Lactoferrin and iron deficiency disorders

Lactoferrin is able to bind iron and regulate the iron balance in the body. Through this ability, Lactoferrin can reduce inflammation and support the immune system by depriving microorganisms of something essential for their growth.  
Specifically, Lactoferrin helps ensure that the correct concentration of free iron is maintained in human fluids. This prevents iron deficiency, release of free radicals and microbial colonisation [1-4].
In 2017, Rosa et al. published an interesting overview article about the modes of action in iron homeostasis [5].
Iron is an essential element for cell growth and proliferation, and essential for DNA replication and energy production. However, it can also have a toxic effect on the body if it is present in excess. Then the delivery of electrons to oxygen can result in the creation of free radicals [6]. These can cause tissue injury and organ damage [7]. 
Under normal circumstances, there is so little free iron in the body that there is no risk of free radicals forming, inflammatory processes arising or microorganisms using iron for reproduction [8,9]. However, if the balance is disturbed and too much free iron is available, the risk of infection and the formation of free radicals increases, as well as the development of inflammation [9].
The equilibrium between the iron present in the blood and that present in tissue is called iron homeostasis. This is strictly controlled by various mechanisms to prevent iron deficiency and excess iron. 
Ferroportin , a transmembrane portein that transports divalent iron ions (Fe2+) from the cell interior into the extracellular space, plays an important role here. In the case of an inflammatory reaction or infection, ferroportin is down-regulated. This is caused by the proinflammatory cytokine interleukin-6 (IL-6) [10,11] and by binding ferroportin to hepcidin, a protein from the liver. Thus the iron remains in the cell.
As a result, there is an iron overload at the cellular level, while at the systemic level, iron deficiency, iron deficiency anaemia and anaemia of inflammation may occur [4,12].
The usual intervention in iron deficiency consists of iron supplementation, based on the assumption that this should increase the haematological parameters again. However, iron homeostasis often cannot be restored in this way, because of undesirable gastrointestinal side-effects during therapy, such as nausea, vomitting, diarrhoea and constipation [7,13-16].
Studies in rats showed increased production of free radicals [8]and severe progression of inflammatory status in the intestine after administration of an iron rich diet [9].
In the case of anaemia of inflammation, the most severe iron homeostasis disorder, the great difficulty of the therapy lies in the high IL-6 levels, with which it is associated [17]. For a long time it has been assumed that the reduction of iron availability in the blood is a defence mechanism against extracellular pathogens [17-19]. However, Rosa et al recommend rethinking classical therapy.  There are bacteria that can penetrate the cell and cause inflammation within. These could benefit from the iron overload within the cell and cause an even stronger reaction [20,21].
It is therefore of the utmost importance to counteract the persistence of the inflammatory state,
to balance iron levels between tissues/secretions and blood, thereby avoiding intracellular iron accumulation, and thus reducing the severity of the infection.
Lactoferrin has a molecular structure that offers various binding possibilities for cells, pathogens, iron and other substances. It belongs to the group of the transferrins and is able to pick up, distribute and dispense tri-valent iron. 
During infection and/or inflammation processes, the concentration of Lactoferrin in the body increases, as it is produced and released by immune cells (neutrophil granulocytes).   This ensures that the freely available iron does not become too high, thus preventing microbial growth and the formation of free radicals. In infected/inflamed host cells, Lactoferrin also exerts an anti-inflammatory effect against interleukin-6 (IL-6) which again prevents intracellular iron overload.
At the same time, lactoferrin shows bacteriostatic activity, because the binding of iron also strongly inhibits bacterial growth and the expression of virulence factors [22,23].
With regard to anaemia of inflammation and the clinical effect of Lactoferrin, a 2006 study in pregnant women [13], showed oral administration of Lactoferrin in combination with iron demonstrated an increase in haematological parameters after 30 days. 
Lactoferrin shows great anti-inflammatory potential in its ability to modulate the inflammatory response regardless of whether it is caused by intracellular bacteria [21,24-26] or triggered via toll-like receptors on the surface of the immune cells [27,28].
Lactoferrin therefore appears to be a key element, not only in the defence system against microorganisms [2,29,30], but also as a central component in inhibiting an inflammatory reaction [31].
The fact that the administration of iron in anaemia of inflammation does not reduce inflammatory processes is not surprising, because iron is itself an amplifier of inflammation [32-34].  From this viewpoint, the authors of the review article mentioned before describe the new approach of treating anaemia of inflammation with lactoferrin instead, as an extremely significant innovation. 
They underline in their approach that, in vivo, the anaemia of inflammation state arises from the delocalisation of iron, i.e. iron overload in cells/tissues and iron deficiency in the blood, rather than from a general lack of iron.