Mechanism of Iron Ion Homeostasis in Intestinal Immunity and Gut Microbiota Remodeling

Abstract

Iron is a vital trace element that plays an important role in humans and other organisms. It plays an active role in the growth, development, and reproduction of bacteria, such as Bifidobacteria. Iron deficiency or excess can negatively affect bacterial hosts. Studies have reported a major role of iron in the human intestine, which is necessary for maintaining body homeostasis and intestinal barrier function. Organisms can maintain their normal activities and regulate some cancer cells in the body by regulating iron excretion and iron-dependent ferroptosis. In addition, iron can modify the interaction between hosts and microorganisms by altering their growth and virulence or by affecting the immune system of the host. Lactic acid bacteria such as Lactobacillus acidophilus (L. acidophilus), Lactobacillus rhamnosus (L. rhamnosus), and Lactobacillus casei (L. casei) were reported to increase trace elements, protect the host intestinal barrier, mitigate intestinal inflammation, and regulate immune function. This review article focuses on the two aspects of the iron and gut and generally summarizes the mechanistic role of iron ions in intestinal immunity and the remodeling of gut microbiota.

Keywords: gut; gut microbiota; intestinal immunity; iron; iron homeostasis.

Figure 1

The four major cell types are responsible for controlling the iron cycle in the body. Dietary iron is absorbed by the small intestinal cells in the duodenum and binds to transferrin in plasma, which is mainly used to produce hemoglobin for new red blood cells. Macrophages recover most of the iron in the body by engulfing red blood cells and breaking down their heme fraction, and then reloading it onto lipotransferrin. Too much iron is stored in the liver’s ferritin. Tf, transferrin.

Figure 2

The transport of iron inside and outside cells. After binding to transferrin, iron ions are taken into the cell by protein receptors on the cell membrane and are separated from transferrin in an acidic environment. Enzymes reduce the ions to ferrous ions, and then they are excreted into the cell. Additionally, Dcytb can also convert iron ions to ferrous ions, and DMT1 mediates them into the cell. Some of the iron ions are stored as ferritin, whereas the rest are expelled from the cell, thus maintaining the iron ion content. Tf, transferrin; TfR, transferrin receptor; DMT1, divalent metal-ion transporter 1; FPN1, ferroportin 1; Dcytb, duodenal cytochrome b; LIP, iron pool.

Figure 3

Examples of the functions of major metabolites of intestinal microbes. Gut microbiota are located on the outside of the intestinal epithelium, with the intestinal epithelial cells acting as a separator between them and the inner environment. Nevertheless, metabolites created by gut microbiota can penetrate channel proteins and enter the inner intestine, resulting in a variety of effects by going through different cell cycle pathways. This figure mainly gives examples of the roles of the most important metabolites and the organs or cells in which they act.

Figure 4

Microorganisms and the brain—gut axis. (A) Serotonin (5-HT) as a critical regulator of gut-brain-microbiome axis signaling. SCFAs can enter the bloodstream from the intestinal cavity via FFARs, which can then activate TPH1 to produce and release 5-HT in ECC cells. This free 5-HT can be transmitted to the Vagus nerve through IPAN, thus influencing the brain’s central nervous system. Additionally, SCFAs can bind fatty acid receptors on epithelial immune cells and nerve cells (e.g., the Vagus nerve), thereby regulating downstream processes such as movement, secretion, and enterocerebral signal transduction. Additionally, (B) other metabolites produced by the gut microbiota are involved in neural activity. Gut microbiota produce various metabolites, such as 5-HT, dopamine (a precursor of Neurohormone), GABA, Norepinephrine, etc., which can influence neural activity. These metabolites can be transported through the nerve Endocrine system, HPA axis pathway, intestinal mucosal barrier, and blood—brain barrier, altering sleep, anxiety, depression, and other brain emotional activities. SCFAs, short-chain fatty acids; FFARs, free fatty acid receptors; TPH1, tryptophan hydroxylase 1; 5-HT, serotonin; ECC, enterochromophilia; GABA, γ-Aminobutyric acid; IPAN, intrinsic primary afferent neuron.

Figure 5

The key regulators of iron homeostasis and major iron cycling pathways. The human body obtains iron mainly through the ingestion of food, such as meat and vegetables. The iron is absorbed into the body through the intestinal epithelial cells, which are regulated by two major proteins: SLC11A2(FPN), an iron importer, and SLC40A1(DMT1), an iron exporter. These two proteins work together to maintain the balance of iron ion concentration in the intestinal cells. Additionally, the hepcidin hormone is able to inhibit the synthesis of ferroportin, thus regulating the transport of iron ions. This hormone is also regulated by a negative feedback loop, which reduces its effect and allows the transport of iron to continue in an orderly manner. The ferroptosis pathway is also involved in this cycle, which involves the entry of free trivalent iron into cancer cells via transferrin. This process generates a large amount of toxic hydroxyl radicals and reactive oxygen species (ROS) through the Fenton reaction, resulting in an increased level of oxidative stress that leads to programmed cancer cell death. The figure also reveals the influence of gut microbiota on human health. Gut microbiota can be advantageous, yet they can also cause illnesses, like abnormal gastrointestinal metabolism. FPN, ferroportin; Tf, transferrin; Dcytb, duodenal cytochrome b; DMT1, divalent metal-ion transporter 1; TfR, transferrin receptor; GSH, glutathione. ↓: downregulation; ↑: upregulation.