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The Effects of Iron Supplementation and Fortification on the Gut Microbiota: a Review

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The Effects of Iron Supplementation and Fortification on the Gut Microbiota: a Review Review The Effects of Iron Supplementation and Fortification on the Gut Microbiota: A Review Emma CL Finlayson-Trick 1 , Jordie AJ Fischer 2,3 , David M Goldfarb 1,3,4 and Crystal D Karakochuk 2,3,* 1 Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; efi[email protected] (E.C.F.-T.); [email protected] (D.M.G.) 2 Department of Food, Nutrition and Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; jordie.fi[email protected] 3 British Columbia Children’s Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada 4 Department of Pathology and Laboratory Medicine, BC Children’s and Women’s Hospital and University of British Columbia, Vancouver, BC V6T 1Z7, Canada * Correspondence: [email protected] Received: 30 August 2020; Accepted: 24 September 2020; Published: 26 September 2020 Abstract: Iron supplementation and fortification are used to treat iron deficiency, which is often associated with gastrointestinal conditions, such as inflammatory bowel disease and colorectal cancer. Within the gut, commensal bacteria contribute to maintaining systemic iron homeostasis. Disturbances that lead to excess iron promote the replication and virulence of enteric pathogens. Consequently, research has been interested in better understanding the effects of iron supplementation and fortification on gut bacterial composition and overall gut health. While animal and human trials have shown seemingly conflicting results, these studies emphasize how numerous factors influence gut microbial composition. Understanding how different iron formulations and doses impact specific bacteria will improve the outcomes of iron supplementation and fortification in humans. Furthermore, discerning the nuances of iron supplementation and fortification will benefit subpopulations that currently do not respond well to treatment. Keywords: iron supplementation; gut microbiome; iron metabolism; gastrointestinal homeostasis 1. Introduction The majority of living organisms require iron for survival. Iron can exist in one of two oxidation states, and due to this redox potential, can function in several fundamental processes, such as respiration, DNA replication, energy production, and cellular proliferation [1]. Humans absorb iron from their diet in a dynamic, tightly regulated process within the intestine [2]. In addition to controlling the amount of iron absorbed, this process dictates iron availability for the complex community of bacteria living in the intestine, hereafter referred to as the gut microbiota. As such, many bacteria have developed sophisticated systems to obtain, store, and regulate iron. Iron deficiency and excess both impact gut microbial health and lead to diseases, such as iron deficiency anemia and iron overload, respectively. Iron deficiency is highly prevalent worldwide and is commonly treated with oral iron supplements and fortificants [3]. In this review, we cover the effects of oral iron supplementation and fortification on gut health and disease. We begin with an overview of how the body acquires and utilizes iron. Then, we discuss the complex relationship between iron homeostasis and the gut microbiome. Finally, we summarize the microbial changes that occur following iron supplementation and fortification in animal and human trials, and we identify areas in need of continued research. In this literature review, we used PubMed and MEDLINE databases to search for articles related to Gastrointest. Disord. 2020, 2, 327–340; doi:10.3390/gidisord2040030 www.mdpi.com/journal/gastrointestdisord Gastrointest. Disord. 2020, 2 328 “human iron metabolism”, “bacterial iron metabolism”, “iron and gut flora”, and “the effects of iron on the gut microbiota/microbiome in animals and/or humans”. 2. OverviewGastrointest. of Iron Disord. Absorption 2020, 2 FOR PEER REVIEW 2 Humansto search lose for approximately articles related to 0.5–2“human mg iron of metabolism” iron every, day “bacterial from iron skin metabolism” cell desquamation,, “iron and gut intestinal epithelialflora” cell, (IEC)and “the sloughing, effects of iron and on urine the gut and microbiota/ sweat productionmicrobiome [in4 ].animals Additional and/or humans.” iron may also be lost during specific2. Overview physiological of Iron Absorption processes, such as menstruation and lactation [5]. To balance this loss, the human duodenum and proximal jejunum absorb approximately 2 mg of dietary iron daily, a small Humans lose approximately 0.5–2 mg of iron every day from skin cell desquamation, intestinal proportion of the total daily dietary intake [6,7]. Iron from the diet is found primarily as heme, derived epithelial cell (IEC) sloughing, and urine and sweat production [4]. Additional iron may also be lost from myoglobinduring specific and hemoglobin,physiological processes, or nonheme such as iron, menstruation derived fromand lactation plants and[5]. To iron-fortified balance this loss, foods [6]. Nonhemethe iron human exists duodenum in two and forms proximal as reduced jejunum ferrous absorb ironapproximate or oxidizedly 2 mg ferric of dietary iron. iron IECs, daily, known a as enterocytes,small can proportion absorb of only the total ferrous daily irondietary (Figure intake 1[6,7].). As Iron such, from ferricthe diet iron is found is reduced primarily to as ferrous heme, iron by the membrane-boundderived from myoglobin ferric and reductase hemoglobin, duodenal or nonheme cytochrome iron, derived B (Dcytb)from plants that and is iron expressed-fortified on the apical brushfoods border[6]. Nonheme membrane iron exists of IECs in two [8 ].forms Once as inreduced the ferrous ferrous form,iron or ironoxidized is transported ferric iron. IECs, across the known as enterocytes, can absorb only ferrous iron (Figure 1). As such, ferric iron is reduced to apical membraneferrous iron of enterocytesby the membrane by the-bound 12 transmembrane ferric reductase domain duodenal protein, cytochrome divalent B (Dcytb) metal transporterthat is 1 (DMT1, alsoexpressed known on the as Nramp2)apical brush [9 ].border Within membrane enterocytes, of IECs iron [8]. isOnce stored in the in ferritin,ferrous form, used iron in ais variety of cellulartransported processes, across ortransported the apical membrane into systemic of enterocytes circulation by the by 12 crossingtransmembrane the basolateral domain protein, membrane throughdivalent the 12 transmembranemetal transporter 1 (DMT1, domain also protein, known as ferroportin Nramp2) [9] [10. Within]. Ferroportin enterocytes, is iron also is stored expressed in on macrophagesferritin, and used hepatocytes in a variety [of10 cellular]. On the processes, basolateral or transported membrane, into hephaestinsystemic circulation oxidizes by ferrouscrossing iron to the basolateral membrane through the 12 transmembrane domain protein, ferroportin [10]. ferric iron, enabling the transportation of iron in the blood by transferrin [5]. In comparison to nonheme Ferroportin is also expressed on macrophages and hepatocytes [10]. On the basolateral membrane, iron, hemehephaestin absorption oxidizes remains ferrous enigmatic iron to ferric [11 iron,]. There enabling are twothe transportation current hypotheses of iron in for the intestinal blood by heme absorption:transferrin Either [5]. heme In comparison is endocytosed to nonheme from iron, the apicalheme absorption membrane remains or transported enigmatic [11]. through There are a specific receptortwo into current the cytosol hypotheses [12]. for intestinal heme absorption: Either heme is endocytosed from the apical membrane or transported through a specific receptor into the cytosol [12]. Figure 1.FigureAbsorption 1. Absorption of nonheme of nonheme iron iron by by intestinal intestinal epithelial epithelial cell cellss (IECs (IECs).). Ferric Ferric iron ironis first is reduced first reduced to ferrousto ironferrous by iron duodenal by duodenal cytochrome cytochrome B (Dcytb)B (Dcytb) on on thethe apical membrane. membrane. Then, Then, ferrous ferrous iron is iron is transportedtransported across theacross apical the apical membrane membrane by by divalent divalent metal metal transporter transporter 1 (DMT1). 1 (DMT1). Once Once inside inside the cell, the cell, iron is storediron is in stored ferritin, in fer transportedritin, transported across across the basolateral the basolateral membrane membrane by by ferroportin, ferroportin, or or used used in in a a variety of cellularvariety processes. of cellular After processes. transport After across transport the across basolateral the basolateral membrane, membrane, ferrous ferrous iron iron is oxidized is oxidized to ferric to ferric iron by hephaestin. Ferric iron is then transported by transferrin in circulation. Iron iron by hephaestin. Ferric iron is then transported by transferrin in circulation. Iron absorption is reduced when hepcidin binds to ferroportin because hepcidin causes the internalization and degradation of ferroportin. The figure created with www.BioRender.com. Gastrointest. Disord. 2020, 2 329 3. Maintenance of Systemic Iron Homeostasis Humans have no active iron excretory mechanism; therefore, systemic iron homeostasis is primarily regulated at the point of absorption. Hepcidin, a peptide hormone produced by the liver, is considered the master regulator of systemic iron homeostasis [13]. Hepcidin binds to and degrades ferroportin, which consequently impacts how iron is recycled by macrophages, absorbed by IECs, and stored by hepatocytes [14,15]. Hepcidin expression is upregulated when iron stores are adequate
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