Lactoferrin – a protein with diverse biological properties

Lactoferrin is highly active in combating infections as well as simultaneously strengthening the immune system [1,2]. It attacks disease-causing bacteria [3,4], viruses [5], fungi [6] and parasites [7] via several mechanisms.  It can reduce inflammation [1,2] and allergies, protect the body from oxidative stress, slow down aging processes and help reduce cancer risk [8]. The properties of Lactoferrin have been investigated widely in research studies.

Versatile applications

The applications of Lactoferrin are wide-ranging – not just limited to the regulation of the iron and beneficial effects on the microbiome [9,10]. It also has a very specific regulating effect on the balance of the Th1/Th2 cell activity of the immune system [11].
In addition, Lactoferrin can improve general wound healing and regeneration, and regulate oxidative status in the human body [12].

Bovine (bLF) und human (hLF) Lactoferrin

Generally speaking, Lactoferrin is usually referred to without making a concrete distinction between bovine and human Lactoferrin (hLF).  Human lactoferrin is a single polypeptide chain consisting of 691 amino acids, whereas bovine Lactoferrin is composed of 689 amino acids. 

Lactoferrin in oral administration

Lactoferricin is a key molecule for binding of Lactoferrin to cells and affects how it works. The structures of this key peptide are almost identical in human Lactoferrin and cow’s milk Lactoferrin (bovine Lactoferrin). Lactoferrin from cow’s milk can bind to the same receptors and cells as human Lactoferrin [13], and is preferred for use as a supplement. There have been no reports of adverse reactions in the countless studies on Lactoferrin. 

The biological properties of Lactoferrin – at a glance 

  • Iron-regulating properties
  • Immune modulating properties
  • Anti-inflammatory properties
  • Antimicrobial properties
  • Probiotic properties
  • Antioxidant properties
  • Cell proliferative (cell regenerating/building) properties
  • Anticancer (anti-cancer/preventive) properties
  • Metabolism regulating properties

Iron regulating properties 

A major function of Lactoferrin is the ability to regulate iron. Lactoferrin has been shown to be a safer and more effective for the treatment of iron deficiency than the pure supplementation of iron [14].
Iron is a vital element for humans. It is forms part of the red pigment in blood cells – haemoglobin. It’s not just about the providing colour, it is essential for the function of haemoglobin, namely the transport of oxygen into our tissues. Iron also has an important role to play in detoxification.
Lactoferrin ensures that the correct concentration of free iron is maintained.  This prevents iron deficiency, free radical release and microbial colonisation [15,16].
Lactoferrin is not only a suitable iron source, but also performs significant anti-inflammatory and immune-regulating functions. 
Cytokines released in chronic inflammation, such as Interleukin 6 (IL-6), causing an increase in hepcidin.  This can reduce how much iron goes into circulation. With a chronically activated immune system, the effect can be iron deficiency. IL-6 is reduced by Lactoferrin, resulting in regulation of iron distribution [17].

Immune modulation properties 

Lactoferrin is enormously potent, but is not a lone wolf.  It interacts with various white blood cells. These cells specialise in the defence against pathogens, and regulate both the innate and the acquired immune response (= reaction of the immune system to either foreign, or previously encountered, organisms or substances). Lactoferrin directs the appropriate interaction of immune cells along with other signalling molecules. 
Lactoferrin has the interesting ability to regulate the maturation and differentiation of the various T-helper cells.  It can help restore equilibrium within the immune system [11].
This property can also have a regulating effect on allergies, since Lactoferrin can inhibit the production of histamine, an important signal molecule in allergic reactions.
Lactoferrin can either activate or weaken almost all the main components of the immune system through various mechanisms. 
Maturation and migration of immune cells can be regulated, as well as the formation of messenger molecules through which the cells communicate with each other [18,19].  Lactoferrin supports the process where immune cells attach themselves to pathogens, attacking them and rendering them harmless [20]. Substances, which in turn activate immune cells, can also be regulated by Lactoferrin [19]. It also stimulates the tumour-damaging (cytotoxic) activity of natural killer cells, an important target in cancer therapy [21].
Through these interactions, it is able to influence both adaptive and innate components [18,22] as well as strengthen them [23]. It can also modulate the release of anti-inflammatory signalling substances (cytokines) [17,24].

Anti-inflammatory properties 

Lactoferrin shows strong anti-inflammatory and protective functionality.  It does this via antimicrobial action, and also the ability to inhibit inflammatory cytokines (tumour necrosis factor alpha, interleukin-1β and interleukin-6) [25]. 
The aim is to limit inflammation processes, in order to minimise tissue damage and prevent systemic inflammation, from affecting different regions of the body. 

Antimicrobial properties 

Microorganisms (bacteria, viruses, fungi, parasites) have been a constant threat during the evolution of Homo sapiens – and still are today.
Our immune system is forced to constantly learn and develop, and the assailants and their strategies keep changing.  Although humans have the most differentiated immune system of all mammals, a small virus – as shown impressively during the coronavirus pandemic – can become a real threat.

Lactoferrin and viruses 

Lactoferrin can block the receptors that use viruses to navigate the human body, thus inhibiting their spread. The effectiveness of Lactoferrin in the fight against viruses is particularly noteworthy because no other endogenous substance has such presence at the entry portals to the body.
Viruses infect our cells by inserting their own genetic material (either in the form of RNA or DNA) into human cells and thereby „reprogramming“ them. 
Lactoferrin can degrade viral RNA and DNA and thus prevent them from causing damage in the cell. It can also block the binding of viruses to human host cells.  Lactoferrin can also bind directly to viruses and damage them. 
Lactoferrin acts in the acute phase of infection, inhibiting the virus penetrating the cell, as well as when the virus has already entered the cell [13]. 

Lactoferrin and bacteria

Our quality of life depends heavily on whether we can absorb adequate amounts of iron. This applies not only to us humans, but to virtually all living beings, including pathogenic bacteria.  Many of them have even developed special strategies to absorb enough iron. For example, the well-known gut bug E. coli simply produces its own iron-binding substance.
Due to its iron-binding effect, Lactoferrin deprives the bacteria of iron and – even if there are enough other nutrients – causes it to „starve.“
In addition to this iron-binding effect, Lactoferrin has the ability to cleave amino acid chains (proteins). In this sense it is a „protease“. Many bacteria and viruses use proteins to dock onto and infect the human cells. Lactoferrin destroys the „anchor proteins,“ leaving the pathogens to float helplessly.
Lactoferrin can also bind directly to the cell membrane of bacteria and destroy them. For the bacterial cell, this a deadly process, because without its membrane, it „leaks“ and key cell components are lost.

Anti-biofilm activity of lactoferrin 

The protease activity is probably also the reason why Lactoferrin is able to destroy biofilms.  Biofilms are formed by various bacteria to protect them against external influences such as dehydration. They are also a kind of home-made defence against other bacteria. For example, dental plaque is a biofilm made by specific oral bacteria. 
Something that is capable of dissolving a biofilm is highly desirable in medical terms. It has been shown that biofilms play a role in almost every disease.  Examples include: cancer [26], back pain [27], Alzheimer’s disease [28], asthma [29], rheumatoid arthritis [30,31].

Lactoferrin and fungi/parasites 

Besides bacteria and viruses, there are other pathogens, such as fungi and parasites. These infections are less common than viral or bacterial diseases, but they can also be dangerous. The antifungal effect of Lactoferrin has been demonstrated against the fungus Candida albicans, which can cause infections in the oral and genital regions. Even fungal strains that had become resistant to conventional agents could be successfully combated with Lactoferrin.
Lactoferrin inhibits and kills parasites and fungi in various ways. The most common, as in the case of Candida or Entamoeba histolytica, is via damage to their cell membranes [32,33]. Lactoferrin can also inhibit intracellular growth [34].

Probiotic properties 

Research shows more and more, that humans are not only hosts for a wide variety of microorganisms, but that the microbiome represents an integral part of the individual – a complete „whole“.
Many scientists now work from the assumption that a disturbed relationship between one’s microbial „friends“ and potential pathogens, is a major cause of multiple diseases.
Scientific studies have shown that Lactoferrin, as part of the innate immune system, can reduce potentially pathogenic fungi, viruses and bacteria.  It does not attack symbiotic bacteria, instead can promote their growth [10]. This ability is probably the result of a long-standing evolutionary learning process. 
It has been observed that Lactoferrin increases the growth rate (40-200%) of beneficial bacteria (such as Bifidobacterium bifidum, B. longum, B. lactis, B. infantis, Lactobacillus reuteri, L. rhamnosus and L. coryniformis) [10,31]. 

Antioxidant properties 

Antioxidants are considered important, health-promoting micronutrients. Free radicals are formed in all oxygen-breathing organisms as part of „normal“ metabolic processes. They can damage components of our cells and body, thus leading to premature aging [35]. Physical demand, exercise and stress, can also give rise to free radicals. Antioxidants are compounds that neutralize these reactive molecules and prevent them from causing harm. 
Oxidative stress and free radical damage play an important role in almost all disease. 
In numerous diseases, it is the same final reaction that ultimately leads to tissue damage. This is the Haber-Weiss reaction, in which the relatively harmless oxygen products, superoxide and hydrogen peroxide are converted into the highly aggressive hydroxyl radical.
Lactoferrin is a potent antioxidant in several respects. It works indirectly by binding certain messenger substances, thereby preventing an unnecessary antibacterial response from immune cells, which is a significant source of free radicals. It also acts via binding the iron that originates from cell destruction, or the overproduction of activated immune cells [36].

Cell regenerating and cell building properties 

If wound healing does not progress properly, Lactoferrin can help to stimulate the healing process. One outstanding capability is in cell proliferation, the ability to stimulate the regeneration and formation of cells. These are important repair processes, which can benefit, for example, diabetes patients with non-closing wounds.
Fibroblasts and keratinocytes, cells involved in wound healing, are recruited via specific cytokines [37]. Studies show that the process of healing sores in mucous membranes, like the oral mucosa, concluded faster when treated with Lactoferrin [38].  Patients with bone necrosis treated with Lactoferrin also benefited from significantly faster wound healing [39].

Anticancer properties 

Lactoferrin shows a suppressive effect in the development of cancer [40].  This effect may be due to Lactoferrin blocking certain endogenous enzymes involved in cancer development. Here, too, the iron-binding abilities of Lactoferrin may be important. 
A tumour requires iron in order to multiply the tumour cells.  The tumour can „claim“ iron for itself, and interfere with normal iron metabolism (via activation of hypoxia-inducible factor/HIF) [41].
Lactoferrin’s ability to bind iron can thereby inhibit growth and proliferation of tumour cells, not just microorganisms. 
It shows high selectivity for cancer cells, and there is a wide range of potential therapeutic targets – proliferation, survival, migration, invasion and metastasis. 
Important factors necessary for tumour formation can be inhibited (Vascular Endothelial Growth Factor/VEGF) [42] and the formation of tumour cells can be actively suppressed [43]. 
Studies have repeatedly shown that Lactoferrin can attack cancer cells directly. It can also distinguish them from normal cells, which it does not attack [44].
Lactoferrin can prevent development of cancer, or inhibit cancer growth, by enhancing the adaptive immune response [45]. Lactoferrin can significantly increase the anti-tumour activity (cytotoxicity) of natural killer cells that destroy cancer cells [46,47]. Also worth mentioning is the activating effect on other important immune cells in the fight against cancer (neutrophil granulocytes, lymphocyte-activated killer cells and macrophages) [48].
Finally, Lactoferrin was recently found to be an ideal carrier for chemotherapeutics, even in the treatment of brain tumours, due to its ability to cross the blood-brain barrier. Thus, it appears a promising tool for cancer prevention and treatment, especially in combination therapies [45].

Metabolic regulatory properties 

Lactoferrin can make a positive impact on human fat metabolism. 
Studies have shown that the Lactoferrin is capable of effectively preventing elevated blood levels of homocysteine and leptin, substances involved in fat metabolism. It has the potential to be used as a therapeutic agent in fat metabolism disorders and arteriosclerosis.
Lactoferrin has been shown to reduce the amount of visceral fat („belly fat“) by promoting fat cleavage and breakdown (lipolysis) and general anti-adipogenic activity [49], along with an effect on the behaviour of insulin [50].