enhance iron absorption via side effects, such as diarrhea, constipation, gastritis, dyspepsia, nausea,
decreasing pH, increasing the lactic acid bacteria, activating phytases, and intestinal inflammation [75]. These undesirable effects may occur
and generating organic acids [59]. due to increased free radicals, damage to the epithelium, and change in
In an in vitro experiment, p-hydroxyphenyllactic acid, which is the gut microbiota composition [24]. Oral iron supplements are simple
excreted by Lactobacillus fermentum, reduced Fe3+ to Fe2+ similarly to and cheap options, but some patients cannot benefit from oral iron
DcytB and induced iron uptake by enterocytes [60]. 1,3-diaminopro formulations due to their low absorption rate. Therefore, i.v. iron
pane and reuterin, gut microbiota metabolites, have been shown to treatment is preferred in this case to increase patient compliance [75].
suppress intestinal iron absorption via inhibiting HIF-2α in mice and Intravenous iron treatment may be preferred in inflammatory bowel
alleviate iron overload [23]. Propionibacterium freudenreichii produced disease with an unbalanced microbiota [76]. Although the importance
propionic acids and increased the iron transfer from proximal colon of iron for microorganisms is well-known, the effect of iron levels on the
mucosa [61]. The oral freeze-dried probiotic mixture contains nine gut microbiota is not adequately understood. Dietary iron deprivation
probiotic bacterial strains (Bifidobacterium spp., Lactobacillus spp. and caused an enhancement of anaerobes, micro-aerophiles, lactobacilli, and
Lactococcus lactis), was increased the intestinal commensal abundance, enterococci, excluding coliforms, in the mouse colon [77]. In
the iron bioavailability and duodenal iron absorption in the rats [62]. iron-deficient media, the growth of E. coli and Salmonella Typhimurium
The same supplement significantly diminished the hair iron level and were significantly disrupted, while Lactobacillus rhamnosus was not
did not change the serum iron level in obese postmenopausal women affected [78]. Higher Lactobacillus/Leuconostoc/Pediococcus spp. and
[63]. Oral Bifidobacterium longum CECT 7347 administration to weanling Enterobacteriaceae and lower Bacteroides spp. and Roseburia spp./Eu
rats increased liver iron deposition [64]. Probiotic complex including bacterium rectale levels were detected in the gut microbiota of
Bifidobacteria and Lactobacilli sp., augmented iron level through intesti iron-deficient rats [79]. Iron deficiency was related to decreased Lac
nal dysbiosis correction in chronic kidney disease patients [65]. Pro tobacilli level of feces composition in Indian women [80].
biotic strain and freeze-dried Lactobacillus plantarum 299 v that has Iron is essential for bacterial growth, thus, iron overload may affect
survived transition through the gastrointestinal system, increased the composition [24] and metabolic processes of the gut microbiota
non-heme iron absorption via intestinal bacteria colonization in pre [81]. Bifidobacteriaceae and Lactobacillaceae levels were decreased and
menopausal women [59,66]. Roseburia and Prevotella levels were increased after iron administration
in an in vitro study [82]. In a recent study, antibiotic treatment was
4. The effects of iron deficiency and iron supplements on the gut given concomitantly with iron-sufficient diet in mice, after the treatment
microbiota regimen mice were fed either with an iron-sufficient or
iron-supplemented diet [83]. The oral iron-supplemented diet increased
Anaemia is a condition in which the red blood cell count (haemo the luminal iron concentration and this may further promote the growth
globin and/or hematocrit) is below the normal level and affects and virulence of pathogens in dysbiosis, and lead to unfavorable changes
approximately one-third of the worldwide population [67]. Pregnant in gut microbiota [83]. Administration of oral iron-supplemented diet
women, infants, and children are at increased risk of anaemia due to after antibiotic treatment resulted in shifts towards the dominant
increased iron needs during fetal development or growth [68]. The composition of Bacteroidetes phylum, increased Parasutterella and Bac
etiology of anaemia is multifactorial but the most common cause is iron teroidetes levels, and decreased Bilophila and Akkermansia levels have
deficiency [69] and iron deficiency is classified into three stages based occurred during the recovery of gut microbiota [83]. Dietary iron caused
on erythropoiesis [70]. In stage I, negative iron balance causes stored lower levels of Firmicutes and Bacteroidetes and higher levels of Proteo
iron deficiency and haematological disorder does not occur at this stage bacteria in the feces of mice with colitis [84]. Diets containing different
[70]. In stage II, the iron level is insufficient for erythropoiesis in the concentrations of ferrous sulfate (iron-deficient, iron-sufficient and
bone marrow and has clinical significance [70]. Stage III is named iron iron-supplemented diets) caused increased luminal iron levels in parallel
deficiency anaemia and the haemoglobin level is under the normal level with the iron content of the diet in mice with colitis [24]. The increase in
[70] and iron deficiency anaemia occurs when iron homeostasis for luminal iron concentrations changes the composition of the fecal
erythrocyte production is not sustained [69]. Iron homeostasis is microbiota, augmented the relative abundance of the Firmicutes bacte
maintained by compensating for daily iron loss through iron absorption, rial phylum, but did not affect its diversity [24].
but this balance may be disrupted due to limited oral iron absorption Oral iron therapy alters the microbiota in favor of pathogenic mi
[71]. In cases where iron loss is greater than absorbed iron, iron defi croorganisms in iron deficiency patients. Most pathogenic bacteria, such
ciency and subsequent iron deficiency anaemia may occur [71]. Iron as Vibrio cholerae and Shigella species have multiple iron uptake systems
deficiency anaemia is caused by blood loss (hemorrhage, hyper which are contributed to the growth, metabolic regulation, and viru
menorrhea, blood donation, and gastrointestinal bleeding), infectious lence [85,86]. Iron deficiency anaemia is common in inflammatory
3
bowel disease patients. Oral/i.v. iron replacement therapies restored Table 1

iron deficiency in these patients and i.v. iron increased the ferritin level Clinical studies on the association between gut microbiota and iron.
more than oral treatment [76]. Collinsella aerofaciens, Faecalibacterium Study Design Population Main findings References
prausnitzii, Ruminococcus bromii, Dorea sp. were less abundant, while
A cross-over Healthy, Swedish Probiotic strain [59]
Bifidobacterium was more abundant following oral therapy compared to single-blind women of Lactobacillus plantarum
i.v. iron therapy in the feces [76]. An inverse relationship was found study reproductive age 299 v increased iron
between fecal iron and Lactobacilli levels in a cohort study, including in (n = 22). absorption.
children [87]. In a study of African children, although the consumption A single-blinded Healthy, Swedish Freeze-dried [66]
placebo- female volunteers of Lactobacillus plantarum
of iron-fortified biscuits did not affect the iron status, enteropathogens, controlled reproductive age 299 v increased iron
such as E. coli, Salmonella and Shigella spp. were increased, and Lacto sequential trial (n = 42). absorption.
bacilli was decreased in the gastrointestinal tract [88]. Iron supple A randomized, Stage 3a of chronic Multi-probiotics [65]
mentation in this population induces pathogenic gut microbiota open-label, kidney disease (Bifidobacteria and
placebo- patients (n = 28). Lactobacilli) were
composition [88].
controlled, associated with
Another study showed that oral iron supplementation used in South single-center increased iron levels.
African children did not notably affect the dominant gut bacterial groups intervention
[89]. Following the oral iron treatment, the abundance of short-chain study
fatty acids decreased, and the human fecal metabolome was altered A randomized Obese Using an oral nine- [63]
prospective, postmenopausal strain freeze-dried
[90]. Iron supplement (6 mg/kg/day) reduced commensal and patho double-blind, women (n = 73). powder probiotic
genic E. coli and Shigella spp. in American infants and toddlers with iron comparative, supplement for 12-
deficiency or anaemia [91]. In another study by the same group, placebo- week has affected iron
micronutrient powder with iron (12.5 mg) altered the gut microbiota in controlled, metabolism, and iron
multicenter was significantly
Kenyan infants who were not anemic [92]. An increase in Escherichia
trial decreased in hair
and Clostridium and a decrease in Bifidobacterium were found in fecal samples.
samples [92]. In a study performed on healthy Kenyan infants, the iron A randomized, 6–14 years old Iron-fortified biscuit [88]
supplement caused an increase in Enterobacteriaceae, such as pathogenic double-blind, African children caused an increase in
E. coli, and a reduction in Lactobacillus, Bifidobacterium, and increased controlled trial (n = 139). enteropathogens and a
decrease in Lactobacilli
body iron levels [25]. Higher level of plasma haemoglobin and ferritin
spp.
levels and lower soluble transferrin receptor levels were found in A randomized, 6–11 years old South Oral ferrous sulfate [89]
healthy Kenyan infants who were receiving iron therapy [93]. In this placebo- African children supplementation did
study, Bifidobacteriaceae and Lactobacillaceae were found less, and controlled (n = 49). not notably affect the
intervention dominant gut bacteria.
Clostridiales were found in higher amounts after the iron therapy in feces
trial
of healthy Kenyan infants [93]. Moreover, supplementation of prebiotic A randomized, 6-months old Kenyan The iron supplement [25]
galacto-oligosaccharides to iron treatment has eliminated this difference double-blind infants (n = 115). caused an increase in
and thus was suggested that it may alleviate the adverse effects of iron controlled trial Enterobacteriaceae, and
[93]. In the stool samples of Pakistani children who received vitamin a reduction in
Lactobacillus and
and iron supplements, bacterial diversity decreased [94]. However, in
Bifidobacterium.
another study of Bangladeshi children who consumed high-iron drinking A randomized, 9–24 months old Iron therapy (6 mg/ [91]
water, standard (12.5 mg iron) and low-iron (5 mg iron) supplements double-blind, American infants and kg/day) for 8-week
did not make a significant difference in the gut microbiota [95]. Clinical controlled trial toddlers with iron was caused the
deficiency or decrease in Escherichia
studies in the literature on a bidirectional relationship between gut
anaemia (n = 37). coli and Shigella spp. in
microbiota and iron are summarized in Table 1 the fecal samples.
A randomized, 6-months old Kenyan The use of iron [92]
5. Iron deficiency and supplements in susceptibility to bacterial double-blind, infants (n = 33). (12.5 mg)-containing
infections controlled trial micronutrient powder
for 3-month caused an
increase in Escherichia
Iron, a critical factor in the human immune system, is also necessary and Clostridium and a
for the survival of many pathogens. An increase in susceptibility to in decrease in
fections may occur as a result of a reduced immune response to iron Bifidobacterium in the
fecal microbiota.
deficiency [96]. Restricting free iron is the first line of host defence
A cohort study 2–5 years Indian An inverse association [87]
mechanisms against pathogens due to their virulence by using iron children (n = 40). between the
sources in the host body [97,98]. In an acute infection, the host-driven abundance of iron and
iron withdrawal comes into play to prevent the growth of these patho Lactobacillus was found
gens [99]. This process, which is carried out to limit the pathogenicity of in fecal samples of
children.
microorganisms, is termed ’nutritional immunity’ [99]. On the other A randomized, 6.5–9.5 months Following the iron [93]
hand, it is known that iron is sequestered not only from pathogens but double-blind Kenyan infants therapy,
also from erythroid progenitor cells in cases of autoimmune disease, controlled (n = 155). Bifidobacteriaceae and
malignancy, or persistent infection, and this is one of the main mecha study Lactobacillaceae were
decreased, and
nisms that play a role in anaemia of chronic inflammation [100].
Clostridiales were
In a prospective study in southern Israel, anaemia (78.9% of study increased in fecal
population has iron deficiency) was found that an independent risk samples.
factor for diarrhea and respiratory disease in infants and suggested that A randomized, Patients with Crohn’s After oral iron therapy, [76]
anaemia may contribute to augmented infection rates in toddlers [101]. open-label, disease (n = 31), Collinsella aerofaciens,
controlled trial ulcerative colitis Faecalibacterium
In another prospective study, iron deficiency anaemia was more com (n = 22) and control prausnitzii,
mon in children with acute lower respiratory tract infections, and Ruminococcus bromii,
anaemic children were more susceptible to acute lower respiratory tract (continued on next page)
infections [102]. Helicobacter pylori infection was related to an increased
4
Table 1 (continued ) iron chelators in infection (Fig. 2).

Study Design Population Main findings References
6.1. Siderophores
subjects with iron and Dorea sp. were less,
deficiency (n = 19). while Bifidobacterium
was found to be more Siderophores are low-molecular-weight iron-chelating molecules
than i.v. iron secreted by Gram-negative and Gram-positive bacteria in response to
treatment. iron deficiency, and this molecule scavenges Fe3+ [112]. Most bacteria
A clinical study Patients with iron After treatment with [90]
use siderophores to acquire iron via specific receptors to maintain
deficiency anaemia. iron, the abundance of
Pre-treatment with short-chain fatty acids growth, replication, and metabolic functions (Fig. 2a) [113]. There is a
oral ferrous sulfate decreased, and gut struggle between the pathogen and host to acquire iron. The affinity of
supplementation microbiota bacterial siderophores to iron is high and they seize the iron from host
(n = 45) and two composition altered. iron-binding proteins, such as lipocalin-2 (siderocalin) and lactoferrin.
months later
(n = 32).
In this way, siderophores may overcome the host defense mechanism
A randomized 12–24 months Vitamin and iron [94] and alter iron utilization in favor of the pathogen [114]. Enterobacteri
controlled trial Pakistani children supplements were aceae secrete siderophores called enterobactin to scavenge iron from the
(n = 80). related to reduced extracellular site [115]. Enterobactin may harm the host’s iron ho
bacterial diversity and
meostasis [116] and may increase the survival of intracellular bacteria,
augmented destructive
protozoan and fungal such as Salmonella enterica serovar Typhimurium in macrophages [117].
communities. Furthermore, immunization with siderophores in mice before exposure
A randomized 2–5 years old The gut microbiota of [95] to Salmonella enterica resulted in reduced pathogen colonization and
controlled trial Bangladeshi children children was not increased Lactobacillus in the gut [118]. Vibrio and Yersinia species are
(n = 53) who drink different between the
groundwater with a standard (12.5 mg
some siderophilic bacteria whose pathogenicity is augmented in the
high concentration of iron) or low-iron presence of free iron. Especially in individuals with hereditary hemo
iron (≥ 2 mg/L). micronutrient powder chromatosis, susceptibility to infections and sepsis caused by these
(5 mg iron) group. bacteria may increase [119,120].
Siderophore-mediated iron acquisition mechanism by bacteria tip
ped the scale in the hosts’ favor and led to the development of
risk of iron deficiency anaemia [103]. However, the clinical studies have
siderophore-conjugated antibiotics, also referred to ‘Trojan-horse anti
conflicting results on the relationship between iron deficiency and sus
biotics’ [121]. These antibiotics may be beneficial in the treatment of
ceptibility to bacterial infections, and more evidence-based studies are
drug-resistant bacterial infection [112]. Indeed, drug-resistant bacteria
needed on this subject [104,105].
(methicillin-resistant Staphylococcus aureus and metallo-β-lactamase
Oral iron supplements are primary treatment option for iron defi
producers – Pseudomonas aeruginosa and Acinetobacter baumannii) were
ciency in pregnant women and children, especially in low-income
challenged by either exogenous siderophores (exochelin-MS and
countries. Acute iron (ferrous sulfate) administration resulted in an
deferoxamine-B) and their combination with antibiotics. The combina
increased number of E. coli, Yersinia enterocolitica, Salmonella enterica
tion showed a synergistic inhibitory effect on drug-resistant bacterial
serovar Typhimurium, and Staphylococcus epidermidis in serum samples
growth [122]. There is an urgent need to develop novel drugs, partic
from healthy male Gambian subjects, acute oral iron administraton
ularly in combating Gram-negative bacteria due to antimicrobial resis
resulted in an increase of transferrin saturation and total serum iron
tance [123]. Synthetic siderophores conjugated antibiotics considered a
level [106]. Long-term use of oral iron supplements was ascribed to
plausible treatment approach that aim to achieve iron scavenging in the
increased septic shock 30-day mortality in hospitalized patients with
treatment of Gram-negative bacterial infections [113]. Cefiderocol (i.v.)
Gram-negative bacteremia [107]. Contrarily, oral iron supplements for
is the first siderophore conjugated antibiotic approved by FDA in 2019
four-week before blood donation was not associated with the infection
for the treatment of complicated urinary tract infections and nosocomial
risk [108]. Iron supplements caused lower ferritin and slightly lower
pneumonia caused by Gram-negative bacteria [124].
hemoglobin levels compared to nonusers [108]. A comprehensive sys
tematic review and meta-analysis, revealed that i.v. iron was associated
with an enhanced risk of infection compared to oral iron [109]. How 6.2. Hepcidin
ever, studies show controversial results and clinical deterioration of
infections depending on the type of bacteria [110]. The impact of di Hepcidin is an antimicrobial hormone produced by the liver and
etary iron and iron supplements, as well as iron overloading, on the mainly secreted by hepatocytes [21]. The hepcidin production increases
prognosis of infectious diseases remains a debate [110]. Since iron is a when plasma iron levels are high, and it leads to the degradation of iron
pivotal element for the metabolic pathway of other living organisms, exporter FPN on cells. The degradation of FPN inhibits the release of iron
including human and gut microbiota, both iron deficiency and iron into the blood [97,98] and limits the access of pathogens to iron (Fig. 2
overload may be detrimental in infections. Thus, iron supplements are a b) [125]. Hepcidin overexpression as a serious consequence of any
double-edged sword. It is important to monitor iron supplement treat infection or chronic inflammation may also result in hypoferremia,
ment against the possibility of iron overload and interfere immediately anaemia of inflammation and anaemia of chronic disease. Conversely,
with iron chelators to prevent infection. Physicians should carefully the inhibition of hepcidin expression is occurred in hypoxia and eryth
evaluate this point. ropoiesis [97,98]. Hepcidin regulates serum iron resulting in hypo
ferremia by reducing FPN in macrophages, duodenum, and hepatocytes
6. Iron targeted therapy approaches in infection [126]. Iron retention in the same cells may be beneficial to cope with
extracellular bacterial infection; however, it may have a disadvantage in
Considering the bidirectional role of iron in infections, the devel enhancing intracellular bacteria propagation, Salmonella enterica [127].
opment of iron-targeted treatment strategies is important to maintain Supporting that, inflammatory IFN-γ reduced intracellular bacterial load
the normal metabolic function of the human body. These strategies through increasing iron export from macrophages [128]. On the other
should block iron uptake in the pathogen bacteria selectively, but not in hand, hepcidin led to an iron overload in macrophages cytosol but not in
human cells and commensal bacteria [111]. In this part, we discussed Salmonella-containing vacuole (SCV), which worsens the infection due
the possible role of siderophores, hepcidin, iron-binding proteins, and to insufficient amount of bactericidal reactive oxygen species produc
tion in SCV [129]. In vitro hepcidin overexpression occurred in response
5
Fig. 2. Effects of siderophores, hepcidin, lipocalin-2, and iron chelators in infectious diseases. In infection, siderophores favor pathogenic bacteria, while hepcidin
and lipocalin-2 act against them. A combination of iron chelator and antibiotics may be beneficial for the treatment of infectious diseases.
to mycobacterium and IFN-γ stimulation in mouse macrophages [130]. [137]. Hepcidin supplementation could decrease morbidity and mor
In a study, wild-type or hepcidin knockout C57BL/6 mice were tality resulting from lipopolysaccharide toxicity in mice [138,139].
infected with Klebsiella pneumoniae [131]. Hepcidin deficient mice had LDN-193189 and oversulfated heparins was proven to have hepcidin
higher iron levels during the infection and had lower survival rates. inhibitory activity in in vitro. Application of these molecules resulted in
Hepcidin analogue treatment improved bacterial burden and reduced hepcidin expression in uninfected mice, but not in infected mice
pneumonia-related mortality in these animals [131]. In line with the [140]. This data suggested the fact that there may be other compensa
previous study, hepcidin deficiency led to the greater invasion of the tory signaling pathways during infection which facilitate hepcidin
bacteria, and hepcidin-overexpressing adenovirus injection resulted in expression to protect host against pathogens [140].
an increased survival rate in animals [132]. Hepcidin showed direct
antimicrobial activity on Mycobacterium tuberculosis. Incubation of
6.3. Iron-binding proteins
bacteria with hepcidin for six-hour resulted in a 50% reduction in
colony-forming units, and the data from 72-hour of incubation were
In mammals, iron-binding proteins lipocalin-2 and lactoferrin are
comparable. Hepcidin caused structural changes in bacteria [130]. The
secreted to reduce microbial iron availability [141,142]. Lipocalin-2 has
overexpression of hepcidin was seen in group A Streptococcus necrotizing
been upregulated via Toll-like receptors in response to bacterial infec
fasciitis patients [133]. In a mice model of this disease, hepcidin treat
tion and suppresses the growth of bacteria (Fig. 2b) [142–145]. Thus, it
ment prevents systemic dissemination of the bacteria [133]. Hepcidin
has positive regulatory effect on the immune system. Lipocalin-2 hinders
shows beneficial effect through neutrophil recruitment [133] and
siderophore-mediated iron sequestration by bacteria, and protects
increasing the macrophage function [132] and oxidative stress [134],
against pathogens [146]. Depletion of lipocalin-2 leads to susceptibility
besides its role in iron homeostasis. Iron regulatory mechanisms in in
to bacterial infections [144,147,148] and dysbiosis in gut microbiota
fections are not exclusively hepcidin dependent; involvement of the
[149]. Recombinant lipocalin-2 administration reduced the infection
hepcidin depends upon the type of bacteria [128,135]. Beyond its
intensity caused by various bacteria, such as Salmonella Typhimurium
therapeutic effect, hepcidin was also suggested as a diagnostic
[150], Enterobacteriaceae [151], E. coli [152]. While lipocalin-2
biomarker of bacterial infection in febrile children, especially in
increased the iron composition in macrophages and thereby promoted
gastrointestinal and urinary tract infections [136]. According the most
bacterial growth in the early stages of M. tuberculosis infection [153], it
studies, hepcidin agonists seem like promising treatment approaches
has been proposed to reduce intracellular M. tuberculosis growth in
however, their efficacy may be limited to siderophilic bacteria like
another study [154]. Furthermore, lipocalin-2 modulated the immune
Y. enterocolitica, which require plasma-free iron for their replication
cell function, which is another mechanism that may be attributed to its
6
antibacterial effect beyond iron restricting pathway for bacteria [145, found superior to either drug alone against methicillin-resistant S. aureus
155]. (MRSA) and vancomycin-intermediate S. aureus (VISA) strains. The ef
Lactoferrin sequesters extracellular iron and serves as a key molecule fect was postulated to increase the binding of vancomycin to S. aureus
in the immune and inflammatory process associated with iron homeo cell membrane by deferasirox [181]. Deferiprone or deferasirox in
stasis [114]. Lactoferrin enhances iron absorption and has been pro combination with tobramycin showed synergistic effect on reducing
posed to be beneficial for iron deficiency anaemia in infants [156], biofilm and virulence of P. aeruginosa [182]. Some studies revealed the
children with irritable bowel disease [157], and pregnant women [158]. possible effect of iron chelators in infectious diseases. Deferiprone ag
It is produced by neutrophils and is an iron-scavenging antimicrobial gravates the growth of A. baumannii in iron sufficient media but not in
factor for the body [100,159]. Lactoferrin can compete with bacterial iron-rich and in iron-poor media [183]. Different effects of the defer
siderophores for iron in the gut, so it may prevent the pathogen colo iprone depending on the media were attributed to its iron binding ca
nization [160]. Lactoferrin itself and as a nutraceutical have been sug pacity and to mobilize the iron which may promote the expansion of
gested to protect against viruses and bacteria [161]. Antibacterial bacterial cells [183]. Deferoxamine suppressed Porphyromonas gingivalis
activity of both human and bovine lactoferrin against growth through deprivation of hemin (Fe3+-protoporphyrin IX) and had
Gram-positive/Gram-negative bacteria has been shown in in vitro and in a synergistic antimicrobial effect of hydrogen peroxide and metronida
vivo studies [162]. Human lactoferrin versus bovine lactoferrin was zole [184]. In vivo and in vitro studies have shown that DIBI, is effective
evaluated against A. baumannii in clinical isolates from different against A. baumannii mediated pneumonia infection by supporting the
anatomical sites [164]. Both lactoferrins inhibit the biofilm formation of host iron restriction mechanism and inhibiting the utilization of iron by
A. baumannii strains [163]. Yet, human lactoferrin has a slightly greater bacteria [185]. These studies pave the way for the possible beneficial
antibacterial activity ascribed to a wide range of antibiofilm activity effects of iron chelator and antibiotic combination to cope with infec
[163]. Lactoferrin purified from human breast milk inhibited bacterial tious diseases. However, the chelators may show different effects
growth/biofilm and prevented adherence of the Group B Streptococcus to depending on the bacteria and an appropriate chelator should be chosen
gestational membranes [164]. Lactoferrin reduced pathogenic bacteria based on previous studies considering their level of evidence.
(E. coli and Salmonella) in weanling pigs’ intestines, lactoferrin supple
mentation promoted the growth of beneficial gut bacteria Lactobacillus 7. Conclusion
and Bifidobacterium [165]. Human lactoferrin has a prophylactic role as
an antibacterial and anti-inflammatory agent against Streptococcus Iron is a pivotal element in all living organisms, thus both iron
mutans infection in lactoferrin knockout mice [166]. A systematic re deficiency and iron overload may be detrimental for the susceptibility to
view revealed that lactoferrin supplementation reduced late-onset sepsis infections. Therefore, iron supplements are a double-edged sword and it
in preterms [167]. The beneficial role of lactoferrin in E. coli-mediated is essential to monitor iron supplement treatment against the possibility
urinary tract infection was attributed to its modulatory effect on innate of iron overload and related infections. In such circumstances, inter
immune responses [168]. Lactoferricin and lactoferrampin are fering with iron chelators would help to reduce the iron levels and
lactoferrin-derived peptides with antimicrobial activity, but the under infection risk. However, every patient should be evaluated individually
lying mechanism remains elucidated [169]. and carefully considering existing infection and their routine diet habits.
The physician should bear in mind the possible deleterious effect of iron
6.4. Iron chelators supplements. In light of the findings obtained from this review, the
benefits and harms of iron supplementations in infection disease were
Iron chelators are used in iron overload-related diseases and have reported. Further clinical studies would yield more insights into iron
gained importance in recent years as a beneficial adjunctive therapy to homeostasis and its interactions between pathogens/commensal
antibiotics in infections (Fig. 2c) [170]. In the clinical setting, iron microbiota members. A better understanding of these interactions may
chelators are used for the treatment of the conditions characterized by help us both comprehending the pathogenesis/prognosis of many dis
iron overload, such as hereditary haemochromatosis, thalassaemia as eases and developing of novel therapeutic strategies.
well as other blood transfusion-dependent anaemias [171]. Natural iron
chelator deferoxamine, which is produced by Streptomyces, has diver 8. CRediT authorship contribution statement
gent effects on bacterial growth in different species [172], thus it may
exacerbate some infections. Deferoxamine (s.c., i.v.), and two synthetic Zinnet Şevval AKSOYALP: Conceptualization, Methodology,
chelators, deferiprone (oral tablet) and deferasirox (oral tablet), are Investigation, Resources, Writing – original draft, Writing – review &
approved by FDA [170]. Additionally, DIBI (3-hydroxypyridin-4-one editing. Aybala TEMEL: Conceptualization, Methodology, Investiga
chelator), is a novel iron chelator molecule that was designed to have tion, Resources, Writing – original draft, Writing – review & editing.
antimicrobial activity [173]. In addition to the natural and synthetic Betul Rabia ERDOGAN: Conceptualization, Methodology, Investiga
iron chelators used in treatment, some food sources also contain com tion, Resources, Writing – original draft, Writing – review & editing.
pounds such as phytic acid, polyphenols, caffeic acid, quercetin, cur
cumin, gallic acid which have iron chelating properties [174]. Iron poor Declaration of Competing Interest
and iron chelators rich diet may trigger iron deficiency in people. This
situation may change the prognosis and the use of iron chelators in the The authors declare that they have no known competing financial
infectious diseases. Deferoxamine promoted the growth of interests or personal relationships that could have appeared to influence
Y. enterocolitica but deferiprone did not aggravate Y. enterocolitica the work reported in this paper.
septicemia [175]. This effect can be ascribed to that deferoxamine acts
as a siderophore increasing iron acquisition of the bacteria [176].
Acknowledgements
Deferoxamine enhanced the growth of Klebsiella pneumoniae but not of
Aeromonas hydrophila compared to deferiprone and deferasirox in thal
Figure were presented by using images from Servier Medical Art
assemic patients blood cultures [177]. DIBI was suggested the most
(http://smart.servier.com).
promising iron chelator compared to FDA approved iron chelators in
sepsis treatment [178]. Deferoxamine promotes growth of Vibrio vulni
References
ficus in comparison to deferasirox [179], and a combination of defer
asirox and ciprofloxacin showed a synergistic effect against V. vulnificus [1] S. Sirisinha, The potential impact of gut microbiota on your health:current status
in vitro [180]. Combination of deferasirox and vancomycin therapy was and future challenges, Asian Pac. J. Allergy Immunol. 34 (4) (2016) 249–264.
7
[2] K. Lange, M. Buerger, A. Stallmach, T. Bruns, Effects of antibiotics on gut [32] N. Kamada, Y.G. Kim, H.P. Sham, B.A. Vallance, J.L. Puente, E.C. Martens,
microbiota, Dig. Dis. 34 (3) (2016) 260–268. G. Nunez, Regulated virulence controls the ability of a pathogen to compete with
[3] H.X. Wang, Y.P. Wang, Gut microbiota-brain axis, Chin. Med J. 129 (19) (2016) the gut microbiota, Science 336 (6086) (2012) 1325–1329.
2373–2380. [33] M. Gagnon, E.E. Kheadr, G. Le Blay, I. Fliss, In vitro inhibition of Escherichia coli
[4] K.K. Kondepudi, P. Ambalam, I. Nilsson, T. Wadstrom, A. Ljungh, Prebiotic-non- O157:H7 by bifidobacterial strains of human origin, Int. J. Food Microbiol. 92 (1)
digestible oligosaccharides preference of probiotic bifidobacteria and (2004) 69–78.
antimicrobial activity against Clostridium difficile, Anaerobe 18 (5) (2012) [34] C.M. Guinane, E. Barrett, G.F. Fitzgerald, D. van Sinderen, R.P. Ross, C. Stanton,
489–497. Genome sequence of Bifidobacterium breve DPC 6330, a strain isolated from the
[5] C.G. Buffie, E.G. Pamer, Microbiota-mediated colonization resistance against human intestine, J. Bacteriol. 193 (23) (2011) 6799–6800.
intestinal pathogens, Nat. Rev. Immunol. 13 (11) (2013) 790–801. [35] F.M. Trejo, J. Minnaard, P.F. Perez, G.L. De Antoni, Inhibition of Clostridium
[6] A. Adak, M.R. Khan, An insight into gut microbiota and its functionalities, Cell difficile growth and adhesion to enterocytes by Bifidobacterium supernatants,
Mol. Life Sci. 76 (3) (2019) 473–493. Anaerobe 12 (4) (2006) 186–193.
[7] S. Grenham, G. Clarke, J.F. Cryan, T.G. Dinan, Brain-gut-microbe communication [36] M. Kankainen, L. Paulin, S. Tynkkynen, I. von Ossowski, J. Reunanen,
in health and disease, Front Physiol. 2 (2011) 94. P. Partanen, R. Satokari, S. Vesterlund, A.P. Hendrickx, S. Lebeer, S.C. De
[8] B. Yilmaz, H. Li, Gut microbiota and iron: the crucial actors in health and disease, Keersmaecker, J. Vanderleyden, T. Hamalainen, S. Laukkanen, N. Salovuori,
Pharmaceuticals 11 (4) (2018). J. Ritari, E. Alatalo, R. Korpela, T. Mattila-Sandholm, A. Lassig, K. Hatakka, K.
[9] C.J. Donskey, Antibiotic regimens and intestinal colonization with antibiotic- T. Kinnunen, H. Karjalainen, M. Saxelin, K. Laakso, A. Surakka, A. Palva,
resistant gram-negative bacilli, Clin. Infect. Dis. 43 43 (Suppl 2) (2006) S62–S69. T. Salusjarvi, P. Auvinen, W.M. de Vos, Comparative genomic analysis of
[10] N. Kamada, S.U. Seo, G.Y. Chen, G. Nunez, Role of the gut microbiota in Lactobacillus rhamnosus GG reveals pili containing a human- mucus binding
immunity and inflammatory disease, Nat. Rev. Immunol. 13 (5) (2013) 321–335. protein, Proc. Natl. Acad. Sci. USA 106 (40) (2009) 17193–17198.
[11] T.B. Devi, K. Devadas, M. George, A. Gandhimathi, D. Chouhan, R.J. Retnakumar, [37] J. Reunanen, I. von Ossowski, A.P. Hendrickx, A. Palva, W.M. de Vos,
S.M. Alexander, J. Varghese, S. Dharmaseelan, S.K. Chandrika, V.T. Jissa, B. Das, Characterization of the SpaCBA pilus fibers in the probiotic Lactobacillus
G.B. Nair, S. Chattopadhyay, Low bifidobacterium abundance in the lower gut rhamnosus GG, Appl. Environ. Microbiol 78 (7) (2012) 2337–2344.
microbiota is associated with helicobacter pylori-related gastric ulcer and gastric [38] P. Banerjee, G.J. Merkel, A.K. Bhunia, Lactobacillus delbrueckii ssp. bulgaricus B-
cancer, Front Microbiol 12 (2021), 631140. 30892 can inhibit cytotoxic effects and adhesion of pathogenic Clostridium
[12] Y.L. Loke, M.T. Chew, Y.F. Ngeow, W.W.D. Lim, S.C. Peh, Colon carcinogenesis: difficile to Caco-2 cells, Gut Pathog. 1 (1) (2009) 8.
the interplay between diet and gut microbiota, Front Cell Infect. Microbiol 10 [39] S.C. Andrews, A.K. Robinson, F. Rodriguez-Quinones, Bacterial iron homeostasis,
(2020), 603086. FEMS Microbiol Rev. 27 (2–3) (2003) 215–237.
[13] M. Million, M. Maraninchi, M. Henry, F. Armougom, H. Richet, P. Carrieri, [40] M.Y. Zeng, N. Inohara, G. Nunez, Mechanisms of inflammation-driven bacterial
R. Valero, D. Raccah, B. Vialettes, D. Raoult, Obesity-associated gut microbiota is dysbiosis in the gut, Mucosal Immunol. 10 (1) (2017) 18–26.
enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and [41] M.D. Fleming, I. Hamza, Mitochondrial heme: an exit strategy at last, J. Clin.
Methanobrevibacter smithii, Int. J. Obes. 36 (6) (2012) 817–825. Invest 122 (12) (2012) 4328–4330.
[14] K. Socala, U. Doboszewska, A. Szopa, A. Serefko, M. Wlodarczyk, A. Zielinska, [42] A. Jain, E.L. Connolly, Mitochondrial iron transport and homeostasis in plants,
E. Poleszak, J. Fichna, P. Wlaz, The role of microbiota-gut-brain axis in Front Plant Sci. 4 (2013) 348.
neuropsychiatric and neurological disorders, Pharmacol. Res. 172 (2021), [43] D.F. Wallace, The regulation of iron absorption and homeostasis, Clin. Biochem
105840. Rev. 37 (2) (2016) 51–62.
[15] W. Barcik, R.C.T. Boutin, M. Sokolowska, B.B. Finlay, The role of lung and gut [44] J.D. Cook, Adaptation in iron metabolism, Am. J. Clin. Nutr. 51 (2) (1990)
microbiota in the pathology of asthma, Immunity 52 (2) (2020) 241–255. 301–308.
[16] S.V. Lynch, Gut microbiota and allergic disease. new insights, Ann. Am. Thorac. [45] J.M. McDermid, B. Lonnerdal, Iron, Adv. Nutr. 3 (4) (2012) 532–533.
Soc. 13 Suppl 1 (2016) S51–S54. [46] R.S. Gibson, V. Raboy, J.C. King, Implications of phytate in plant-based foods for
[17] B.J.H. Verhaar, A. Prodan, M. Nieuwdorp, M. Muller, Gut microbiota in iron and zinc bioavailability, setting dietary requirements, and formulating
hypertension and atherosclerosis: a review, Nutrients 12 (10) (2020). programs and policies, Nutr. Rev. 76 (11) (2018) 793–804.
[18] L.-X. Lv, H.-Y. Jiang, R. Yan, L. Li, Interactions between gut microbiota and hosts [47] T. Ems, K. St Lucia, M.R. Huecker, Biochemistry, Iron Absorption, StatPearls,
and their role in infectious diseases, Infect. Microbes Dis. 1 (1) (2019) 3–9. Treasure Island (FL), 2022.
[19] J.K. Nicholson, E. Holmes, J. Kinross, R. Burcelin, G. Gibson, W. Jia, S. Pettersson, [48] H. Drakesmith, E. Nemeth, T. Ganz, Ironing out ferroportin, Cell Metab. 22 (5)
Host-gut microbiota metabolic interactions, Science 336 (6086) (2012) (2015) 777–787.
1262–1267. [49] B.K. Fuqua, C.D. Vulpe, G.J. Anderson, Intestinal iron absorption, J. Trace Elem.
[20] P. Pushpanathan, G.S. Mathew, S. Selvarajan, K.G. Seshadri, P. Srikanth, Gut Med Biol. 26 (2–3) (2012) 115–119.
microbiota and its mysteries, Indian J. Med. Microbiol 37 (2) (2019) 268–277. [50] H. Saito, Metabolism of iron stores, Nagoya J. Med. Sci. 76 (3–4) (2014) 235–254.
[21] A. Lopez, P. Cacoub, I.C. Macdougall, L. Peyrin-Biroulet, Iron deficiency anaemia, [51] Y.M. Shah, T. Matsubara, S. Ito, S.H. Yim, F.J. Gonzalez, Intestinal hypoxia-
Lancet 387 (10021) (2016) 907–916. inducible transcription factors are essential for iron absorption following iron
[22] Y. Seyoum, K. Baye, C. Humblot, Iron homeostasis in host and gut bacteria - a deficiency, Cell Metab. 9 (2) (2009) 152–164.
complex interrelationship, Gut Microbes 13 (1) (2021) 1–19. [52] M. Taylor, A. Qu, E.R. Anderson, T. Matsubara, A. Martin, F.J. Gonzalez, Y.
[23] N.K. Das, A.J. Schwartz, G. Barthel, N. Inohara, Q. Liu, A. Sankar, D.R. Hill, M. Shah, Hypoxia-inducible factor-2alpha mediates the adaptive increase of
X. Ma, O. Lamberg, M.K. Schnizlein, J.L. Arques, J.R. Spence, G. Nunez, A. intestinal ferroportin during iron deficiency in mice, Gastroenterology 140 (7)
D. Patterson, D. Sun, V.B. Young, Y.M. Shah, Microbial metabolite signaling is (2011) 2044–2055.
required for systemic iron homeostasis, Cell Metab. 31 (1) (2020), 115-130 e6. [53] K. Skrypnik, J. Suliburska, Association between the gut microbiota and mineral
[24] M. Constante, G. Fragoso, J. Lupien-Meilleur, A. Calve, M.M. Santos, Iron metabolism, J. Sci. Food Agric. 98 (7) (2018) 2449–2460.
supplements modulate colon microbiota composition and potentiate the [54] V.D. Appanna, Dysbiosis, probiotics, and prebiotics: in diseases and health.
protective effects of probiotics in dextran sodium sulfate-induced colitis, Inflamm. Human Microbes-The Power Within, Springer, 2018, pp. 81–122.
Bowel Dis. 23 (5) (2017) 753–766. [55] J.M. Laparra, M. Díez-Municio, M. Herrero, F.J. Moreno, Structural differences of
[25] T. Jaeggi, G.A. Kortman, D. Moretti, C. Chassard, P. Holding, A. Dostal, prebiotic oligosaccharides influence their capability to enhance iron absorption in
J. Boekhorst, H.M. Timmerman, D.W. Swinkels, H. Tjalsma, J. Njenga, deficient rats, Food Funct. 5 (10) (2014) 2430–2437.
A. Mwangi, J. Kvalsvig, C. Lacroix, M.B. Zimmermann, Iron fortification [56] V. Garcés, A. Rodríguez-Nogales, A. González, N. Gálvez, M.E. Rodríguez-
adversely affects the gut microbiome, increases pathogen abundance and induces Cabezas, M.L. García-Martin, L. Gutiérrez, D. Rondó n, Olivares M.n, J. Gá lvez,
intestinal inflammation in Kenyan infants, Gut 64 (5) (2015) 731–742. Bacteria-carried iron oxide nanoparticles for treatment of anemia, Bioconjug.
[26] M. Bohnhoff, C.P. Miller, Enhanced susceptibility to Salmonella infection in Chem. 29 (5) (2018) 1785–1791.
streptomycin-treated mice, J. Infect. Dis. (1962) 117–127. [57] S.K. Adiki, C.K. Perla, G. Saha, P. Katakam, V. Theendra, Enhancement in iron
[27] D. van der Waaij, J.M. Berghuis-de Vries, L.-v Lekkerkerk, Colonization resistance absorption on intake of chemometrically optimized ratio of probiotic strain
of the digestive tract in conventional and antibiotic-treated mice, J. Hyg. (Lond. ) Lactobacillus plantarum 299v with iron supplement pearl millet, Biol. Trace
69 (3) (1971) 405–411. Elem. Res. 190 (1) (2019) 150–156.
[28] U. Stiefel, C.J. Donskey, The role of the intestinal tract as a source for [58] N. Scheers, L. Rossander-Hulthen, I. Torsdottir, A.-S. Sandberg, Increased iron
transmission of nosocomial pathogens, Curr. Infect. Dis. Rep. 6 (6) (2004) bioavailability from lactic-fermented vegetables is likely an effect of promoting
420–425. the formation of ferric iron (Fe 3+), Eur. J. Nutr. 55 (1) (2016) 373–382.
[29] S. Kim, A. Covington, E.G. Pamer, The intestinal microbiota: antibiotics, [59] M. Hoppe, G. Onning, A. Berggren, L. Hulthen, Probiotic strain Lactobacillus
colonization resistance, and enteric pathogens, Immunol. Rev. 279 (1) (2017) plantarum 299v increases iron absorption from an iron-supplemented fruit drink:
90–105. a double-isotope cross-over single-blind study in women of reproductive age, Br.
[30] T. de Sablet, C. Chassard, A. Bernalier-Donadille, M. Vareille, A.P. Gobert, J. Nutr. 114 (8) (2015) 1195–1202.
C. Martin, Human microbiota-secreted factors inhibit shiga toxin synthesis by [60] A. Gonzalez, N. Galvez, J. Martin, F. Reyes, I. Perez-Victoria, J.M. Dominguez-
enterohemorrhagic Escherichia coli O157:H7, Infect. Immun. 77 (2) (2009) Vera, Identification of the key excreted molecule by Lactobacillus fermentum
783–790. related to host iron absorption, Food Chem. 228 (2017) 374–380.
[31] R.B. Ferreira, N. Gill, B.P. Willing, L.C. Antunes, S.L. Russell, M.A. Croxen, B. [61] D. Bougle, N. Vaghefi-Vaezzadeh, N. Roland, G. Bouvard, P. Arhan, F. Bureau,
B. Finlay, The intestinal microbiota plays a role in Salmonella-induced colitis D. Neuville, J.L. Maubois, Influence of short-chain fatty acids on iron absorption
independent of pathogen colonization, PLoS One 6 (5) (2011), e20338. by proximal colon, Scand. J. Gastroenterol. 37 (9) (2002) 1008–1011.
8
[62] K. Skrypnik, P. Bogdanski, M. Schmidt, J. Suliburska, The effect of multispecies [88] M.B. Zimmermann, C. Chassard, F. Rohner, K. N’Goran E, C. Nindjin, A. Dostal,
probiotic supplementation on iron status in rats, Biol. Trace Elem. Res 192 (2) J. Utzinger, H. Ghattas, C. Lacroix, R.F. Hurrell, The effects of iron fortification on
(2019) 234–243. the gut microbiota in African children: a randomized controlled trial in Cote
[63] K. Skrypnik, P. Bogdanski, M. Sobieska, J. Suliburska, The effect of multistrain d’Ivoire, Am. J. Clin. Nutr. 92 (6) (2010) 1406–1415.
probiotic supplementation in two doses on iron metabolism in obese [89] A. Dostal, J. Baumgartner, N. Riesen, C. Chassard, C.M. Smuts, M.
postmenopausal women: a randomized trial, Food Funct. 10 (8) (2019) B. Zimmermann, C. Lacroix, Effects of iron supplementation on dominant
5228–5238. bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised,
[64] J.M. Laparra, M. Olivares, Y. Sanz, Oral administration of Bifidobacterium placebo-controlled intervention trial in South African children, Br. J. Nutr. 112
longum CECT 7347 ameliorates gliadin-induced alterations in liver iron (4) (2014) 547–556.
mobilisation, Br. J. Nutr. 110 (10) (2013) 1828–1836. [90] A. Ahmed, R. Slater, S. Lewis, C. Probert, Using volatile organic compounds to
[65] M. Simeoni, M.L. Citraro, A. Cerantonio, F. Deodato, M. Provenzano, investigate the effect of oral iron supplementation on the human intestinal
P. Cianfrone, M. Capria, S. Corrado, E. Libri, A. Comi, A. Pujia, L. Abenavoli, metabolome, Molecules 25 (21) (2020).
M. Andreucci, M. Cocchi, T. Montalcini, G. Fuiano, An open-label, randomized, [91] M. Tang, D.N. Frank, L. Sherlock, D. Ir, C.E. Robertson, N.F. Krebs, Effect of
placebo-controlled study on the effectiveness of a novel probiotics administration vitamin E with therapeutic iron supplementation on iron repletion and gut
protocol (ProbiotiCKD) in patients with mild renal insufficiency (stage 3a of microbiome in US iron deficient infants and toddlers, J. Pedia Gastroenterol.
CKD), Eur. J. Nutr. 58 (5) (2019) 2145–2156. Nutr. 63 (3) (2016) 379–385.
[66] M. Hoppe, G. Onning, L. Hulthen, Freeze-dried Lactobacillus plantarum 299v [92] M. Tang, D.N. Frank, A.E. Hendricks, D. Ir, F. Esamai, E. Liechty, K.M. Hambidge,
increases iron absorption in young females-Double isotope sequential single-blind N.F. Krebs, Iron in micronutrient powder promotes an unfavorable gut microbiota
studies in menstruating women, PLoS One 12 (12) (2017), e0189141. in Kenyan infants, Nutrients 9 (7) (2017).
[67] N.J. Kassebaum, R. Jasrasaria, M. Naghavi, S.K. Wulf, N. Johns, R. Lozano, [93] D. Paganini, M.A. Uyoga, G.A.M. Kortman, C.I. Cercamondi, D. Moretti, T. Barth-
M. Regan, D. Weatherall, D.P. Chou, T.P. Eisele, S.R. Flaxman, R.L. Pullan, S. Jaeggi, C. Schwab, J. Boekhorst, H.M. Timmerman, C. Lacroix, S. Karanja, M.
J. Brooker, C.J. Murray, A systematic analysis of global anemia burden from 1990 B. Zimmermann, Prebiotic galacto-oligosaccharides mitigate the adverse effects
to 2010, Blood 123 (5) (2014) 615–624. of iron fortification on the gut microbiome: a randomised controlled study in
[68] A.L. Fisher, E. Nemeth, Iron homeostasis during pregnancy, Am. J. Clin. Nutr. 106 Kenyan infants, Gut 66 (11) (2017) 1956–1967.
(Suppl 6) (2017) 1567S–1574S. [94] A. Popovic, C. Bourdon, P.W. Wang, D.S. Guttman, S. Soofi, Z.A. Bhutta, R.H.
[69] J.L. Miller, Iron deficiency anemia: a common and curable disease, Cold Spring J. Bandsma, J. Parkinson, L.G. Pell, Micronutrient supplements can promote
Harb. Perspect. Med 3 (7) (2013). disruptive protozoan and fungal communities in the developing infant gut, Nat.
[70] N. Gattermann, M.U. Muckenthaler, A.E. Kulozik, G. Metzgeroth, J. Hastka, The Commun. 12 (1) (2021) 6729.
evaluation of iron deficiency and iron overload, Dtsch Arztebl Int 118 (49) (2021) [95] S. Rahman, G.A.M. Kortman, J. Boekhorst, P. Lee, M.R. Khan, F. Ahmed, Effect of
847–856. low-iron micronutrient powder (MNP) on the composition of gut microbiota of
[71] F. Bermejo, S. Garcia-Lopez, A guide to diagnosis of iron deficiency and iron Bangladeshi children in a high-iron groundwater setting: a randomized controlled
deficiency anemia in digestive diseases, World J. Gastroenterol. 15 (37) (2009) trial, Eur. J. Nutr. 60 (6) (2021) 3423–3436.
4638–4643. [96] J.L. Beard, Iron biology in immune function, muscle metabolism and neuronal
[72] S.R. Bloor, R. Schutte, A.R. Hobson, Oral Iron Supplementation—Gastrointestinal functioning, J. Nutr. 131 (2S-2) (2001) 568S–579S.
Side Effects and the Impact on the, Gut Microbiota 12 (2) (2021) 491–502. [97] H. Drakesmith, A.M. Prentice, Hepcidin and the iron-infection axis, Science 338
[73] D. Moretti, J.S. Goede, C. Zeder, M. Jiskra, V. Chatzinakou, H. Tjalsma, A. Melse- (6108) (2012) 768–772.
Boonstra, G. Brittenham, D.W. Swinkels, M.B. Zimmermann, Oral iron [98] M.P. Soares, G. Weiss, The Iron age of host-microbe interactions, EMBO Rep. 16
supplements increase hepcidin and decrease iron absorption from daily or twice- (11) (2015) 1482–1500.
daily doses in iron-depleted young women, Blood 126 (17) (2015) 1981–1989. [99] E.D. Weinberg, Nutritional immunity. Host’s attempt to withold iron from
[74] G.A. Kortman, M. Raffatellu, D.W. Swinkels, H. Tjalsma, Nutritional iron turned microbial invaders, JAMA 231 (1) (1975) 39–41.
inside out: intestinal stress from a gut microbial perspective, FEMS Microbiol Rev. [100] M. Nairz, G. Weiss, Iron in infection and immunity, Mol. Asp. Med 75 (2020),
38 (6) (2014) 1202–1234. 100864.
[75] T.G. DeLoughery, Safety of oral and intravenous iron, Acta Haematol. 142 (1) [101] A. Levy, D. Fraser, S.D. Rosen, R. Dagan, R.J. Deckelbaum, C. Coles, L. Naggan,
(2019) 8–12. Anemia as a risk factor for infectious diseases in infants and toddlers: results from
[76] T. Lee, T. Clavel, K. Smirnov, A. Schmidt, I. Lagkouvardos, A. Walker, M. Lucio, a prospective study, Eur. J. Epidemiol. 20 (3) (2005) 277–284.
B. Michalke, P. Schmitt-Kopplin, R. Fedorak, D. Haller, Oral versus intravenous [102] S.Q. Hussain, M. Ashraf, J.G. Wani, J. Ahmed, Low hemoglobin level a risk factor
iron replacement therapy distinctly alters the gut microbiota and metabolome in for acute lower respiratory tract infections (ALRTI) in children, J. Clin. Diagn. Res
patients with IBD, Gut 66 (5) (2017) 863–871. 8 (4) (2014) PC01–PC03.
[77] G.R. Tompkins, N.L. O’Dell, I.T. Bryson, C.B. Pennington, The effects of dietary [103] L. Hudak, A. Jaraisy, S. Haj, K. Muhsen, An updated systematic review and meta-
ferric iron and iron deprivation on the bacterial composition of the mouse analysis on the association between Helicobacter pylori infection and iron
intestine, Curr. Microbiol 43 (1) (2001) 38–42. deficiency anemia, Helicobacter 22 (1) (2017).
[78] B.A. Parmanand, L. Kellingray, G. Le Gall, A.W. Basit, S. Fairweather-Tait, [104] F.A.M. Jonker, E. Te Poel, I. Bates, M. Boele van Hensbroek, Anaemia, iron
A. Narbad, A decrease in iron availability to human gut microbiome reduces the deficiency and susceptibility to infection in children in sub-Saharan Africa,
growth of potentially pathogenic gut bacteria; an in vitro colonic fermentation guideline dilemmas, Br. J. Haematol. 177 (6) (2017) 878–883.
study, J. Nutr. Biochem. 67 (2019) 20–27. [105] F.A. Jonker, M. Boele van Hensbroek, Anaemia, iron deficiency and susceptibility
[79] A. Dostal, C. Chassard, F.M. Hilty, M.B. Zimmermann, T. Jaeggi, S. Rossi, to infections, J. Infect. 69 (Suppl 1) (2014) S23–S27.
C. Lacroix, Iron depletion and repletion with ferrous sulfate or electrolytic iron [106] J.H. Cross, R.S. Bradbury, A.J. Fulford, A.T. Jallow, R. Wegmüller, A.M. Prentice,
modifies the composition and metabolic activity of the gut microbiota in rats, C. Cerami, Oral iron acutely elevates bacterial growth in human serum, Sci. Rep.
J. Nutr. 142 (2) (2012) 271–277. 5 (1) (2015) 1–7.
[80] R. Balamurugan, R.R. Mary, S. Chittaranjan, H. Jancy, R. Shobana Devi, B. [107] A. Atamna, H. Hamud, W. Daud, T. Shochat, J. Bishara, A. Elis, Chronic use of
S. Ramakrishna, Low levels of faecal lactobacilli in women with iron-deficiency oral iron supplements is associated with poor clinical outcomes in patients with
anaemia in south India, Br. J. Nutr. 104 (7) (2010) 931–934. gram-negative bacteremia, Eur. J. Clin. Microbiol. Infect. Dis. 38 (4) (2019)
[81] X. Qi, Y. Zhang, H. Guo, Y. Hai, Y. Luo, T. Yue, Mechanism and intervention 689–693.
measures of iron side effects on the intestine, Crit. Rev. Food Sci. Nutr. 60 (12) [108] K.A. Kaspersen, K.M. Dinh, S. Mikkelsen, M.S. Petersen, L.T. Erikstrup, O.
(2020) 2113–2125. B. Pedersen, E. Sørensen, H. Hjalgrim, A. Rigas, K.R. Nielsen, Oral iron
[82] G.A. Kortman, B.E. Dutilh, A.J. Maathuis, U.F. Engelke, J. Boekhorst, K.P. Keegan, supplementation is not associated with short-term risk of infections: results from
F.G. Nielsen, J. Betley, J.C. Weir, Z. Kingsbury, L.A. Kluijtmans, D.W. Swinkels, the Danish Blood Donor Study, Transfusion 59 (6) (2019) 2030–2038.
K. Venema, H. Tjalsma, Microbial metabolism shifts towards an adverse profile [109] A.A. Shah, K. Donovan, C. Seeley, E.A. Dickson, A.J. Palmer, C. Doree,
with supplementary iron in the tim-2 in vitro model of the human colon, Front S. Brunskill, J. Reid, A.G. Acheson, A. Sugavanam, Risk of infection associated
Microbiol 6 (2015) 1481. with administration of intravenous iron: a systematic review and meta-analysis,
[83] T. Cuisiniere, A. Calvé, G. Fragoso, M. Oliero, R. Hajjar, E. Gonzalez, M.M. Santos, JAMA Netw. Open 4 (11) (2021) e2133935-e2133935.
Oral iron supplementation after antibiotic exposure induces a deleterious [110] M. Nairz, G. Weiss, 5. Infections associated with iron administration, Essent. Met.
recovery of the gut microbiota, BMC Microbiol. 21 (1) (2021) 1–15. Med. Ther. Use Toxic. Met. Ions Clin. (2019) 123–156.
[84] A. Mahalhal, J.M. Williams, S. Johnson, N. Ellaby, C.A. Duckworth, M.D. Burkitt, [111] U.E. Schaible, S.H. Kaufmann, Iron and microbial infection, Nat. Rev. Microbiol. 2
X. Liu, G.L. Hold, B.J. Campbell, D.M. Pritchard, C.S. Probert, Oral iron (12) (2004) 946–953.
exacerbates colitis and influences the intestinal microbiome, PLoS One 13 (10) [112] B. Khasheii, P. Mahmoodi, A. Mohammadzadeh, Siderophores: importance in
(2018), e0202460. bacterial pathogenesis and applications in medicine and industry, Microbiol. Res.
[85] S.M. Payne, E.E. Wyckoff, E.R. Murphy, A.G. Oglesby, M.L. Boulette, N.M. Davies, (2021), 126790.
Iron and pathogenesis of Shigella: iron acquisition in the intracellular [113] M.G. Page, The role of iron and siderophores in infection, and the development of
environment, Biometals 19 (2) (2006) 173–180. siderophore antibiotics, Clin. Infect. Dis. 69(Supplement_7) (2019) S529–S537.
[86] E.E. Wyckoff, A.R. Mey, A. Leimbach, C.F. Fisher, S.M. Payne, Characterization of [114] B.R. Wilson, A.R. Bogdan, M. Miyazawa, K. Hashimoto, Y. Tsuji, Siderophores in
ferric and ferrous iron transport systems in Vibrio cholerae, J. Bacteriol. 188 (18) iron metabolism: from mechanism to therapy potential, Trends Mol. Med 22 (12)
(2006) 6515–6523. (2016) 1077–1090.
[87] S. Kalipatnapu, S. Kuppuswamy, G. Venugopal, V. Kaliaperumal, B. Ramadass, [115] J.R. Pollack, J.B. Neilands, Enterobactin, an iron transport compound from
Fecal total iron concentration is inversely associated with fecal Lactobacillus in Salmonella typhimurium, Biochem Biophys. Res Commun. 38 (5) (1970)
preschool children, J. Gastroenterol. Hepatol. 32 (8) (2017) 1475–1479. 989–992.
9
[116] M. Ellermann, J.C. Arthur, Siderophore-mediated iron acquisition and [143] H. Wu, E. Santoni-Rugiu, E. Ralfkiaer, B.T. Porse, C. Moser, N. Høiby,
modulation of host-bacterial interactions, Free Radic. Biol. Med 105 (2017) N. Borregaard, J.B. Cowland, Lipocalin 2 is protective against E. coli pneumonia,
68–78. Respir. Res. 11 (1) (2010) 1–8.
[117] P. Saha, X. Xiao, B.S. Yeoh, Q. Chen, B. Katkere, G.S. Kirimanjeswara, M. Vijay- [144] Y.R. Chan, J.S. Liu, D.A. Pociask, M. Zheng, T.A. Mietzner, T. Berger, T.W. Mak,
Kumar, The bacterial siderophore enterobactin confers survival advantage to M.C. Clifton, R.K. Strong, P. Ray, Lipocalin 2 is required for pulmonary host
Salmonella in macrophages, Gut Microbes 10 (3) (2019) 412–423. defense against Klebsiella infection, J. Immunol. 182 (8) (2009) 4947–4956.
[118] C.S. Detweiler, A new way to beat intestinal pathogens, Trends Microbiol. 25 (3) [145] Q. Wang, S. Li, X. Tang, L. Liang, F. Wang, H. Du, Lipocalin 2 protects against
(2017) 169–170. Escherichia coli infection by modulating neutrophil and macrophage function,
[119] J. Arezes, G. Jung, V. Gabayan, E. Valore, P. Ruchala, P.A. Gulig, T. Ganz, Front. Immunol. (2019) 2594.
E. Nemeth, Y. Bulut, Hepcidin-induced hypoferremia is a critical host defense [146] X. Xiao, B.S. Yeoh, M. Vijay-Kumar, Lipocalin 2: an emerging player in iron
mechanism against the siderophilic bacterium Vibrio vulnificus, Cell Host homeostasis and inflammation, Annu. Rev. Nutr. 37 (2017) 103–130.
Microbe 17 (1) (2015) 47–57. [147] D. Lim, H.K. Kim, J.-H. Jeong, Y.S. Jung, S.E. Lee, H.-C. Jang, S.-I. Jung, H.-
[120] F.A. Khan, M.A. Fisher, R.A. Khakoo, Association of hemochromatosis with S. Choi, J.H. Rhee, S.-G. Lee, Lipocalin2 induced by bacterial flagellin protects
infectious diseases: expanding spectrum, Int J. Infect. Dis. 11 (6) (2007) 482–487. mice against cyclophosphamide mediated neutropenic sepsis, Microorganisms 8
[121] B.C. Chu, A. Garcia-Herrero, T.H. Johanson, K.D. Krewulak, C.K. Lau, R. (5) (2020) 646.
S. Peacock, Z. Slavinskaya, H.J. Vogel, Siderophore uptake in bacteria and the [148] T. Berger, A. Togawa, G.S. Duncan, A.J. Elia, A. You-Ten, A. Wakeham, H.E. Fong,
battle for iron with the host; a bird’s eye view, Biometals 23 (4) (2010) 601–611. C.C. Cheung, T.W. Mak, Lipocalin 2-deficient mice exhibit increased sensitivity to
[122] K. Gokarn, R.B. Pal, Activity of siderophores against drug-resistant Gram-positive Escherichia coli infection but not to ischemia-reperfusion injury, Proc. Natl. Acad.
and Gram-negative bacteria, Infect. Drug Resist. 11 (2018) 61. Sci. 103 (6) (2006) 1834–1839.
[123] World Health Organization, Global antimicrobial resistance and use surveillance [149] P. Klüber, S.K. Meurer, J. Lambertz, R. Schwarz, S. Zechel-Gran, T. Braunschweig,
system (GLASS) report: 2021, (2021). S. Hurka, E. Domann, R. Weiskirchen, Depletion of lipocalin 2 (LCN2) in mice
[124] Y.Y. Syed, Cefiderocol: a review in serious gram-negative bacterial infections, leads to dysbiosis and persistent colonization with segmented filamentous
Drugs 81 (13) (2021) 1559–1571. bacteria, Int. J. Mol. Sci. 22 (23) (2021) 13156.
[125] K. Michels, E. Nemeth, T. Ganz, B. Mehrad, Hepcidin and host defense against [150] M. Nairz, D. Ferring-Appel, D. Casarrubea, T. Sonnweber, L. Viatte, A. Schroll,
infectious diseases, PLoS Pathog. 11 (8) (2015), e1004998. D. Haschka, F.C. Fang, M.W. Hentze, G. Weiss, Iron regulatory proteins mediate
[126] E. Nemeth, T. Ganz, Regulation of iron metabolism by hepcidin, Annu. Rev. Nutr. host resistance to Salmonella infection, Cell Host Microbe 18 (2) (2015) 254–261.
26 (2006) 323–342. [151] D. Lim, H.K. Kim, J.H. Jeong, Y.S. Jung, S.E. Lee, H.C. Jang, S.I. Jung, H.S. Choi,
[127] S. Chlosta, D.S. Fishman, L. Harrington, E.E. Johnson, M.D. Knutson, M. Wessling- J.H. Rhee, S.G. Lee, C. Park, M. Song, H.E. Choy, Lipocalin2 induced by bacterial
Resnick, B.J. Cherayil, The iron efflux protein ferroportin regulates the flagellin protects mice against cyclophosphamide mediated neutropenic sepsis,
intracellular growth of Salmonella enterica, Infect. Immun. 74 (5) (2006) Microorganisms 8 (5) (2020).
3065–3067. [152] B.-X. Guo, Q.-Q. Wang, J.-H. Li, Z.-S. Gan, X.-F. Zhang, Y.-Z. Wang, H.-H. Du,
[128] R. Abreu, L. Essler, P. Giri, F. Quinn, Interferon-gamma promotes iron export in Lipocalin 2 regulates intestine bacterial survival by interplaying with siderophore
human macrophages to limit intracellular bacterial replication, Plos One 15 (12) in a weaned piglet model of Escherichia coli infection, Oncotarget 8 (39) (2017)
(2020), e0240949. 65386.
[129] D. Lim, K.S. Kim, J.-H. Jeong, O. Marques, M. Song, T.-H. Lee, J.I. Kim, H.-S. Choi, [153] S.L. Dahl, J.S. Woodworth, C.J. Lerche, E.P. Cramer, P.R. Nielsen, C. Moser, A.
J.-J. Min, D. Bumann, The hepcidin-ferroportin axis controls the iron content of R. Thomsen, N. Borregaard, J.B. Cowland, Lipocalin-2 functions as inhibitor of
Salmonella-containing vacuoles in macrophages, Nat. Commun. 9 (1) (2018) innate resistance to Mycobacterium tuberculosis, Front. Immunol. (2018) 2717.
1–12. [154] J. Choi, S.-N. Cho, J. Lee, S.-H. Son, D.T. Nguyen, S.-A. Lee, C.-H. Song, Lipocalin
[130] F.B. Sow, W.C. Florence, A.R. Satoskar, L.S. Schlesinger, B.S. Zwilling, W. 2 regulates expression of MHC class I molecules in Mycobacterium tuberculosis-
P. Lafuse, Expression and localization of hepcidin in macrophages: a role in host infected dendritic cells via ROS production, Cell Biosci. 11 (1) (2021) 1–14.
defense against tuberculosis, J. Leukoc. Biol. 82 (4) (2007) 934–945. [155] Y.-L. Chang, Z. Wang, S. Igawa, J.E. Choi, T. Werbel, A. Di Nardo, Lipocalin 2: a
[131] K.R. Michels, Z. Zhang, A.M. Bettina, R.E. Cagnina, D. Stefanova, M.D. Burdick, new antimicrobial in mast cells, Int. J. Mol. Sci. 20 (10) (2019) 2380.
S. Vaulont, E. Nemeth, T. Ganz, B. Mehrad, Hepcidin-mediated iron sequestration [156] K. Chen, G. Zhang, H. Chen, Y. Cao, X. Dong, H. Li, C. Liu, Dose effect of bovine
protects against bacterial dissemination during pneumonia, JCI Insight 2 (6) lactoferrin fortification on iron metabolism of anemic infants, J. Nutr. Sci. Vitam.
(2017). (Tokyo) 66 (1) (2020) 24–31.
[132] Y. Yang, C. Zeng, S. Yang, Y. Zhang, S. Song, S. Liu, Q. Shu, X. Fang, Q. Chen, [157] D. El Amrousy, D. El-Afify, A. Elsawy, M. Elsheikh, A. Donia, M. Nassar,
Airway epithelial hepcidin coordinates lung macrophages and immunity against Lactoferrin for iron-deficiency anemia in children with inflammatory bowel
bacterial pneumonia, Shock 54 (3) (2020) 402–412. disease: a clinical trial, Pedia Res (2022).
[133] M. Malerba, S. Louis, S. Cuvellier, S.M. Shambat, C. Hua, C. Gomart, A. Fouet, [158] J. Artym, M. Zimecki, M.L. Kruzel, Lactoferrin for prevention and treatment of
N. Ortonne, J.-W. Decousser, A.S. Zinkernagel, Epidermal hepcidin is required for anemia and inflammation in pregnant women: a comprehensive review,
neutrophil response to bacterial infection, J. Clin. Investig. 130 (1) (2020) Biomedicines 9 (8) (2021).
329–334. [159] P.K. Singh, M.R. Parsek, E.P. Greenberg, M.J. Welsh, A component of innate
[134] M.J. Pascoe, J. Lueangsakulthai, D. Ripley, R.H. Morris, S.E. Maddocks, Exposure immunity prevents bacterial biofilm development, Nature 417 (6888) (2002)
of Escherichia coli to human hepcidin results in differential expression of genes 552–555.
associated with iron homeostasis and oxidative stress, FEMS Microbiol. Lett. 365 [160] B. Lonnerdal, Excess iron intake as a factor in growth, infections, and
(10) (2018) fny089. development of infants and young children, Am. J. Clin. Nutr. 106 (Suppl 6)
[135] A.C. Moreira, J.V. Neves, T. Silva, P. Oliveira, M.S. Gomes, P.N. Rodrigues, (2017) 1681S–1687S.
Hepcidin-(in) dependent mechanisms of iron metabolism regulation during [161] D.B. Kell, E.L. Heyden, E. Pretorius, The biology of lactoferrin, an iron-binding
infection by Listeria and Salmonella, Infect. Immun. 85 (9) (2017) e00353–17. protein that can help defend against viruses and bacteria, Front. Immunol. (2020)
[136] J.-H. Yan, X.-Y. Cai, Y.-H. Huang, The clinical value of plasma hepcidin levels in 1221.
predicting bacterial infections in febrile children, Pediatr. Neonatol. 60 (4) (2019) [162] S.A. González-Chávez, S. Arévalo-Gallegos, Q. Rascón-Cruz, Lactoferrin:
377–381. structure, function and applications, Int. J. Antimicrob. Agents 33 (4) (2009),
[137] D. Stefanova, A. Raychev, J. Arezes, P. Ruchala, V. Gabayan, M. Skurnik, B. 301. e1-301. e8.
J. Dillon, M.A. Horwitz, T. Ganz, Y. Bulut, Endogenous hepcidin and its agonist [163] T.M. Avery, R.L. Boone, J. Lu, S.K. Spicer, M.A. Guevara, R.E. Moore, S.
mediate resistance to selected infections by clearing non–transferrin-bound iron, A. Chambers, S.D. Manning, L. Dent, D. Marshall, Analysis of antimicrobial and
Blood, J. Am. Soc. Hematol. 130 (3) (2017) 245–257. antibiofilm activity of human milk lactoferrin compared to bovine lactoferrin
[138] I. De Domenico, T.Y. Zhang, C.L. Koening, R.W. Branch, N. London, E. Lo, R. against multidrug resistant and susceptible acinetobacter baumannii clinical
A. Daynes, J.P. Kushner, D. Li, D.M. Ward, J. Kaplan, Hepcidin mediates isolates, ACS Infect. Dis. 7 (8) (2021) 2116–2126.
transcriptional changes that modulate acute cytokine-induced inflammatory [164] J. Lu, J.D. Francis, M.A. Guevara, R.E. Moore, S.A. Chambers, R.S. Doster, A.
responses in mice, J. Clin. Invest 120 (7) (2010) 2395–2405. J. Eastman, L.M. Rogers, K.N. Noble, S.D. Manning, Antibacterial and anti-biofilm
[139] Y.H. Huang, Y.L. Yang, M.M. Tiao, H.C. Kuo, L.T. Huang, J.H. Chuang, Hepcidin activity of the human breast milk glycoprotein lactoferrin against group B
protects against lipopolysaccharide-induced liver injury in a mouse model of streptococcus, Chembiochem 22 (12) (2021) 2124–2133.
obstructive jaundice, Peptides 35 (2) (2012) 212–217. [165] Y.-Z. Wang, T.-Z. Shan, Z.-R. Xu, J. Feng, Z.-Q. Wang, Effects of the lactoferrin
[140] A. Hoffmann, L.V. de Souza, M. Seifert, L. Von Raffay, D. Haschka, P. Grubwieser, (LF) on the growth performance, intestinal microflora and morphology of
M. Grander, A.-M. Mitterstiller, M. Nairz, M. Poli, Pharmacological targeting of weanling pigs, Anim. Feed Sci. Technol. 135 (3–4) (2007) 263–272.
BMP6-SMAD mediated hepcidin expression does not improve the outcome of [166] S.K. Velusamy, D.H. Fine, K. Velliyagounder, Prophylactic effect of human
systemic infections with intra-or extracellular gram-negative bacteria in mice, lactoferrin against Streptococcus mutans bacteremia in lactoferrin knockout mice,
frontiers in cellular and infection, Microbiology (2021) 675. Microbes Infect. 16 (9) (2014) 762–767.
[141] C.C. Yen, C.J. Shen, W.H. Hsu, Y.H. Chang, H.T. Lin, H.L. Chen, C.M. Chen, [167] M. Pammi, K.S. Gautham, Enteral lactoferrin supplementation for prevention of
Lactoferrin: an iron-binding antimicrobial protein against Escherichia coli sepsis and necrotizing enterocolitis in preterm infants, Cochrane Database Syst.
infection, Biometals 24 (4) (2011) 585–594. Rev. 3 (2020).
[142] T.H. Flo, K.D. Smith, S. Sato, D.J. Rodriguez, M.A. Holmes, R.K. Strong, S. Akira, [168] K.A. Patras, A.D. Ha, E. Rooholfada, J. Olson, S.P.R. Rao, A.E. Lin, V. Nizet,
A. Aderem, Lipocalin 2 mediates an innate immune response to bacterial infection Augmentation of urinary lactoferrin enhances host innate immune clearance of
by sequestrating iron, Nature 432 (7019) (2004) 917–921. uropathogenic Escherichia coli, J. Innate Immun. 11 (6) (2019) 481–495.
10
[169] E. Biasibetti, S. Rapacioli, N. Bruni, E. Martello, Lactoferrin-derived peptides Aeromonas hydrophila isolated from transfusion-dependent thalassemia patients,
antimicrobial activity: an in vitro experiment, Nat. Prod. Res. 35 (24) (2021) Hemoglobin 33 (5) (2009) 352–360.
6073–6077. [178] C. Lehmann, M. Aali, J. Zhou, B. Holbein, Comparison of treatment effects of
[170] C. Scott, B.E. Holbein, C. Lehmann, Iron should be restricted in acute infection, different iron chelators in experimental models of sepsis, Life 11 (1) (2021) 57.
Front Biosci. Landmark 25 (71) (2020) 673–682. [179] G.P. Neupane, D.M. Kim, Comparison of the effects of deferasirox, deferiprone,
[171] E. Poggiali, E. Cassinerio, L. Zanaboni, M.D. Cappellini, An update on iron and deferoxamine on the growth and virulence of Vibrio vulnificus, Transfusion
chelation therapy, Blood Transfus. 10 (4) (2012) 411. 49 (8) (2009) 1762–1769.
[172] D. Eto, K. Watanabe, H. Saeki, K.-I. Oinuma, K.-I. Otani, M. Nobukuni, [180] G. Neupane, D.-M. Kim, In vitro time-kill activities of ciprofloxacin alone and in
H. Shiratori-Takano, H. Takano, T. Beppu, K. Ueda, Divergent effects of combination with the iron chelator deferasirox against Vibrio vulnificus, Eur. J.
desferrioxamine on bacterial growth and characteristics, J. Antibiot. 66 (4) Clin. Microbiol. Infect. Dis. 29 (4) (2010) 407–410.
(2013) 199–203. [181] G. Luo, B. Spellberg, T. Gebremariam, H. Lee, Y. Xiong, S. French, A. Bayer,
[173] R. Gumbau-Brisa, M.T.C. Ang, B.E. Holbein, M. Bierenstiel, Enhanced Fe3+ A. Ibrahim, Combination therapy with iron chelation and vancomycin in treating
binding through cooperativity of 3-hydroxypyridin-4-one groups within a linear murine staphylococcemia, Eur. J. Clin. Microbiol. Infect. Dis. 33 (5) (2014)
co-polymer: wrapping effect leading to superior antimicrobial activity, BioMetals 845–851.
33 (6) (2020) 339–351. [182] S. Moreau-Marquis, G.A. O’Toole, B.A. Stanton, Tobramycin and FDA-approved
[174] G.J. Kontoghiorghes, C.N. Kontoghiorghe, Iron and chelation in biochemistry and iron chelators eliminate Pseudomonas aeruginosa biofilms on cystic fibrosis cells,
medicine: new approaches to controlling iron metabolism and treating related Am. J. Respir. Cell Mol. Biol. 41 (3) (2009) 305–313.
diseases, Cells 9 (6) (2020). [183] L. de Leseleuc, G. Harris, R. KuoLee, W. Chen, In vitro and in vivo biological
[175] B. Lesic, J. Foulon, E. Carniel, Comparison of the effects of deferiprone versus activities of iron chelators and gallium nitrate against Acinetobacter baumannii,
deferoxamine on growth and virulence of Yersinia enterocolitica, Antimicrob. Antimicrob. Agents Chemother. 56 (10) (2012) 5397–5400.
Agents Chemother. 46 (6) (2002) 1741–1745. [184] J.H. Moon, Y. Herr, S.W. Kim, J.Y. Lee, In vitro activity of deferoxamine against
[176] G.J. Kontoghiorghes, A. Kolnagou, A. Skiada, G. Petrikkos, The role of iron and Porphyromonas gingivalis, FEMS Microbiol Lett. 323 (1) (2011) 61–67.
chelators on infections in iron overload and non iron loaded conditions: prospects [185] M.D.C. Parquet, K.A. Savage, D.S. Allan, M.T.C. Ang, W. Chen, S.M. Logan, B.
for the design of new antimicrobial therapies, Hemoglobin 34 (3) (2010) E. Holbein, Antibiotic-resistant acinetobacter baumannii is susceptible to the
227–239. novel iron-sequestering anti-infective DIBI in vitro and in experimental
[177] G.C.-F. Chan, S. Chan, P.-L. Ho, S.-Y. Ha, Effects of chelators (deferoxamine, pneumonia in mice, Antimicrob. Agents Chemother. 63 (9) (2019).
deferiprone and deferasirox) on the growth of Klebsiella pneumoniae and
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Journal of Trace Elements in Medicine and Biology 75 (2023) 127093

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

Iron in infectious diseases friend or foe?: The role of gut microbiota

Fig. 1. Factors affecting the gut microbiota and

bowel disease patients. Oral/i.v. iron replacement therapies restored Table 1

Table 1 (continued ) iron chelators in infection (Fig. 2).

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