The use of iron in essential basic metabolic pathways is inherent to both microorganisms, pathogenic or not, and their hosts. It is also a core component of the innate immune response to infection in humans.[1] During the coevolution of humans with bacteria the shared requirement of microorganisms and their hosts for this important nutrient has shaped the pathogen–host relationship, with particularly obvious effects on the innate human immune response to infections that result in inflammation.
Below I discuss how pathogens compete with hosts for this resource vital to their proliferation and growth, iron. How the human immune system uses iron deprivation as a core component of its response to any infection causing inflammation [2], and how in diseases that do not involve infection but are characterised by chronic inflammation, this leads to iron deficiency anaemia.
Because inflammation caused by infection resolved one way or the other, our ancestors got better or they died, our adaptation to inflammation involving withholding iron during inflammation does not have an “off switch”. As a consequence the modern epidemic of immunological disorders that almost universally involve inflammation often result in iron deficiency anaemia leading to a host of secondary symptoms such as enervation, fatigue, etc. [3]
I also describe how helminthic therapy based on Necator americanus which feeds on the host blood paradoxically improves iron status in those suffering from chronic immunological disorders, allergic diseases and classic autoimmune diseases particularly Crohn’s disease of the ileum, it’s most common form (ileocolitis). [4]
My discussion of the mechanisms by which chronic inflammation causes anaemia, as well as how inflammation in the ileum, as is the case with Crohn’s disease and others, amplifies the effect. How this makes anaemia more likely for Crohn’s sufferers but also more responsive to helminthic therapy in terms of improvements to their iron status.[5]
Most bacteria responsible for diseases in mammals, including us of course, require iron. Iron is not abundant in most living things despite being one of the most common elements in the universe. Because of its toxicity it is not a nutrient that we store well.
So it is no surprise perhaps, that part of the immune response to infection, which invariably includes inflammation, involves withholding iron from bacteria, a clever defence mechanism.[6]
Inflammation is the trigger for the mechanism by which iron is withheld, by blocking absorption and sequestering iron in the body, making it unavailable to bacteria, but also to the body for things like red blood cell formation.
If inflammation is the result of a chronic immune disease and never stops the result is anaemia. Which makes the host more vulnerable over the long term to infectious illness. [7]. Inflammation adapted as a short-term immune response and has a multitude of deleterious health consequences if it is chronic.
For bacteria to survive, thrive and multiply they must obtain iron. Bacteria that infect mammals do this in a variety of ways: releasing iron-binding molecules called siderophores and then reabsorbing them to recover iron; scavenging iron from haemoglobin and transferrin.[8]
Iron is a toxic element and demands a high metabolic price of bacteria to utilise. The scarcer it is, the harder it is to obtain, the greater the metabolic price they must pay to obtain it.
Iron-deficient or deprived bacteria reproduce more slowly and are weaker and less capable, less healthy.
So our control of iron levels available to bacteria involved in infections is a very important defence against many infections.
The effect also makes people with high levels of iron, as occurs in the disease haemochromatosis, more vulnerable to, and more likely to contract bacterial infections.
This suggests hookworms could be an effective passive treatment option for haemochromatosis but I have not yet examined it to calculate the number of hookworms required, however this journal entry suggest a population of 300-400 A. Duodenale. [9][9,10][9]
As effective and as interesting as this aspect of our immune systems is, it causes problems when inflammation is not an appropriate response as is the case with almost all immunological disorders, such as autoimmunity or allergy.
Inflammation is part of our immune systems initial response, it is a protective response involving white blood cells, blood vessels, and cytokines. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair. Part of how it accomplishes this is to make our tissues porous to larger elements of the immune system's signalling system and methods for delivering various weapons to fight infectious organisms like bacteria. Mostly that means white blood cells.
By making our tissues more porous white blood cells can reach the site of infection, engage with the bacterium or bacteria, and signal other parts of the immune system to send the appropriate white blood cells, cytokines, and to develop antibodies particular to the organism or organisms present. All good.
In response to inflammation (as a result of circulating levels of pro-inflammatory cytokines), a marker of bacterial infection, our livers titrate the quantities of Hepcidin it produces (an iron uptake regulator) to starve bacteria of iron. But the effect is systemic and not localised to the area of infection because under the circumstances we evolved inflammation is "never" chronic, never long-lasting.[11]
Chronic inflammation has until now not been an evolutionary pressure on humans, so none of the consequences of chronic inflammation has resulted in adaptations, although anyone whose reproductive future has been stunted by modern life is living evidence of unnatural selection at work.
High Hepcidin levels cause serum (blood borne) iron to drop by sequestering iron from biological processes in the body. It does so by confining iron inside macrophages (a class of white blood cells that engulf or eat things that shouldn't be lying around), and some within liver cells. It also reduces iron absorption in the ileum, Route 1 for iron and it's transport molecules.
This is the reason so many of you with immunological disorders are iron deficient anaemic, and therefore why some of you are tired much of the time, often dull-witted or foggy, pallid, sad, bad company and less likely to reproduce.
Anaemia particularly affects those of you with inflammatory disorders affecting the terminal ileum, a double whammy.
The ileum is where most of the iron and its transport molecules in your body was originally absorbed. An example of a disease of inflammation affecting the ileum is the most common form of Crohn's disease (85% of all Crohn's cases approx.). Others are food allergies, coeliac disease, and so on.
It also suggests the manner in which hookworm (counter-intuitively a blood-sucking intestinal worm, and a lovely one at that) in particular so quickly rid those who host it for immunological diseases, of anaemia.
Hookworms live in the ileum, where it has been observed they have a strong localised effect on inflammation affecting the tissues surrounding where they are or have recently been attached to feed.[12]
Hookworms shuffle off to a new feeding site roughly once every day. This immediately increases iron absorption and clearly in excess of what they eat since anaemia recedes rapidly after infection with hookworm and keeps it at bay so long as they are resident.
It should also be noted that the epithelial cells with which they are in direct contact and penetrate slightly to feed, produce various cytokines in response to local stimuli and as a result of immunological signalling. It can be of little doubt that this close contact is involved with hookworms and whipworms interaction and responses to immune system status and responses to the worms themselves. [13]
I propose that this localised effect on inflammation in the ileum, where iron and its transport molecules are absorbed, in terms of the total inflamed area that is calmed, is related to a multiple of the numbers of hookworm hosted and the size of the area calmed by each adult hookworm. As well as to the period of persistence of the anti-inflammatory effect once each hookworm detaches to migrate to a new site. With sufficient population density inflammation in the ileum becomes almost impossible.
It is also well known that helminths, like hookworm, whipworm and others that have humans as their definitive host (the one in which they complete their reproductive cycle) reduce immune dysregulation, allergy and autoimmunity, and the inflammation that almost invariably results from those types of conditions via systemic immune modulation. Hosting helminths in animal models of anaphylaxis in humans has been shown to entirely eliminate anaphylaxis which is a rapid and violent inflammatory allergic reaction that can result in death.[14]
I propose that by reducing inflammation in areas they do not attach to feed via systemic immunomodulatory molecules, hookworms indirectly up-regulate iron absorption by reducing circulating levels of pro-inflammatory cytokines, and so down-regulate the production of Hepcidin by the liver. That also results in a release of sequestered iron from macrophages, and the liver itself.
Thus explaining the reason we see such rapid and apparently paradoxical improvement in iron status in Crohn's sufferers after treatment with hookworms.
So long as the subject has sufficient dietary iron and does not suffer from an additional disorder that causes anaemia via a different mechanism, I believe that this is how hookworms, that feed on our blood and increase our need for iron, can be used to cure anaemia in those suffering from chronic inflammatory conditions.
© Jasper Lawrence, 2018 All rights reserved.
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