Lactoferrin is a naturally occurring iron binding glycoprotein with a molecular weight of 80 kDa, which is found in the milk of many mammals including humans and cows, as well as in the saliva, tears and other secretions. In cow milk, the levels of lactoferrin are highest in colostrum (~1.5 g/L) followed by milk (~0.15 g/L). In comparison, lactoferrin levels are much higher in humans – 7 g/L and 1 g/L in colostrum and mature milk respectively.
The lactoferrin protein comprises of two globular lobes. In each lobe, a ferric ion (Fe3+) is bound at the bottom of a deep cleft. At neutral pH the iron is bound extremely tight to the protein; in an acidic environment, the iron is released. There are three forms of lactoferrin according to its iron saturation level: apo-lactoferrin (iron free), a monoferric form (one Fe3+), and holo-lactoferrin (two Fe3+ bound). The ability to bind iron underpins many of lactoferrins functions, and also gives rise to its characteristic pink colour.
Lactoferrin is an important component of the immune system of the body. It is released from certain types of white blood cells at sites of inflammation and has anti-microbial and anti-inflammatory activity.
The history of bovine (cow) lactoferrin dates back to 1939 when a red protein in milk was first reported. However, it was not until the 1960’s that it was fully identified. Since then there have been more than 7,000 research articles listed on Pubmed and 1,500 patents relating to lactoferrin published.
It is an exciting time for lactoferrin with new emerging benefits such as its ability to help reduce acne, prevent iron deficiency in pregnancy, promote the breakdown of fat, supporting bone growth and helping brain and cognitive development. Lactoferrins key actions to explore are:
- Lactoferrin in infant health and nutrition
- Supporting a healthy immune function
- Antibacterial, antiviral and antifungal properties
- Support healthy gut flora and digestive health
- Regulation of iron absorption and metabolism
- Anti-oxidant and anti-inflammatory activity
Emerging research also indicates lactoferrin may even directly support the development of the infants brain and its ability to learn new things6. A recent study has found that lactoferrin may also help infants have softer stooling7. In comparison to human breast milk, cow’s milk has less lactoferrin. Premium infant formulas often supplement their formula with extra lactoferrin in order to get closer to human milk.
Lactoferrin is a highly abundant protein in mother’s breast milk. Lactoferrin quantities are at their peak in early milk and it is at this early stage of infancy where it plays its most important role for the best infant nutrition 1. Lactoferrin helps in the delivery of iron to infants 2 – a mineral that is super important in development of a healthy brain. It is believed to assist the developing infants immune system, as well as help prevent infections3 through its powerful anti-microbial affects, giving young infants a strong defence against disease causing bacteria and viruses4. Emerging research indicates lactoferrin may even directly support the development of the infants brain and its ability to learn new things5.
Lactoferrin supports the infants developing digestive system where it promotes the growth of good bacteria such as the Bifidobacterium, and supports the growth of intestinal cells 6–8. A recent study has found that lactoferrin may also help infants have softer stools9. Lactoferrin has been found to reduce the severity of diarrhoea in children10.
In comparison to human breast milk, cow’s milk has less lactoferrin. Infant formula is often supplemented with extra lactoferrin in order to bring the level closer to human breast milk.
There is considerable evidence for lactoferrin being involved in the stimulation of the immune system11, including enhancing production and/or activation of immune cells, such as lymphocytes and Natural Killer 12,13. Lactoferrins positive charge allows it to bind to negatively charged molecules on the surface of various cells of the immune system14 and it has been suggested that this association can trigger signalling pathways that lead to cellular responses such as activation, differentiation and proliferation.
In adults, Lactoferrin has been found to be effective at reducing the severity and duration of common colds15. Immuno-modulation may also play a critical role in the anti-cancer function of lactoferrin. Oral administration of bovine lactoferrin has been shown to inhibit cancer formation in the colon and other organs in rats and lung metastasis in mice16. Enhanced expression of cytokines, and subsequent activation of immune cells is likely the underlying mechanism.
In addition to inducing systemic immunity, lactoferrin can promote skin immunity and inhibit allergic responses. It induces the immune system against skin allergens, causing migration to the reaction site of specialised immune cells of the skin 17.
Lactoferrin is known to exert a broad-spectrum primary defence activity against bacteria (both gram positive and gram negative), fungi, protozoa and viruses. Lactoferrin is able to sequester iron away from bacteria. Iron is critical to the growth of bacteria, therefore removing it causes growth to slow or stop. This is the basis for lactoferrins bacteriostatic activity 18. Lactoferrin can bind to certain components on the surface of bacterial cells and essentially remove them, which is thought to cause perforation of the bacterial cell wall leading to cell death18.
Lactoferrin acts against the spread of viruses by diverting them from the cells they are targeting. Many viruses tend to bind to the specific proteins of the cell membranes to facilitate entry into the cell. Lactoferrin binds to these proteins, preventing the attachment of the virus particles19. Lactoferrin can also bind directly to viral particles, such as hepatitis. Research has shown promising effects of lactoferrin against a range of viruses including herpes simplex virus 1 and 2, cytomegalovirus, HIV, hepatitis C virus, hantaviruses, rotaviruses, poliovirus type 1, human respiratory syncytial virus and murine leukaemia viruses19. Lactoferrin also reduces virus replication after the virus has penetrated into the cell through its interactions with the immune system – affecting natural killer cells, granulocytes and macrophages, which play a crucial role in the early stages of viral infections.
Lactoferrin has a number of actions that contribute to a healthy digestive system. Lactoferrin has been found to improve gut barrier function and support the growth of intestinal cells 6,20–23, prevent microbial infection that may be linked to Chron’s disease 24 and promote the growth of beneficial bacteria while killing harmful bacteria thus contributing to the development of a healthy microflora environment8,25–27 .
Stomach ulcers can be caused by H. pylori infection. In a number of clinical studies, lactoferrin, either alone or in combination with the standard triple therapy, has been shown to be effective at eradicating H.pylori 28–30
Iron deficiency is the most common nutrient deficiency in the world. Pregnant women and children are the most at risk populations, due to the rapid physiological changes and inadequate nutrient consumption31. Healthy iron levels are necessary for immune, muscle & cognitive function, and iron supplementation is recommended during pregnancy to reduce the risk of preterm labour, pre-eclampsia & low birthweight infants.
Consumption of lactoferrin has been shown to help restore haematological parameters including number of red blood cells, haemoglobin, and total serum iron and serum ferritin concentrations in pregnant and non-pregnant women suffering iron deficiency32–34. In addition, these studies showed that lactoferrin had almost no side effects compared to iron supplements such as ferrous sulphate.
It is thought that the mechanism of this activity is independent of lactoferrins iron content, and actually occurs by lactoferrin modulating serum IL-6, hepcidin and ferroportin levels, thus permitting iron export from tissues to blood and restoring haematological parameters 33.
Lactoferrin has also been shown to improve the absorption and utilization of iron in endurance athletes, and minimise the build-up of blood lactate35 thus supporting athletic performance.
As an iron binding protein, lactoferrin can bind highly reactive free iron that causes oxidative stress. This activity may also contribute to lactoferrins anti-inflammatory activity: By scavenging free iron in inflamed tissue, lactoferrin prevents iron-catalysed free-radical damage at inflamed sites36.
Although the mechanisms are not yet fully understood, lactoferrin can also directly regulate the inflammatory response37. This effect may be due to an inhibition of the production of pro-inflammatory cytokines by lactoferrin binding to molecules that interact with a specific receptor signalling cascade, which is instrumental in the inflammatory response to microbial infection. For example, lactoferrin can bind to bacterial endotoxins38, which are components of certain gut-derived bacteria and are major stimulators of inflammation.
In one study it was found that oral lactoferrin treatment may have an anti-inflammatory effect on pregnant women, reducing pregnancy complications39; peptides (small fragments) derived from lactoferrin during digestion have been found to reduce compounds associated with inflammation in arthritis40 and consumption of lactoferrin has been found to help reduce skin inflammation associated with acne41.
Consumption of lactoferrin has been found to be effective at reducing acne lesions and skin inflammation. In one study, patients 18 to 30 years of age were randomly assigned to ingest fermented milk with 200 mg of lactoferrin daily or fermented milk only (placebo group) in a 12-week, double-blind, placebo-controlled study 41. In the group consuming lactoferrin fermented milk, acne showed improvement by significant decreases in inflammatory lesion count (38.6%), total lesion count (23.1%), and acne grade (20.3%) compared with the placebo group.
In another randomized, double-blind, placebo-controlled trial, 168 subjects aged 13-40 years old took either a capsule containing lactoferrin with vitamin E and zinc, or placebo twice a day for three months 42. At week 10, those taking lactoferrin with vitamin E and zinc showed a significant reduction in total lesions (28.5%), comedones (32.5%) and inflammatory lesions (44%) compared to placebo.
Research has found that lactoferrin might help humans shed body fat. Lactoferrins ability to reduce body fat was first discovered at the cellular level43 where researchers found that lactoferrin can help fight against obesity by inhibiting the accumulation of fat in fat cells and by inhibiting the formation of new fat cells.
Human trials confirm this finding as well. In one study, healthy men and women between 22 and 60 years old took 300 mg of lactoferrin a day for two months. The group taking lactoferrin experienced a 12% reduction in belly fat compared to the group that did not44.
Bone is continually being replaced and maintained in humans, regardless of age. Two different bone cell types are involved in this – osteoclasts, which absorb bone and osteoblasts, which form new bone. At different ages, the activity of these two types of cells differ. In older age, the condition known as osteoporosis is caused when bone resorption is greater than bone formation, resulting in bone loss.
Milk provides nutrition at a time of very rapid skeletal growth and so lactoferrin was researched as potentially having growth effects on bone. Research over the last decade has found that lactoferrin helps support bone growth 45. How it appears to do this is very interesting. Lactoferrin has a double effect – it not only decreases osteoclast activity but also activates osteoblasts to increase bone formation. Currently, these effects have only been tested in animal studies 46–48, however in future we may see these benefits fully tested in humans.
Bega Bionutrients utilises specialised extraction and filtration technology to capture the lactoferrin from the milk before being dried into a powder so that it can be used as an ingredient in a variety of products such as in infant nutritional products, dietary supplements, functional foods, cosmetics and pet products. Click here for more information on Bega Bionutrients lactoferrin [URL LINK: http://begabio.com/product-finder/lactoferrin/]
- Georgieff, M.K, The role or iron in neurodevelopment fetal iron deficiency and the developing hippocampus. Biochem Soc Trans, 2008. 36(Pt 6): p. 1267-71.
- Ke, C., et al, Iron metabolism in infants: influence of bovine lactoferrin from iron-fortified formula. Nutrition, 2015. 31(2):p. 304-9.
- Pammi, M and S.A. Abrams, Oral lactoferrin for the prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev, 2015. 2:p. CD007137.
- Mastromarino, P., et al. Correlation between lactoferrin and beneficial microbiota in breast milk and infant’s feces. Biometals, 2014. 27(5):p. 1077-86
- Oda, H.,et at. Lactoferrin and bifidobacteria. Biometals, 2014. 27(5):p. 915-22
- Chen, Y., et al., Lactoferrin Promotes Early Neurodevelopment and Cognition in Postnatal Piglets by Upregulating the BDNF Signaling Pathway and Polysialylation. Mol Neurobiol, 2015. 52(1): p. 256-69.
- Johnston, W.H., et al., Growth and tolerance of formula with lactoferrin in infants through one year of age: double-blind, randomized, controlled trial. BMC Pediatr, 2015. 15(1): p. 173.
- Ono, T., et al., Potent lipolytic activity of lactoferrin in mature adipocytes. Biosci Biotechnol Biochem, 2013. 77(3): p. 566-71.
- Ono, T., et al., Potent anti-obesity effect of enteric-coated lactoferrin: decrease in visceral fat accumulation in Japanese men and women with abdominal obesity after 8-week administration of enteric-coated lactoferrin tablets. Br J Nutr, 2010. 104(11): p. 1688-95.
- Wu, J., et al., Enteral supplementation of bovine lactoferrin improves gut barrier function in rats after massive bowel resection. Br J Nutr, 2014. 112(4): p. 486-92.
- Queiroz, V.A., A.M. Assis, and R.J.H. C, Protective effect of human lactoferrin in the gastrointestinal tract. Rev Paul Pediatr, 2013. 31(1): p. 90-5.
- Liao, Y., R. Jiang, and B. Lonnerdal, Biochemical and molecular impacts of lactoferrin on small intestinal growth and development during early life. Biochem Cell Biol, 2012. 90(3): p. 476-84.
- Bertuccini, L., et al., Lactoferrin prevents invasion and inflammatory response following E. coli strain LF82 infection in experimental model of Crohn’s disease. Dig Liver Dis, 2014. 46(6): p. 496-504.
- West, N.P., et al., Gut Balance, a synbiotic supplement, increases fecal Lactobacillus paracasei but has little effect on immunity in healthy physically active individuals. Gut Microbes, 2012. 3(3): p. 221-7.
- Legrand, D., Lactoferrin, a key molecule in immune and inflammatory processes. Biochem Cell Biol, 2012. 90(3): p. 252-68.
- Paesano, R., et al., Bovine lactoferrin in preventing preterm delivery associated with sterile inflammation. Biochem Cell Biol, 2012. 90(3): p. 468-75.
- Yan, D., et al., Bovine lactoferricin-induced anti-inflammation is, in part, via up-regulation of interleukin-11 by secondary activation of STAT3 in human articular cartilage. J Biol Chem, 2013. 288(44): p. 31655-69.
- Kim, J., et al., Dietary effect of lactoferrin-enriched fermented milk on skin surface lipid and clinical improvement of acne vulgaris. Nutrition, 2010. 26(9): p. 902-9.
- Vitetta, L., et al., The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: a double blind randomized study. Complement Ther Med, 2013. 21(3): p. 164-71.
- Naot, D., et al., Lactoferrin–a novel bone growth factor. Clin Med Res, 2005. 3(2): p. 93-101.
- Cornish, J., et al., Lactoferrin is a potent regulator of bone cell activity and increases bone formation in vivo. Endocrinology, 2004. 145(9): p. 4366-74.
- Li, W., S. Zhu, and J. Hu, Bone Regeneration Is Promoted by Orally Administered Bovine Lactoferrin in a Rabbit Tibial Distraction Osteogenesis Model. Clin Orthop Relat Res, 2015. 473(7): p. 2383-93.
- Hou, J.M., Y. Xue, and Q.M. Lin, Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway. Acta Pharmacol Sin, 2012. 33(10): p. 1277-84.
- Orsi, N., The antimicrobial activity of lactoferrin: current status and perspectives. Biometals, 2004. 17(3): p. 189-96.
- van der Strate, B.W., et al., Antiviral activities of lactoferrin. Antiviral Res, 2001. 52(3): p. 225-39.