What is Lactoferrin?

Lactoferrin (Lf), previously referred to as lactotransferrin (LTF), has recently come under the spotlight particularly in regards to the COVID-19 worldwide coronavirus pandemic.

Lf is an iron-binding glycoprotein which functions by controlling the free iron in biological fluids. By sequestering iron away, pathogens such as bacteria and viruses which rely on an iron source cannot replicate and cause disease.

Lf belongs to the transferrin protein family, together with serum transferrin (sTf), ovotransferrin (Otrf), melanotransferrin and the inhibitor of carbonic anhydrase, the enzyme that converts carbon dioxide and water to carbonic acid. Lf was first isolated from bovine milk by Sorensen and Sorensen in the late 1930’s.  After much research in the early 1960’s it was determined to be the main iron- binding protein in human milk.

Lf is produced and released by mucosal epithelial cells and neutrophils in various mammals including humans, bovines, goats, horses, dogs and several rodents[1]. The iron-binding properties of Lf give it antibacterial, antimicrobial and an immune modulating activity[2] which is of particular interest to scientists working in immunology and the emergence of new viral and bacterial strains.

Whist human and bovine Lf are not identical, they share a high level of homology or likeness[3].  They both contain a protein which is made up of a single chain containing around 700 amino acids folded into two globular lobes and connected by an alpha helix. It is produced in the mammary gland, as well as in the tear or lacrimal glands, in bronchial membranes, and in the glands that produce saliva[4].

Human colostrum, the first milk produced post-partum, has the highest concentration of Lactoferrin, with levels around 7g/L of Lf followed by mature human milk with levels measured at around 1g/L[5]. One Japanese study measured bovine colostrum across different breads, 24 hours after parturition and found the average Lactoferrin content to be around 2g/L.

Lf plays an extremely important role in these first few days of life sequestering unused iron away from bacteria and viruses, potentially strengthening the infant’s vulnerable immune system.

Diseases or infections in the mammary tissues such as mastitis, (which is a common inflammation of the mammary gland in the breast or udder, typically due to bacterial infection), causes an increase in the production of Lf found in milk, therefore protecting the mother and infant from further infection.

Much research is reinforcing that Lf has important immunological properties, and are helpful as both an antibacterial and antiviral agents. Of particular interest to today’s scientists is the evidence that it can bind to, at least, some of the receptors used by viruses including many coronaviruses and thereby block their entry into the human host. With this capability there is renewed interest in Lf as a supplement to be taken not only to prevent infections but also as part of the therapy in treatment of our modern day viruses[2].

The Antibacterial Functions of lactoferrin

There are two main antibacterial functions of lactoferrin; bacteriostatic and bactericidal. Multiple in vitro and animal studies have shown a protective effect of lactoferrin on infections involving intestinal microorganisms, including rotavirus, Giardia, Shigella, Salmonella and the diarrhoea causing bacteria Escherichia coli. Lactoferrin has two major effects on these enteric pathogens: it inhibits their growth (bacteriostatic) and it impairs the function of virulence factors found on their surface thereby decreasing their ability to adhere or to invade mammalian cells[6]. The latter effect is where the organisms cell wall is compromised often resulting in the death of the bacteria (bactericidal).

It is well known that bacteria utilises the mineral ‘iron’ for its growth and functioning in the human host, however lactoferrin has the ability to sequester or ‘hide away’ free iron therefore removing the essential substance that the bacteria needs to flourish. This is known as bacteriostatsis or the inability of bacteria to multiply or proliferate. Whilst pathogenic or harmful bacterial growth is static, lactoferrin can actually support the growth of certain beneficial bacteria such as Lactobacillus sp. and bifidobacterium sp[7]. In the absence of bioactive compounds such as lactoferrin, most pathogenic bacteria can overcome iron deprivation, acquiring iron by other means from the host’s stores. Therefore bacteriostatsis can often be temporary and the more powerful effect of bactericidal is necessary to stop the invasion of or kill the bacterial strain. This function is completely independent of iron and is directed at the destruction of the bacterial cell wall.

Lactoferrin binds to receptors sites causing the rapid release of substances known as lipopolysaccharides which can have the powerful effect of osmotic shock inducing cell death due to the disruption of the cell wall. Through certain oxidative processes the bacterial membrane permeability is affected resulting in cell breakdown or lysis.

Lactoferrin also prevents the attachment of the bacteria Helicobacter Pylori (H.Pylori) in the stomach, which in turn, aids in reducing digestive system disorders. Bovine Lactoferrin has a more potent effect against H. pylori than human Lactoferrin[8].

Lactoferrin’s Antifungal Nature

With the rise in infections due largely, to increased numbers of immunocompromised or medically vulnerable patients, comes the importance of the discovery of new ‘naturally derived’ agents that can protect and improve the health outcome of the host.

Many yeasts, and fungal strains live harmoniously in the host until the immune system is compromised. Candidiasis is a common fungal infection caused by a yeast (a type of fungus) called Candida. Some species of Candida can cause infection in people; the most common is Candida albicans. Candida normally lives on the skin and inside the body, in places such as the mouth, throat, gut, and vagina, without causing any problems. When infections occur, the body has various defence mechanisms in place to help the host bring the infection under control, otherwise an external treatment maybe warranted.

Lactoferrin, an iron binding glycoprotein found abundantly in mammalian milk has been studied for its various antifungal functions. Positive results have been reported including a wide spectrum of activity across yeasts including Candida Albicans and moulds. Research using Lactoferrin with other antifungal drugs in combination therapy, have been studied also with positive results.  More recent studies now suggest that the main antifungal mechanism of Lactoferrin does not involve iron however, and occurs through a direct interaction with the fungal cell surface[9]

In the early 1970’s, scientists studying the Candida species attributed the antifungal effect of lactoferrin to its ability to sequester or bind iron resulting in a fungistatic effect or the inhibition of the fungal strain to proliferate.  More recent studies now suggest that the main antifungal mechanism of lactoferrin is independent of the iron sequestering effect and occurs through a direct interaction of the glycoprotein with the fungal cell surface, leading to cell membrane damage and leakage[1]. Studies using supernatant protein assays and iodide staining have shown that lactoferrin alters cell surface permeability in Candida. albicans, Candida. krusei, and Cryptococcus neoformans, leading to cell death. Scanning electron microscopy techniques have shown alterations to the fungal cell surface, protein leakage from the cell, swelling and eventual cell collapse. 

Natural products are a significant source of new, effective antimicrobial compounds, and an increasing number are being identified from mammalian sources including human milk and bovine milk proteins. Lactoferrin is effective in its full intact protein state or as one of its smaller derived peptides. The rich source of antimicrobial peptides are produced when cleaved from the polypeptide chain by various proteolytic enzymes.

Lactoferrin and its major naturally cleaved peptide, lactoferricin, have proven broad-spectrum antifungal action, with the smaller peptide exhibiting greater potency than the intact protein. The less well-characterized peptides including Lfampin and Lf(1–11) have also been seen to possess increased antifungal potency in Candida species1

Lactoferrin and its peptides have been shown to function primarily through membrane destabilization and damage to the fungal strain, with immune boosting and iron binding functions playing secondary roles.

Lactoferrin and it’s Antiviral Mechanisms

The most studied mechanism of the antiviral activity of Lactoferrin, is its diversion of virus particles from their target cells. The most powerful activity, demonstrated against both enveloped and naked viruses, lies in the early phase of infection, thus preventing entry of virus into the cell of the host. Lactoferrin has been shown to bind to negatively charged polysaccharide compounds including heparan sulphate glycosaminoglycan cell receptors on the virus particle, thus the virus cannot find the attachment onto the host’s cell wall[10].

Prior to the symptomatic phase, viruses tend to bind to the lipoproteins (fatty molecules) of the cell membranes and then penetrate into the cell where they replicate.  Lactoferrin displays antiviral activity by competing with the virus for these lipoproteins, again diverting the virus away from the host cell and penetration. Lactoferrin has been shown to be effective against both DNA- and RNA-viruses, including rotavirus, a highly contagious virus that can lead to severe diarrhoea in infants and young children, respiratory syncytial virus, herpes viruses and HIV. The antiviral effect of Lactoferrin is most powerful and effective at the start of these infective phases, as it competes with the virus in the host cell, either by blocking cellular receptors, or by direct binding to the virus particles[11].

The strong and extensive antiviral properties of lactoferrin is exciting the scientific community internationally in the wake of the novel Coronavirus strain. It has been hypothesised that lactoferrin may be used as a potential drug for the treatment of COVID-19[12].

Novel coronavirus is the pathogen or organism that causes the disease SARS (severe acute respiratory syndrome).  SARS, discovered in Feb 2003, is highly infective with a high mortality and low cure rate, which make it a major threat to public health. The pathogen is an enveloped, positive-strand RNA virus, composed of spike, envelope, membrane and nucleocapsid protein which attaches to host cells by binding to the glycoprotein heparan sulphate proteoglycans (HSPGs). These glycoproteins are also the binding sites for lactoferrin on the host cells. Studies have shown that lactoferrin can protect the host against a variety of viral infections by preventing the internalization of viruses, such as HSV, and by occupying their binding sites. It has also been demonstrated that HSPGs (binding sites facilitating SARS-CoV entry) are distributed on the host cell surface and, lactoferrin occupies these binding sites to prevent the internalization of SARS-CoV and infection of host cells in the early stages. Therefore, lactoferrin may be useful as a potential therapeutic drug candidate for protecting host cells against SARS-CoV infections[13].

Finally, lactoferrin may be useful in immunomodulation effects in the body.  Lactoferrin administration has been shown to enhance natural killer cell (NK cell) activity and cytokine responses, both very important in the innate immune response or first response in the body leading to protection against viral infections[13].

In conclusion, lactoferrin consumption may protect the host from viral infections through inhibiting the attachment of a virus to the cells, replication of the virus in the cells, and enhancement of systemic immune functions[13].

At what stage of life is Lactoferrin beneficial?

Research is supporting lactoferrin as having a leading role in the development of a strong defence and immune system. From preterm and term neonates’[14] (infants) right through to the elderly and convalescing, lactoferrin as a supplement can play an important role in the health of all people regardless of age.

Preterm and term infants (neonates in their first 4 weeks of life) are breast and/or complementary fed to ensure proper growth and development during this vulnerable time. Human milk contains a wide array of bioactive proteins such as lactoferrin, growth factors, milk secretory cells and stem cells, and other components that help influence the development of a strong immune system to defend the term and preterm newborn against infections. An infant’s increased susceptibility to infection is largely due to the immaturity of their immune system. 

Lactoferrin has emerged as a key player that performs wide-ranging functions to directly and indirectly protect the neonate (infant) against infection[15]. Several small trials have suggested that supplementing the tube fed diet of very preterm infants with lactoferrin, may help to prevent infections and associated complications[16], however more research is essential in this high-risk group to determine correct intakes and optimal schedules to improve morbidity outcomes.

According to recent data from the World Health Organization (WHO), 2.6 million neonates (babies in their first 4 weeks of life) died globally in 2016 alone. Over one third of all deaths of babies occurring in the newborn period were due to infections[13].  The protective effect of breast milk is well known and understood however there is an urgent need for more research to help improve neonatal outcomes around the world.

Meanwhile the adult and elderly population has been dealing with a devastating global pandemic coronavirus infection with over 96 million cases million cases diagnosed and over 2 million deaths[17] (as of 19th January 20201). There is an increasing interest amongst scientists into the possible preventative role and adjunct treatment of lactoferrin[18] in the management of Coronavirus patients.

Lactoferrin is a multifunctional protein involved in many physiological functions, including regulation of iron absorption and immune responses.  It may play a crucial role in the body’s defence against microbial and viral infections and exerting anti-inflammatory effects on various mucosal surfaces. These anti-inflammatory effects help to maintain a strong barrier in the gut mucosa (or lining), making it less permeable to nasty infective microbes. The evidence in lactoferrin as a nutraceutical supplement to improve the health outcomes in all ages of the population is ever increasing.  More research is needed to improve our understanding of the protective role that this versatile milk protein plays in both non-communicable and infectious diseases.

Beta A2 maintain a strong interest in this research and continue to ensure they provide nourishing lactoferrin products to support you and your family through challenging times, at any life stage.

[1] Lactoferrin from Milk: Nutraceutical and Pharmacological Properties. Pharmaceuticals (Basel). 2016 Sep 27;9(4):61. doi: 10.3390/ph9040061

[2] The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Front. Immunol., 28 May 2020

[3] Bovine Lactoferrin, Human Lactoferrin, and Bioactivity. Bhatia, Jatinder. Journal of Pediatric Gastroenterology and Nutrition: December 2011 – Volume 53 – Issue 6 – p 589 doi: 10.1097/MPG.0b013e318233527a

[4] Lactoferrin. Andrew G. Plaut, Joseph St. Geme, in Handbook of Proteolytic Enzymes (Third Edition), 2013. Science Direct.

[5] Concentration of Lactoferrin in Human Milk and Its Variation during Lactation in Different Chinese Populations. Published online 2018 Sep 5. doi: 10.3390/nu10091235

[6] Effect of lactoferrin on enteric pathogens; Theresa J. Ochoa and Thomas G. Cleary.Biochimie. 2009 Jan; 91(1): 30–34.

[7] Ability of lactoferrin to promote the  growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. Petschow B.W.,  Talbott  R.D., Batema  R.P. (1999).  J.  med. Microbiol., 48: 541 – 549.

[8] Bovine lactoferrin is effective to suppress Helicobacter pylori colonization in the human stomach: A randomized, double-blind, placebo-controlled study. Journal of Infection and Chemotherapy. Volume 11, Issue 6, 2005, Pages 265-269

[9] The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Front. Microbiol., 18 January 2017 | Kenya E. Fernandes and Dee A. Carter School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia.

[10] Antiviral properties of lactoferrin – a natural immunity molecule. Berlutti F, Pantanella F, Natalizi T, et al. Molecules. 2011;16(8):6992-7018. Published 2011 Aug 16. doi:10.3390/molecules16086992

[11] Antiviral activities of lactoferrin. Van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. Antiviral Res. 2001 Dec; 52(3):225-39. doi: 10.1016/s0166-3542(01)00195-4. PMID: 11675140.

[12] Lactoferrin for the treatment of COVID‑19 (Review).  Wang Y, Wang P, Wang H, Luo Y, Wan L, Jiang M and Chu Y: Exp Ther Med 20: 272, 2020

[13] Lactoferrin for prevention of common viral infections. Hiroyuki Wakabayashi, Hirotsugu Oda, Koji Yamauchi, Fumiaki Abe. Journal of Infection and Chemotherapy, Volume 20, Issue 11, 2014, Pages 666-671.

[14] Clinical Benefits of Lactoferrin for Infants and Children.  Journal of Pediatrics, Vol 173S

[15] Lactoferrin: A Critical Player in Neonatal Host Defense. Nutrients. 2018 Sep; 10(9): 1228. Published online 2018 Sep 4. doi: 10.3390/nu10091228

[16] Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial. The Lancet Volume 393, ISSUE 10170, P423-433, February 02, 2019

[17] Covid-19 Coronavirus Pandemic. WorldOmeter.

[18] Lactoferrin as Protective Natural Barrier of Respiratory and Intestinal Mucosa against Coronavirus Infection and Inflammation.  International Journal of Molecular Sciences, 2020, 21, 4903; doi:10.3390/ijms21144903  

Special Thanks to Dietitian Kate DiPrima for her contributions to this article.

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