The Body Needs Iron
The human body needs iron for oxygen transport. That oxygen is required for the production and survival of all cells in our bodies. So human bodies tightly regulate iron absorption and recycling. Iron is such an essential element of human life, in fact, that humans use divalent metal transporters (DMT1, NRAMP2, NEDD4, IRE+) for iron absorption and (IRE–) for excreting iron. Most humans prevent iron overload solely by regulating iron absorption. Inflammation reduces the ability of (IRE–) to eliminate excess iron leading disorders of iron or toxic metals overload. Cytokine stimulation of divalent metal transporters increase the toxicity of iron or toxic metals, which starts overwhelming the body’s ability to bind and store or eliminate metals.
Most of the iron in the body is hoarded and recycled by the liver, spleen and lymphatic systems, which breaks down aged red blood cells. However, people lose a small but steady amount by sweating and by shedding cells of the skin and the mucosal lining of the gastrointestinal tract.
This steady loss means that people must continue to absorb iron. They do so via a tightly regulated process that under normal circumstances protects against iron overload.
Like most mineral nutrients, iron from digested food or supplements is almost entirely absorbed in the duodenum by enterocytes of the duodenal lining. These cells have special molecules that allow them to move iron into the body.
Dietary sources of iron include heme iron (meat) or non-heme iron (iron-rich plants), which are less bio-available. Homeostasis of iron is carried out by up- or down-regulation of transferrin and ferritin on cell surfaces to balance absorption, storage, circulation and elimination of iron. Absorption of non-heme iron is mediated by divalent metal transporter 1 (DMT1), to name one.
To be absorbed, dietary iron must be in its ferrous Fe2+ form. A ferric reductase enzyme on the enterocytes’ brush border, Dcytb, reduces ferric Fe3+ to Fe2+. A protein called divalent metal transporter 1 DMT1, which transports all kinds of divalent metals into the body, then transports the iron across the enterocyte’s cell membrane and into the cell.
These intestinal lining cells can then either store the iron as ferritin (in which case the iron will leave the body when the cell dies and is sloughed off into feces) or the cell can move it into the rest of the body, using a protein called ferroportin. The body regulates iron levels by regulating each of these steps. For instance, cells produce more Dcytb, DMT1 and ferroportin in response to iron deficiency anemia.
Anemia of Chronic Inflammation
Inflammatory cytokines also appear to affect other important elements of iron metabolism, including decreasing the ability of the bone marrow to respond to signals calling for the production of new red blood cells.
Chronic inflammation (also known as chronic systemic inflammation) is an inflammatory immune response of prolonged duration that eventually leads to tissue damage. Chronic inflammation is differentiated from acute inflammation by extended duration, lasting anywhere from a week to an indefinite time frame. The exact nature of chronic inflammation depends on the causative agent and the body’s attempts to ameliorate it.
Anemia of Chronic Inflammation, increasingly referred to as “Anemia of Inflammation“, is a form of anemia seen in chronic illness, e.g. from chronic infection, chronic immune activation, autoimmunity, inflammation or malignancy. New discoveries suggest that the syndrome is likely primarily the result of the body’s production of hepcidin, a master regulator of human iron metabolism.
In the short term, the overall effect of these changes is likely positive: it allows the body to keep more iron away from bacterial pathogens in the body, while producing more immune cells to fight off infection. Bacteria, like most life forms, depend on iron to live and multiply. However, if inflammation continues, the effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.
Hepcidin & Bacteria
A proper iron metabolism protects against bacterial infection. Iron is essential for the growth and virulence of many pathogenic enterobacteria, whereas beneficial barrier bacteria, such as lactobacilli, do not require iron. Thus, increasing dietary iron-containing foods or supplements could artificially select gut microbiota for humans that are unfavorable. Iron supplementation produces a potentially more pathogenic gut microbiota profile, and is associated with increased gut inflammation.
If bacteria are to survive, then, they must get iron from the environment. Disease-causing bacteria do this in many ways, including releasing iron-binding molecules or by entering the blood stream to scavenge iron from red blood cell. But the harder they have to work to get iron, the greater a metabolic price they must pay. That means that iron-deprived bacteria reproduce more slowly. So our control of iron levels appears to be an important defense against bacterial infection. And people with increased amounts of iron, like people those taking iron containing supplements, are more susceptible to bacterial infection.
However, although this mechanism is an elegant response to short-term bacterial infection, it can cause problems when inflammation goes on for longer. Since the liver produces hepcidin in response to inflammatory cytokines. Hepcidin in turn stops the release of stored iron in the liver. When this occurs, the sequestration of iron appears to be the major cause of the syndrome of Anemia of Chronic Inflammation, in which not enough iron is available to produce an adequate number of hemoglobin-containing red blood cells. This prompts the body to send out signals that iron is needed causing increased activity of DMT1 and other divalent metal transports.
Metals transported into the body by DMT1
NRAMP2 and DMT1 is a nonspecific metal transporter, which can transport not only Fe, but the toxic metals as well. NRAMP2 (natural resistance-associated macrophage protein 2) and DMT1 (divalent metal transporter 1) are divalent metal transporters that exhibits an unusually broad range of divalent metals, including: iron Fe(2+), zinc Zn(2+), manganese Mn(2+), copper Cu(2+), cadmium Cd(2+), cobalt Co(2+), nickel Ni(2+), and lead Pb(2+), and mercury Hg(2+).
An unusually high amount of iron, copper and zinc was detected in greatly degenerated or already dead nerve cells. Both forms of NRAMP2 and DMT1 were expressed on neurons, astrocytes, and microglia in the abdominal and cranial brains. DMT1 are produced primarily in the intestinal lining, brain, kidney, testis, liver and spleen. Low iron levels in the blood signal the small intestine to increase production of DMT1 and other divalent metal transporters. This increased production of DMT1increases the activity of transporting toxic metal across the intestinal lining.
However the low iron levels are due to inflammatory cytokines stimulating the sequestration of iron in the liver to prevent the production of free radical and iron-loving bacteria.
Toxic Metals – Piggy back
These divalent metal transporters are up-regulated (made more active) by a low levels of iron, which is caused by Anemia of Chronic Inflammation.
Toxic elements such as cadmium, mercury and lead share the same iron transporters in the body, and it may be the reason that iron deficiency or Anemia of Chronic Inflammation predisposes humans to cadmium, mercury and lead toxicity. Toxic elements can “piggy back” on divalent metal transporters (DMT1) and the other homeostatic mechanisms for iron regulation and can pose a second adverse consequence for the patient with either extremely high iron stores or the patient with iron deficiency, which more often than not is Anemia of Chronic Inflammation.
Metals transporter are pH dependent
Studies reveals that transport of iron and other divalent metal ions by DMT1 are pH dependent, but the exact manner in which pH exerts its effect is unknown. Data indicate that DMT1 in an acidic pH increase the affinity for Fe(2+) and provides a driving force for Fe(2+) and other divalent metal transport of iron Fe(2+), zinc Zn(2+), manganese Mn(2+), copper Cu(2+), cadmium Cd(2+), cobalt Co(2+), nickel Ni(2+), and lead Pb(2+), and mercury Hg(2+).
Metals transporter & The Brain
Iron is essential for crucial neuronal functions but is also highly toxic in excess. Iron accumulation in the brain occurs in a number of neurodegenerative diseases. Excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death.
The Divalent Metal Transporter 1 (DMT1), is responsible for iron and other divalent metals uptake from the gut and transport to the brain. The Metal Transport Protein 1 (MTP1) promotes iron export into brain cells. DMT1 has an important role in iron and divalent metal transport into the brain. DMT1 expression is highest in neurons in the striatum, cerebellum, thalamus, ependymal cells lining the third ventricle, and vascular cells throughout the brain.
Metals transporter & Cytokines
Divalent metal transporters are up-regulated by inflammatory cytokines including:
- Tumor necrosis factor (TNF)
- Interferon (IFN)
- Bacterial Lipopolysaccharides (LPS)
- TH-1 Dominance
Metals transporter & Chelation Therapy
This is before and after DNA stool test. In April of 2008, we see that her bacteria count were all up in the fourth and fifth quintile. But after the chelation therapy, in the Nov. 2010 test results, we see that her bacteria are all down here in the first quintiles, with the exception of pathogenic clostridia, mycoplasma and E. coli. I have seen six patients with similar before and after chelation patterns.
The DMT1 and other divalent metal transporters function to transport iron into the body so it can be used to make red blood cells. But inflammation stimulates the divalent metal transporters. If there is no iron around, DMT1 will start transporting heavy metals in this order: : iron Fe(2+), zinc Zn(2+), manganese Mn(2+), copper Cu(2+), cadmium Cd(2+), cobalt Co(2+), nickel Ni(2+), and lead Pb(2+), and mercury Hg(2+).
The toxic metals will be transported into the epithelial cells of the gastrointestinal tract, into the brain, into the kidneys, into the testes, liver and spleen. After arriving in these tissues, heavy metals will then going to promote cell apoptosis (programmed cell death) and keratin formation (scar tissue). This results in an apoptotic/keratinized gut lining, and with no place for the beneficial microbes to colonize. Chelation therapy and metal detoxes increase the inflammatory response, which then upregulates the Divalent Metal Transporters.
When they’re doing the urine test to prove that their chelation therapy works, you have to start wondering where the heavy metal really did go. Not only does it go into the epithelial lining of the gastrointestinal tract, DMT1 is found in high levels in sections of the brain, and this woman had serious brain fog. So it’s no wonder that she’s feeling the way she does, and she’s having a hard time getting better because she’s basically chelated her gastrointestinal tract into this programmed cell death, covered with scar tissue. Then loaded up her brain, kidney and livers tissues with toxic metals.
Reducing inflammation and Restoring NEI Supersystem
The NEI Super-System needs a good nutritional foundation over a long period of time to alleviate or reverse toxic metals in the body and to assist with combating the resulting fully developed autoimmune diseases.
The goal of supplement protocols is to decrease systemic inflammation. Common sources of inflammation include: dysglycemia, food and chemical sensitivities, allergies, oral infections, gastrointestinal infection, viral expressions, mycotoxin infections, bacterial infections, environmental antigenic toxicity, tick infections, essential fatty acid imbalances, impaired liver clearance, diets high in saturated and partially hydrogenated fats, NEI Supersystem dysfunction, pesticide exposure, emotional and structural imbalance caused stress.
The Major Priorities of Functional Medicines approach to elimination of toxic metals is:
- Calm the immune response by supporting Regulatory T and Helper-Cells
- Restore the NEI SuperSystem
- Reduce or eliminate triggering factors
- Reduce structural imbalances
- Improve gastrointestinal function and remove antigens from the body
- Manage dysglycemia
- Improve fatty acid balance
- Optimize liver detoxification and estrogen metabolism
- Prevent / or Alleviate / Minimize Autoimmune Processes
The information presented is supported by peer-reviewed medical literature. For more information call Dr. Dave at Wellness Alternatives. 530-615-4083.