Iron homeostasis in host and gut bacteria - a complex interrelationship

Abstract

Iron deficiency is the most frequent nutritional deficiency in the world with an estimated 1.4 billion people affected. The usual way to fight iron deficiency is iron fortification, but this approach is not always effective and can have undesirable side effects including an increase in the growth and virulence of gut bacterial pathogens responsible for diarrhea and gut inflammation. Iron is mainly absorbed in the duodenum and is tightly regulated in mammals. Unabsorbed iron enters the colonic lumen where many microorganisms, referred to as gut microbiota, reside. Iron is essential for these bacteria, and its availability consequently affects this microbial ecosystem. The aim of this review is to provide further insights into the complex relationship between iron and gut microbiota. Given that overcoming anemia caused by iron deficiency is still a challenge today, gut microbiota could help identify more efficient ways to tackle this public health problem.

Keywords: Anemia; bacteria; gut; human; iron; metabolism; microbiota; rodent.

Figure 1.

Enterocyte iron absorption and systemic iron distribution. Heme iron is transported in the enterocyte by Heme carrier protein 1 (HCP1), and Fe⁺ is released in the cytoplasm by heme oxygenase 1 (HOX1) to join the labile iron pool (LIP). Fe³⁺ is reduced to Fe⁺ by duodenal cytochrome b (DCYTB) in the brush border membrane of duodenal enterocytes, then Fe⁺ joins the LIP via the divalent metal transporter (DMT1). Poly(rC)-binding protein (PCBP) delivers ferrous iron to the iron storage protein, ferritin, and vice versa. PCBP also transports Fe⁺ from the LIP to the basolateral iron exporter, ferroportin. A small proportion of Fe⁺ is also transferred to the mitochondria for synthesis of iron-sulfur clusters (Fe-S) and heme, which can be exported from the mitochondria and enterocytes using feline leukemia virus C receptor (FLVCR). The exported free heme is complexed with hemopexin into a heme-hemopexin complex, which can be directly absorbed by cluster of differentiation (CD91) receptors on the liver and macrophage. Exported Fe⁺ is converted into Fe⁺ by hephaestin, Fe⁺ is then bound to transferrin to be transported to the bone marrow and hepatocytes for erythropoiesis and storage, respectively. This complex then binds to the transferrin receptor-1 (TfR1) on the cell surface of targeted cells and delivers its cargo to the cytosol via endocytosis. Apo-tf, transferrin without iron

Figure 2.

Essential model of the role of hepcidin in maintaining iron homeostasis. Hepcidin produced in the liver downregulates ferroportin expression in enterocytes, macrophages, and hepatocytes in case of inflammation, low iron store, and low transferrin level. The red arrow signal inhibition of hepcidin and the green arrow signal expression of hepcidin. IL 1 and 6, interleukin 1 and 6

Figure 3.

General iron uptake system and ferric uptake regulator (fur)-mediated iron uptake regulation in bacteria. Bacteria can acquire iron ferric iron complexes with siderophores, ferrous iron, transferrin, lactoferrin, hemoglobin and heme complexes using different receptors. Once inside the cell iron is stored, used for protein synthesis and for regulation of the expression of the gene Fur. In presence of iron, Fur forms a complex with Fe³⁺, which binds to the Fur biding sites of bacterial DNA to repress transcription of the genes involved in iron transport. In absence of iron, Fur cancels out repression and the genes are expressed

Figure 4.

Schematic representation of bacterial siderophore-mediated iron uptake in Gram-negative (a) and Gram-positive bacteria (b). Ferric-siderophore complexes are internalized via specific outer membrane receptors, a periplasmic binding protein (PBP), and inner membrane ATP-binding cassette (ABC) transporters. In gram-positive bacteria, the energy required for iron uptake is satisfied by the coupling the proton motive force of the cytoplasmic membrane to the outer membrane via the TonB system (TonB, ExbB, ExbD). LPS, lipopolysaccharides

Figure 5.

Summary of the effect of iron supplementation (plain arrows) and iron deficiency (empty arrows) on fecal bacterial composition at different taxonomic levels. Results are from human (green arrows), animal (blue arrows) and in vitro (red arrows) experiments. The direction of the arrow indicates the effect: the arrow up indicates an increase in the proportion of the taxon, the arrow down indicates a decrease of the proportion of the taxon, and the arrow to the right indicates an absence of effect on the proportion of the taxon.^,,,