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Hemodialysis International 2017; 21:S28–S36

Scholarly Review

Oral iron supplementation: Potential

implications for the gut microbiome and
metabolome in patients with CKD

Guus A. M. KORTMAN,1* Dorien REIJNDERS,2 Dorine W. SWINKELS 1

1
Department of Laboratory Medicine – Translational Metabolic Laboratory-830, Radboud University
Medical Center, Nijmegen, The Netherlands; 2Department of Human Biology, NUTRIM School of
Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht,
The Netherlands

Abstract
Patients with chronic kidney disease (CKD) and loss of kidney function are at increased risk for mor-
bidity and mortality. The risks of CKD are attributed to “uremia,” an increased concentration of ure-
mic retention solutes (toxins) in the plasma. Recently, a colo-renal axis became clearly apparent and
uremia has been associated with an altered gut microbiome composition and metabolism. There is
a high prevalence of anemia in patients with CKD, for which patients are often treated with oral or
intravenous iron. Recent in vivo and in vitro studies have reported adverse effects of oral iron sup-
plementation on the gut microbiota composition, gut metabolome, and intestinal health, which in
turn may result in an increased production of uremic toxins. It may also affect circulating levels of
other microbe-derived molecules, that can act as mediators of immune regulation. Changes in body
iron levels have also been reported to exert subtle effects on host immune function by modulating
immune cell proliferation and differentiation, and by directly regulating cytokine formation and anti-
microbial immune effector mechanisms. Based on the foregoing it is conceivable that oral iron sup-
plementation in iron deficient predialysis CKD patients adversely changes gut microbiota
composition, the gut and systemic metabolome, and host immunity and infection. Future studies
are needed to confirm these hypotheses and to assess whether, compared to IV iron supplementa-
tion, oral iron supplementation negatively impacts on morbidity of CKD, and whether these adverse
effects depend on the iron bioavailability of the iron formulation to the microbiota.

Key words: Iron, iron deficiency anemia, CKD, gut microbiome, metabolome

INTRODUCTION
Iron deficiency anemia (IDA) is a common complication
Correspondence to: D. W. Swinkels, Department of Labo- of chronic kidney disease (CKD) and oral therapy is often
ratory Medicine/TML 830, Radboud University Medical given to predialysis patients. Although iron replacement
Center, P.O. Box 9101, 6500 HB Nijmegen, The Nether- therapy in general improves anemia and quality of life,
lands. E-mail: dorine.swinkels@radboudumc.nl
the effects of oral iron on the underlying renal disease
Conflict of Interest: Authors declare no conflicts of interest.
Disclosure of grants or other funding: This work was partially progression and associated morbidities is unknown.1
funded by the Dutch Kidney Foundation, innovation grant This review focuses on recent findings regarding the
15OI46 to GK and DS. effects of oral iron supplementation on the gut micro-
*Current address: Guus A. M. Kortman, NIZO food research biome and metabolome in CKD and how this might affect
B.V., Kernhemseweg 2, 6718 ZB, Ede, The Netherlands disease progression. So far, no studies on the effects of

C 2017 International Society for Hemodialysis

V
DOI:10.1111/hdi.12553
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Oral iron and the gut microbiome in CKD

oral iron supplementation in CKD patients or CKD- found, as African children on oral iron supplements pre-
models on the gut microbiome and metabolome have sented with increased small intestinal permeability.18
been reported. Therefore, we base our review on the
potential effects in CKD on studies in different target
populations.
GUT MICROBIOTA COMPOSITION
AND METABOLOME IN CKD
IRON AND GUT HEALTH Patients with CKD and loss of kidney function are at
increased risk for morbidity and mortality.19 This is
The mineral iron is an essential building block in all cells attributed to “uremia,” an increased concentration of ure-
of the body and functions in oxygen transport as part of mic toxins in the plasma, as a consequence of decreased
hemoglobin, in mitochondrial function, DNA synthesis renal excretory function.20 Recently, a colorenal axis
and repair, and many enzymatic reactions required for cell became apparent in end stage renal disease and secretion
survival.2,3 Iron deficiency is the most common human of urea into the gastro-intestinal tract has been associated
nutrient deficiency worldwide with more than 2 billion with an altered gut microbiota composition and metabo-
people affected, not only in resource-limited nations (e.g., lism.21–23 This includes a decrease of beneficial gut
in Asia and Africa) but also in well-developed countries.4 microbiota members, most notably Lactobacillaceae, Bifido-
Notably, IDA is a common complication of CKD. Epide- bacteriaceae and Prevotellaceae families. In addition, poten-
miological studies have shown that around 30%, 40%, tially pathogenic members, such as Enterobacteriaceae,
and 70% of predialyses patients with CKD stage 3, 4, and
Enterococcus spp. and Clostridium perfringens were
5, respectively, are anemic.5,6 The prevalence of iron defi-
increased. One of the consequences of an altered gut
ciency in these (anemic CKD) patients has been estimated
microbiota composition and environment in CKD patients
by bone marrow studies at 48% to 98%.7,8 Iron deficiency
is an increased production of uremic toxins, most likely
presents with a diminished red blood cell production and
via enhanced microbial fermentation of undigested pro-
reduced hemoglobin levels, which across the lifespan, can
teins21–25 and in which prolonged transit time may play a
have important consequences for health. The condition
role.26,27 The hypothesis that undigested protein can lead
has been associated with developmental deficits, impaired
to the production of certain uremic toxins by the gut
memory and neurodevelopment, diminished physical
function, depression, fatigue, loss of vitality, preterm deliv- microbiota is supported by a recent study in healthy vol-
ery, and lower infant birth weight.9 unteers. It was shown that a high protein diet led to a sig-
The gut functions as a key modulator of iron homeosta- nificant increase in plasma levels of indoxyl sulfate as well
sis. A sophisticated mechanism of intestinal uptake regu- as significant increases in the urinary excretion of indoxyl
lates the absorption of sufficient quantities of iron to reach sulfate, indoxyl glucuronide, kynurenic acid, quinolinic
daily requirements. In humans, iron is mainly absorbed in acid, and p-cresyl sulfate.28 Comparable results were
the duodenum in the ferrous form (Fe21).2 Oral iron sup- obtained in a rodent study.29 Earlier, by comparing plas-
plementation is an effective and well-studied option to ma from hemodialysis patients with and without colon,
replenish iron stores and therefore the common treatment Aronov et al. already confirmed the colonic origin of the
for IDA. However, adverse effects on the gut microbiota, uremic toxins indoxyl sulfate and p-cresol,30 which are
an increased risk of gut inflammation, constipation, and being conjugated to p-cresyl sulfate and p-cresyl glucuro-
diarrhea have been reported.10–14 Due to its low bioavail- nide in the liver. The cardiovascular and renal toxicity of
ability, iron supplementation generally results in a large these uremic toxins has been demonstrated in several
fraction of unabsorbed iron entering the colon, where it is experimental and clinical studies and concentrations of
potentially available for the gut microbiota. In fact, too indoxyl sulfate and p-cresyl sulfate in serum are negative-
much unabsorbed iron can stimulate virulence of patho- ly correlated with the levels of kidney function.29,31,32
genic bacteria residing in the intestine and may contribute Importantly, the production of uremic toxins and
to an oxidative proinflammatory environment.10 Despite its changes in the gut microbiota composition in CKD may
crucial role in cellular processes, free colonic iron can gen- induce an inflamed and leaky gut by disruption of the
erate toxic free radicals and reactive oxygen species, which colonic epithelial tight junctions barrier.33 The disruption
can directly affect gut epithelial integrity via the promotion of the gut barrier function might result in an increased
of redox stress.15 This impaired integrity has been indicat- exposure of the host to endotoxins, a possible cause of
ed in an in vitro study with Caco-2 cells exposed to micro-inflammation in CKD, and local renal immune cell
iron.16,17 Also in vivo, effects on the epithelium have been responses, accelerated cardiovascular disease and CKD

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Kortman et al.

progression.31,34–36 Gut microbiome alterations may also disease. Iron may for instance negatively affect their
affect circulating levels of other microbe-derived molecules inflamed leaky gut, as it has previously been shown to
and fragments, such as polysaccharide A and peptidogly- worsen the symptoms of the inflamed gut in patients with
cans that may act as mediators of immune regulation in inflammatory bowel disease (IBD), thereby increasing gas-
CKD.37,38 Gut dysbiosis can also lead to decreased produc- trointestinal adverse effects such as nausea, diarrhea, and
tion of beneficial metabolites such as short chain fatty acids abdominal pain.48–52 Importantly, African infants receiv-
(SCFA; mainly acetate, propionate, and butyrate), which ing supplemental iron, show changes of the gut micro-
are the products of anaerobic microbial fermentation of biome composition, with a decreased abundance of the
dietary polysaccharides. SCFAs are indicated to affect a generally beneficial barrier bacteria Lactobacillus spp. and
range of host functions, including energy metabolism, Bifidobacterium spp. Moreover, in these infants iron sup-
immune regulation, and gut motility.35,39,40 In a recent plementation also increased the abundance of potentially
study among hemodialysis patients and controls, Poesen pathogenic strains, such as certain Escherichia coli species,
et al. found that CKD associates with a distinct fecal which was correlated with an increase of the gut inflam-
(microbial) metabolite profile, that might be related to the matory marker calprotectin in feces.13 This shift in micro-
renal function loss, but that may be inferior to effects of bial populations may thus impair the barrier function of
CKD-related dietary restrictions on the gut microbiome.41 the gut epithelium and thereby exert local and systemic
In conclusion, CKD results in profound changes in the inflammatory and immunological effects, that may be
composition of the gut microbiome and disruption of the partly caused by the translocation of bacterial lipopolysac-
barrier function. These abnormalities lead to the genera- charide (LPS). These microbial shifts mediated effects are
tion and absorption of bacterial metabolites and fragments also relevant in CKD.21,36,38 Interestingly, the iron-
that by affecting systemic inflammation, uremic toxicity, induced changes in the gut microbiota composition of
and immunity might contribute to disease progression in African infants are comparable to those reported in CKD-
CKD patients. patients, i.e., a decrease in beneficial species and an
increase in potentially pathogenic species, as described
above. It can therefore be envisaged that oral iron supple-
POTENTIAL CONSEQUENCES OF ORAL mentation in CKD patients may further shift the dysbiotic
IRON THERAPY ON INFECTION, microbiome to a less beneficial profile. Together, these
IMMUNITY, THE GUT MICROBIOME data indicate that oral iron therapy in CKD patients, with
AND THE METABOLOME IN CKD a proinflammatory status and leaky gut, may worsen their
symptoms, possibly mediated by iron-induced changes in
Iron is of central importance in host-pathogen interaction the gut microbiota and/or host immunity.
because of its key role in biological processes, including In a kinetic model of the human large intestine (TIM-2)
mitochondrial respiration and DNA synthesis.2,3,42 Accord- we recently found that supplementary iron increased gut
ingly, the proliferation and pathogenicity of many microor- microbial protein fermentation.53 Proteolytic fermentation
ganisms, are dependent on the availability of iron.43,44 Iron converts proteins and peptides in various end-products
also exerts subtle effects on host immune function by mod- including branched-chain fatty acids (e.g., isobutyrate
ulating immune cell proliferation and differentiation and and isovalerate), and other cometabolites such as ammo-
by directly regulating cytokine formation and antimicrobial nia and uremic toxins such as phenols and indoles.54,55
immune effector mechanisms. Thus, imbalances of iron The latter are also elevated in CKD.56 Based on these
homeostasis can affect the risk for, and the outcome of, results and given that CKD patients already have a higher
infections.43,45,46 Therefore, host iron status (e.g., iron defi- protein fermentation profile it may be hypothesized that
ciency, iron repletion, and iron overload) is also likely to oral iron supplementation in iron deficient CKD patients
influence gut microbiota composition.10 causes an increase in fecal and plasma uremic toxin levels,
Anemia and iron deficiency are very common compli- due to stimulation of the proteolytic activity of the gut
cations in patients with CKD and epidemiological studies microbiota. The increase in plasma uremic toxin levels
suggest that the prevalence of IDA increases as the kidney may be further worsened by an increase in gut transit
function decreases.5,6,8 To correct anemia, CKD patients time caused by oral iron administration that is known to
are often treated with oral iron supplements.47 However, increase the risk for constipation in some patients.57,58
large doses of supplementary oral iron prescribed to these A very recent open-label clinical trial compared the
patients might have adverse effects on their intestinal effects of oral and IV iron replacement therapy on the gut
health that is already affected due to the underlying microbiome and metabolome in patients with IBD.59

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Oral iron and the gut microbiome in CKD

Changes observed in patients treated with oral iron the gut microbiota composition and activity, the bioavail-
included higher levels of cholesterol, palmitate, phospha- ability of current iron formulations to the microbiome has
tidyl glycerol, but not for products of protein fermenta- barely been investigated. The ideal iron preparation shows
tion. These changes were accompanied by a decreased high bioavailability for the host, with a low bioavailability
relative abundance of Collinsella aerofaciens, Faecalibacte- for (pathogenic) gut microbes.
rium prausnitzii, Ruminococcus bromii, and Dorea spp, of To aid in the development of better oral iron formulas,
which the consequences are unknown. In contrast to ear- there is a need to increase our fundamental understand-
lier studies in IBD patients,48–52 these shifts in the gut ing of the mechanisms by which various forms of oral
microbiome and metabolome were dissociated from iron supplementation affect the gut microbiome and
changes in disease activity in these patients.59 thereby the host. Increased insights in fecal iron specia-
Interestingly, there is a trend toward the use of oral tion and availability to the gut microbiota can help us in
iron-based phosphate binders in CKD patients, in very the design of oral iron administration approaches with
large doses. One promising iron-based phosphate binder low availability to the gut microbiota. Notably, even
is ferric citrate, which can both control phosphorus levels when the speciation of supplementary iron in the colon
and improve body iron parameters and Hb levels.60 It would have been known, evaluation of the bioavailability
should however be noted that 6.9% of patients on ferric of the various iron species to the microbiota is far from
citrate therapy experienced gastrointestinal adverse effects obvious.
in one study,60 and in a recent 16 week randomized dou- Large amounts of iron are regularly present in the
ble blind clinical trial in non-dialysis dependent (NDD- colon, which is illustrated by the high concentration of
)CKD patients rates of diarrhea and constipation were iron found in feces of British adults on a standard West-
higher in ferric citrate treated patients compared to place- ern diet and in infants fed with complementary solid
bo treated (20.5% vs. 16.4% and 18.8% vs. 12.9%, foods: approximately 100 mg Fe/g wet weight feces,
respectively).58 Adverse effects on the gut microbiome which is roughly equal to 1.8 mM, and which is much
may play a role in this. Another promising iron-based more than the minimal iron requirement of most bacteri-
phosphate binder, that is not intended for iron therapy, is al species, that is only 1027 to 1025 M.15,62,63 Even the
sucroferric oxyhydroxide. Because of its insolubility and water soluble iron content, potentially reflecting the
low bioavailability this compound might have less adverse amount of readily available iron, in the feces of British
effects on the gut microbiota, but future investigations are adults, with approximately 30 mmol/kg wet weight feces
warranted to confirm this. Both iron-based phosphate (roughly equal to 30 mM), was above the minimal iron
binders have been given in very high doses, compared to requirement of most bacteria. This would suggest that
standard iron replenish therapy.61 This might have con- iron availability in the lumen is not restrictive. Neverthe-
tributed to the frequently reported low gastrointestinal less, evidence from animal studies strongly indicates that
tolerability, that may potentially be due to their effects on iron availability in the colonic lumen is generally limit-
the osmotic potential and/or gut microbiome composition ed.10 Ex vivo iron measurements of water-soluble iron
and activity.61 species in feces might therefore not be accurate or rele-
Thus, conventional as well as novel oral iron supple- vant. This is exemplified by a recent study that shows
that: 1. The iron content of the mouse colonic mucus is
ments such as the phosphate binder ferric citrate may
much lower compared to that of the lumen and that 2.
adversely affect the gut microbiome and gastrointestinal
E. coli siderophore production, an iron uptake mecha-
function of iron deficient patients with CKD, and thereby
nism to fulfill bacterial iron needs and an indicator of
exacerbate kidney function and anemia. Since studies are
low iron availability, was induced when grown on
lacking, this hypothesis needs further investigation.
mucus.64 In the assessment of the iron availability of a
certain oral iron formula to the microbiota, determining
CHALLENGES AND ALTERNATIVES FOR the availability in the outer mucus layer may therefore be
SAFE ORAL IRON FORMULATIONS THAT more relevant.
DO NOT ADVERSELY AFFECT THE GUT To minimize the impact of oral iron administration on
the gut microbiota, strategies to prevent undesired effects
MICROBIOME AND GUT HEALTH
of iron on the gut microbiota need to be developed.
In the past years, much effort has been put in finding an Although this is most important in developing countries
iron formulation with good bioavailability to humans. where infections are highly endemic, it is likely that such
Although it became evident that iron supplements affect strategies also increase the tolerance of the gastrointestinal

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Kortman et al.

tract for oral iron in industrialized countries. Successful proteolytic bacteria, and may shorten intestinal transit
strategies of universal iron administration with a minimal time, hereby lowering uremic toxic production.31,39,67
impact on the gut microbiota depend on the combination Indeed, prebiotics have previously been shown to reduce
of improvement of host iron status of the person in need levels of certain colon-derived uremic toxins in the circu-
with: lation and may reduce the risk for inflammation.31,32,39,68
The provision of prebiotics during oral iron administra-
1. The prevention of gut microbiota iron uptake, or
2. The simultaneous suppression of pathogenic gut tion could therefore potentially synergyze; to reduce
microbes, or microbial uremic toxin production and to counteract an
3. The stimulation of beneficial gut microbiota mem- iron-induced decrease in beneficial species, together con-
bers, hereby restraining pathogenic growth and/or tributing to reduced inflammation.
improving gut health.
A number of potential strategies will be described
below. Limitation of accessibility of orally
administered iron for enteric pathogens
Low-dose highly bioavailable iron
A promising new form of iron preparations is nanocom-
One approach that has recently been tested is the provi-
pound iron. This nanostructured iron is poorly water-
sion of iron in a low dose, but highly bioavailable prepa-
soluble but can be absorbed surprisingly well via endocy-
ration, to prevent large amounts of iron entering the
tosis by intestinal epithelial cells. Rodent studies con-
colon.13 However, in Kenyan infants this approach was
firmed this good bioavailability.69–71 Moreover, effects of
not successful. Their gut microbiome still shifted toward
nanocompound iron on the gut microbiota appear to be
a more pathogenic profile, similar to children that
small based on rodent studies,72 but remains to be further
received a 5 times higher dose. Importantly, while the
investigated in humans and will depend on nanocom-
higher dose improved the iron status of the infants, the
pound stability in the intestinal tract and/or the capability
low dose did not.13 It thus appears that in making dietary
of (pathogenic) bacteria to utilise this iron species.
iron more bioavailable, also the availability for the gut
In addition, more natural forms of iron such as lactofer-
microbiota increases, Therefore, to find the optimal iron
rin might be good candidates to replace current oral iron
preparations and dosage remains challenging.
supplements. Beneficial effects on iron status have been
shown with lactoferrin in infants and pregnant women,73
Provision of probiotics and/or prebiotics whereas it presents with a decreased availability for most
during oral iron administration bacteria. However, more research is warranted since it has
As oral iron administration tends to decrease numbers of been found that certain pathogenic species have developed
generally beneficial Lactobacillaceae and Bifidobacteriaceae, mechanisms to sequester iron from lactoferrin via a lacto-
the simultaneous administration of these probiotic bacte- ferrin receptor or siderophore-mediated uptake,63 thereby
rial families and/or prebiotics may counteract this effect potentially providing these species with a competitive
and contribute to the maintenance of these beneficial advantage over potential beneficial microbes.
strains in the colon. Prebiotic fibers such as fructo- To summarize, many of the oral approaches have
oligosaccharides are able to increase the number of bene- already been tested with regard to bioavailability to the
ficial Bifidobacteriaceae and to decrease colonic pH.65 This host, but assessment of safety should include assessment
suggests that the simultaneous provision of prebiotics of their effects on the gut microbiome. It remains difficult
with iron could be a promising approach to both stimu- to predict in what form the originally administered iron
late colonization of beneficial Bifidobacteriaceae and Lacto- will end up in the colon and to what extent it can be uti-
bacillaceae and iron uptake. In women with low iron lized by the microbes, which is especially important with
status it has been shown that the prebiotic inulin can regard to enteric pathogens. More research on this matter
increase the Bifidobacteriaceae population and decrease will help us to increase the understanding of iron han-
colonic pH, but there was only a trend toward increased dling by the gut microbiome and what oral iron com-
iron uptake.66 Future studies should reveal the benefit pound has the optimal characteristics of high
and safety of this approach. Prebiotic fibers can promote bioavailability for the patient but low availability for the
the growth and activity of saccharolytic bacteria over microbiome.

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Oral iron and the gut microbiome in CKD

Intravenous iron
To avoid adverse effects of iron supplementation on the
gut microbiome, intravenous iron (IV) administration
might be a good alternative as it is less likely for IV
administered iron to affect the gut microbiota com-
pared to oral iron. Nevertheless, it has been shown that
IV iron does affect the mouse microbiota.74 This can
possibly be explained by effects of iron repletion on
host immunity and/or the increase in hemoglobin levels
that may influence the oxygen diffusion into the colonic
epithelium and mucus layers.75,76 Oral and IV iron
Figure 1 Combined effects of oral iron supplementation
may well have different effects on the gut microbiota, and CKD on gut microbiome composition, metabolome,
this is exemplified by a recent study in IBD patients, in and host immunity and infection. These effects add to other
which it has been found that oral iron supplementation (inborn and environmental) factors, and together will deter-
had different effects on gut microbiota composition and mine the morbidity (e.g., progression of the disease) of the
metabolism compared to IV supplemented iron (as patient.
described above), but effects were not compared to
non-supplemented controls.59
From a gut health perspective, it may thus be pre- gastrointestinal intolerance, oral iron is ineffective,
ferred to supplement iron via the IV route, when com- severe anemia is present, or to preserve vascular
pared to traditional oral iron administration. However, access.82
since much is unknown, the preferred route of iron sup- Future development of oral iron compounds with
plementation in CKD is still open for discussion. Deci- improved host to microbiota bioavailability ratio may lead
sions about this route should take into consideration: to less gastrointestinal side effects, while preserving its
severity of anemia and iron deficiency, the Hb response, efficacy as well as the natural barrier of the body to pre-
safety, tolerance and adherence to prior oral iron admin- vent iron overload, and as such result in an increased
istration, costs, and ease of obtaining venous access bal- competitive advantage of oral iron over IV iron.
anced against the desire to preserve venous access
sites.77 Notably, magnetic resonance imaging (MRI)
scans in patients with CKD on hemodialysis and receiv- CONCLUDING REMARKS
ing IV iron therapy have shown liver iron overload in
the majority of patients.78 It is not yet clear, however, Here, we reviewed recent in vitro and in vivo data on the
whether this iron signal from the liver on MRI represents effects of both CKD and oral iron on the gut microbiome
iron uptake in the Kupffer cells of the reticulo- and metabolome, and immunity. Collectively, these data
endothelial system or in the hepatocytes of the liver show it is conceivable that oral iron supplementation in
parenchyma. On the long term iron deposition in espe- iron deficient predialysis CKD patients may further wors-
cially the hepatocytes can cause tissue injury.1 In terms en their clinical condition by adversely changing gut
of beneficial effects on Hb levels, studies comparing oral microbiome composition, the gut and systemic metabo-
to IV iron in NDD-CKD patients have generally found lome, and host immunity and infection (Figure 1). Future
greater efficacy for IV iron.79,80 However, in terms of studies are warranted to confirm these concerns and to
side effects, recently performed small and relatively assess whether—compared to IV iron supplementation
short term RCTs, show no univocal results concerning and placebo—oral iron supplementation negatively
the most optimal route of administration.80,81 Similarly, impacts on the disease progression of CKD patients.
the KDIGO-guideline from 2012 states that “a clearly Therefore, until more is known about local gut and sys-
defined advantage or preference for IV compared to oral temic adverse effects of oral iron in patients with CKD,
iron was not supported by available evidence in NDD- we recommend to carefully weigh the positive effects of
CKD patients.”77 Thus in such patients, the route of iron supplementary iron on preventing symptoms of iron defi-
administration can be either IV or oral. The European ciency against the possible adverse effects on gut micro-
Renal Best Practice position statement recommends a biome composition and activity, the systemic
minimum 3-month trial of oral iron unless there is metabolome, infection, and host immunity.

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Kortman et al.

ACKNOWLEDGMENTS 13 Jaeggi T, Kortman GA, Moretti D, et al. Iron fortifica-

tion adversely affects the gut microbiome, increases
We thank Roos Masereeuw, Jack Wetzels, Simone Moo- pathogen abundance and induces intestinal inflamma-
ren, Sjoerd Emonts, Koen Venema and Rian Roelofs for tion in Kenyan infants. Gut. 2014; 64:731–742.
fruitful discussions. 14 Chaplin S, Bhandari S. Oral iron: Properties and cur-
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Manuscript received February 2017; revised March 2012; 23:12–18.
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Oral ferrous sulfate supplements increase the free
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