Nature, as we know, manages to offer us the opportunity every day to maintain our state of health and well-being through an almost infinite series of substances that are supplied to us by the mineral, vegetable and animal world.

Lactoferrin is one of them.

Also called lactotransferrin, Lactoferrin is a glycoprotein composed of 703 amino acids, whose main action is to transport iron and at the same time regulate the immune system. It was identified by Sorensen in 1939 inside in cow's milk.

In reality this protein is very abundant especially in colostrum, not only human but of many mammals. In the body, lactoferrin circulates mainly in the blood plasma.

The ability of lactoferrin to bind the ferric ion (Fe3 +) is twice higher than transferrin, the main plasma protein responsible for transporting iron in the bloodstream (both are part of the same family of proteins - called transferrins - capable of binding and transferring ions Fe3 +).

Each lactoferrin molecule can bind two ferric ions to itself and based on this saturation it can exist in three distinct forms: apolactoferrin (iron-free), monoferrin lactoferrin (linked to a single ferric ion) and ololactoferrin (which binds two ions to itself ferrici). The activity of the protein is also maintained in acidic environments and in the presence of proteolytic enzymes, including those secreted by microorganisms.
The ability of lactoferrin to bind iron also suggests its good antioxidant activity. By sequestrating the excess iron, it prevents it from producing the well-known pro-oxidant effects.

As already written, the first milk that a woman produces after childbirth, colostrum, is particularly rich in lactoferrin, which favors the development of good bacteria, helping the newborn to fight the pathogenic bacteria responsible for gastroenteritis and the annoying colic of the newborn. .

Over the weeks, the concentration of lactoferrin in milk decreases, together with the development of the infant's immune defenses.

In addition to milk, saliva, tears and mucous membranes in general, Lactoferrin is a very important constituent of white blood cells, in particular of neutrophil granulocytes, but it is possible that it is also produced by other cells, immune and otherwise.

What is lactoferrin used for in nature?

Antibacterial properties

The antimicrobial properties of lactoferrin are mainly due to the ability to bind iron, removing it from the metabolism of those bacterial species that must use it for their own multiplication and to attach themselves to the intestinal mucosa (bacteriostatic effect). Lactoferrin also has a direct antibacterial action (bactericidal) thanks to the ability to damage the outermost layers of the cell membrane, interacting in particular with the Lipopolysaccharide (LPS) of some GRAM negative bacterial species.
Its ability to bind with Iron, which is one of the fundamental substances for bacterial development, is the basis of the bacteriostatic effect of Lactoferrin (Arnold et al., 1980). The absence of this metal is one of the main causes of bacterial growth inhibition of Escherichia coli (Brock, 1980). The bactericidal effect of Lactoferin was also highlighted for the interaction with the N-terminal receptors for Lactoferrin on the surfaces of many pathogenic microorganisms. The binding of Lactoferrin with these receptor sites is able to induce cell death in Gram negative bacteria, through a structural alteration of the bacterial lipopolysaccharide, which therefore leads to an increase in permeability and greater susceptibility to lysosomal enzymes and antibacterial agents (Arnold et al., 1977; Yamauchi et al., 1993; Leitch and Willcox, 1998; Zemankova et al.; 2017).
The reason why we find Lactoferrin concentrated above all in the mucous membranes is presumably linked to the fact that these tissues are particularly exposed to attack by pathogens and Lactoferrin would serve in these cases to naturally reduce the possibility of microbial development that would have an infection as a result.
During antibiotic therapies, lactoferrin can on the one hand increase the susceptibility of bacteria to drug therapies and on the other hand, in synergy with probiotics, promote the growth of beneficial intestinal bacterial strains (Lactobacillus or Bifidobacterium) which are less dependent on the availability of iron . Obviously, such a therapeutic strategy can be adopted only and exclusively after specific medical advice.
(Molecules. 2020 Dec 8; 25 (24): 5763. Doi: 10.3390. Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens Daniela Zarzosa-Moreno et Al.)

Thanks to its strategic position on the mucosal surface, Lactoferrin therefore represents one of the most important defense mechanisms against intestinal bacteria which attack humans and animals through the intestinal mucosa. Lactoferrin also appears to be involved in the inhibition of growth and the proliferation of a series of pathogens including Gram negative and Gram positive bacteria, Viruses, Protozoa, Fungi (Kirkpatrick et al., 1971) in particular Candida albicans (Viejo-Diaz , 2005).

In vitro, Lactoferrin is able to prevent the formation of the Pseudomonas aeruginosa biofilm. In fact, this bacterium in the absence of iron has poor mobility which results in the impossibility of surface adhesion (Singh et al., 2002).

Lactoferrin for the prevention of post antibiotic diarrhea
In a randomized study (Alison et al., 2011) the use of Lactoferrin in post antibiotic diarrhea (AAD) was evaluated. The study observed a significant reduction in diearea between the treated group and the placebo group, reporting that this glycoprotein may be useful in the prevention of AAD.

Antiviral properties

The antiviral effect of lactoferrin is due to its ability to bind to the glycosaminoglycans of the plasma membrane of cells, preventing the virus from entering and stopping the infection in the bud; this mechanism appeared particularly effective against Herpes Simplex, herpes viruses in general and even HIV. It is also capable of binding itself directly to the virus, effectively preventing it from attacking cells and penetrating them.
(Antiviral Res. 2001 Dec; 52 (3): 225-39. Doi: 10.1016 / s0166-3542 (01) 00195-4. Antiviral activities of lactoferrin BW van der Strate, L Beljaars, G Molema, MC Harmsen, DK Meijer )

Lactoferrin is capable of binding viral DNA and RNA (Yi et al., 1997). A few years ago an in vitro study was conducted on the activity of Lactoferrin against the main pathogenic viruses (Hiroyuki et al., 2014) and a review on the main therapeutic results obtained from the administration of Lactoferrin during infections caused by the most common viruses. Lactoferrin in vitro demonstrates inhibitory activity against a large variety of viruses. The antiviral therapeutic effects of lactoferrin for oral administration in both humans and various animals were also measured. Lactoferrin has shown therapeutic effects against the most common viral infections such as colds, flu, viral gastroenteritis, herpes.

Lactoferrin is also shown to be effective in the fight against certain mycoses, such as Candida for example.
(Odontology. 2015 Jan; 103 (1): 50-5. Effects of bovine lactoferrin to oral Candida albicans and Candida glabrata isolates recovered from the saliva in elderly people Akino Komatsu, Tazuko Satoh, Hiroyuki Wakashi, Fumiaki Ikedabaya)

There is also evidence of a possible role of lactoferrin as an antitumor agent, demonstrated on numerous occasions on chemically induced tumors in laboratory rats.
(Nutr Rev. 2014 Dec; 72 (12): 763-73. Doi: 10.1111 / nure.12155. Anticancer effects of lactoferrin: underlying mechanisms and future trends in cancer therapy Yunlei Zhang, Cristovao F Lima, Ligia R Rodrigues)

Lactoferrin in children

In children, lactoferrin can act as an important source of iron and facilitates intestinal absorption.
Braz J Med Biol Res. 1994 Jul; 27 (7): 1527-31. Iron uptake from lactoferrin by intestinal brush-border membrane vesicles of human neonates. G Rosa, NM Trugo

Iron is the only mineral present in breast milk in smaller quantities than the infant needs. This pseudo-deficiency is filled in every way by the stocks accumulated during fetal life.
Remember that breast milk is undoubtedly the most important food for the newborn, as it guarantees the intake of all nutrients, but above all it contains them in the most appropriate proportions.

Lactoferrin receptors are present on intestinal tissue, immunocompetent cells such as monocytes / macrophages, neutrophil granulocytes, lymphocytes, platelets and some bacteria.

The scientific literature recognizes lactoferrin a wide spectrum of biological activities, all extremely interesting, ranging from the control of the bioavailability of iron to the modulation of the immune system in its antimicrobial, antiviral, antifungal, up to the anti-inflammatory and antioxidant activity.

Lactoferrin and immune defenses

The protective effect of Lactoferrin is manifested through the reduction of the production of pro-inflammatory cytokines or tumor necrosis factors such as TNF-α or interleukins such as IL-1β and IL-6 (Machnicki et al., 1993; Haversen et al., 2002).

Enzymatic activity of lactoferrin

Among its many activities, lactoferrin is able to hydrolyze RNA.
In one of the first scientific papers published in the prestigious journal Nature, entitled "RNase inhibition of reverse transcriptase activity in human milk", it was found that Lactoferrin, the RNase of milk, inhibits the reverse transcription of retroviruses that cause breast cancer (observed first of all in mice).
Nature 1974 Oct 25; 251 (5477): 737-40. doi: 10.1038 / 251737a0. RNase inhibition of reverse transcriptase activity in human milk JJ McCormick, LJ Larson, MA Rich

It has been observed that the female Parsi population (Freddie Mercury belonged to a Parsi family) in Western India, having a reduced quantity of RNase in milk compared to other groups, shows an incidence of breast cancer three times higher than the average.
Nature. 1976 Aug 26; 262 (5571): 802-5. doi: 10.1038 / 262802a0. Human milk samples from different ethnic groups contain RNase that inhibits, and plasma membrane that stimulates, reverse transcription. MR Das, LC Padhy, R Koshy, SM Sirsat, MA Rich

Therefore, milk ribonucleases, and in particular lactoferrin, could play an important role in the pathogenesis mechanism just mentioned.

Bone activity

Lactoferrin has been shown to have positive effects on bone turnover, helping to decrease mineral resorption and increase calcium deposit. This was demonstrated by a decrease in the levels of two bone resorption markers (deoxypyridinoline and N-telopeptide) and by an increase in the levels of two bone formation markers (osteocalcin and alkaline phosphatase).
Osteoporos Int. 2009 Sep; 20 (9): 1603-11. doi: 10.1007 / s00198-009-0839-8. Milk ribonuclease-enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women S Bharadwaj, AGT Naidu, GV Betageri, NV Prasadarao, AS Naidu.

It is also capable of reducing the formation of osteoclasts, which corresponds to a decrease in pro-inflammatory responses and an increase in anti-inflammatory responses. All this results in a reduction in bone resorption.
Inflamm Res. 2010 Nov; 59 (11): 971-8. doi: 10.1007 / s00011-010-0211-7. Inflammatory responses improve with milk ribonuclease-enriched lactoferrin supplementation in postmenopausal women. Satish Bharadwaj, Tezus AG Naidu, Guru V Betageri, Nemani V Prasadarao, A Satyanarayan Naidu

Interaction with nucleic acids

One of the important properties of lactoferrin is its ability to bind with nucleic acids.
The fraction of this protein extracted from milk contains RNA 3,3%, although it binds preferably to double-stranded DNA rather than single-stranded RNA.
Recent studies have attributed to lactoferrin promoting properties on the activity of osteoblasts and chondrocytes, cells respectively responsible for the production of bone and cartilage tissue.
(Endocrinology. 2004 Sep; 145 (9): 4366-74. Doi: 10.1210 / en.2003-1307. Epub 2004 May 27. Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo. Jillian Cornish et Al

Laboratory diagnostics

The concentration of lactoferrin in the faeces can be evaluated to look for the presence of inflammatory bowel diseases such as ulcerative colitis or Crohn's disease. These conditions are often accompanied by an increase in fecal lactoferrin.

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