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Lactoferrin—an Iron-Binding Glycoprotein on First-Line Defense in the Innate Immune System

by Noelle Patno, PhD

What is lactoferrin?

Lactoferrin is an iron-binding glycoprotein found in most body fluids (including saliva, tears, bile, small intestine secretions, vaginal secretions, and more) and highly similar across species. First identified in bovine milk in 1939, it was later isolated from human milk in 1960 and other fluids as well as blood plasma (specifically, the immune cells called neutrophils). The highest concentration may be found in human colostrum at 8 mg/mL with breast milk levels at 1.5-5 mg/mL.1

What does lactoferrin do?

While lactoferrin is one of the iron-binding proteins and cooperates with others in iron metabolism2 activities, which are necessary for producing energy, transporting/storing oxygen, and detoxifying from drugs,3 lactoferrin plays a major defense role that does not necessarily depend on its iron-binding function.1 Under normal circumstances, plasma levels of lactoferrin are low. Exercise has been shown to induce lactoferrin secretion in the blood,4 saliva,5,6 and immune cells (salivary granulocytes).7 During inflammation, infection, excessive intake of iron, or tumor growth, lactoferrin levels increase in the blood. As a biomarker of disease, fecal lactoferrin was demonstrated in a meta-analysis to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).8 Lactoferrin may also be a biomarker in tears for dry eye syndrome.9 Since neutrophils store lactoferrin, they can release lactoferrin during immune defense to bind to iron, bacteria, or host surfaces. Mucosal epithelial cells and many immune cells have receptors for lactoferrin. Residing on the mucosal surface of a cell allows lactoferrin to act in a first-line defense strategy as part of the innate immune system.10

More than 70 years of research on this glycoprotein have explored its antimicrobial, antiviral, anti-inflammatory, immunomodulatory, and antitumorigenic effects, and all these functions may be dependent or independent of lactoferrin’s ability to bind iron.1

Antiviral activity

Lactoferrin may attach to viruses or block viruses from attaching to receptors on the host cells.11 The list of pathogenic viruses that lactoferrin inhibits in vitro includes the following: herpes simplex virus, hepatitis B virus, hepatitis C virus (HCV), alphavirus, adenovirus, avian flu, enterovirus 71, echovirus 6, Japanese encephalitis virus, respiratory syncytial virus, influenza A virus, parainfluenza virus, cytomegalovirus, poliovirus, rotavirus, and human immunodeficiency virus (HIV), with clinical evidence for enterovirus 71, HCV, norovirus, and rotavirus.12

Lactoferrin can bind to receptors on host cells, including the following cell surface receptors:

  • Heparan sulfate proteoglycans (HSPGs) or heparan sulfate (HS)
  • Glycosaminoglycans (GAGs)
  • LDL receptor

Its behavior by binding to these receptors has demonstrated inhibition to several of the viruses listed above.13

Immunomodulatory behavior

Some examples of lactoferrin’s defense role include its activity in airways, mucosal surfaces, skin affected by allergies, salivary biomarker, vaginal defense protein, and immunological protection for newborns.11 The literature also includes contradicting evidence of lactoferrin’s effects on inflammation in different in vitro cell models, which resulted in a later analysis showing that different experimental conditions (different cell types or pathogens or different sources of lactoferrin) caused variability in the results.1 Some of the more interesting results include the following:

  • Bovine lactoferrin decreasing cytokines such as IL-1Beta, IL-6, IL-8, NF-kB1
  • This decrease in IL-6 activity was later confirmed in multiple studies on anemic pregnant and nonpregnant women1,14

Lactoferrin specifically influences certain immune cells impacted through mechanisms that include maturation of B and T cells, induction of immunoglobulins IgA and IgG, proliferating T-cells, promoting the phagocytic activity of macrophages, and dampening monocytes’ activation of NFkB.15 Lactoferrin also can block the release of histamine from human colonic mast cells,16 which may also be beneficial for allergies. Relatedly, these in vitro effects of inhibiting mast cell tryptase was applied to an in vivo case, showing that lactoferrin supplementation supported respiratory health in allergic sheep.

Antibacterial, antifungal evidence and applications17

Lactoferrin prevents bacterial, viral, and fungal/pathogenic adhesion, invasion, and colonization and is considered an antibiofilm therapeutic agent.18 Binding to iron allows lactoferrin to prevent bacteria from using that iron for growth and proliferation, which contributes to lactoferrin’s antibacterial properties. Lactoferrin’s attachment to iron inhibits bacteria dependent on iron (such as E. coli) from growing, while it may donate iron to lower iron-requiring beneficial bacteria (Lactobacillus or Bifidobacterium spp.). By binding iron, lactoferrin also prevents the iron from initiating reactive oxygen species.1,10 Excessive iron in the blood, on the other hand, is a risk for lethal infections by bacteria; it is important for lactoferrin and other iron-binding proteins to scavenge the iron.2

Additional specific mechanisms include the following:

  • Preventing pathogenic bacteria from adhering and forming biofilms on host cells, sometimes through binding to the bacterial surfaces or the host cells’ glycosaminoglycans (including heparan sulfate)1
  • Binding to bacterial surfaces (LPS) that trigger cell-death in those bacteria and through degradation of proteins that bacteria such as Shigella flexneri or enteropathogenic E. coli use to colonize and form biofilms10
  • Disrupting lectin-dependent adhesion of Pseudomonas aeruginosa or stimulating the bacteria to move, with the ability to permeate or proteolytically degrade the biofilm, studies show in vitro18
  • Reduce biofilms of periodontal pathogens in vitro, Porphyromonas gingivalis and Prevotella intermedia19
  • Severe, refractory oral candidiasis resolved by mouthwash containing bovine lactoferrin and lysozyme in a case report20
  • Pilot study, randomized, double-blind, crossover design, using a mouthwash containing lactoferrin, lysozyme, and lactoperoxidase21
  • In vitro activity against Staphylococcus (including MRSA), Streptococcus mitis, Acinetobacter baumanii, pseudomonas spp., Klebsiella spp., and E. coli, Candida22

Clinical research supporting the therapeutic use of lactoferrin

Supplementation with human or bovine lactoferrin have been used experimentally to aid in vulnerable populations such as infants and pregnant women in addition to healthy or infected patients. Bovine lactoferrin has been shown in clinical trials as described below.

A review23 listed studies in critically ill and very low birth weight newborn babies (unless otherwise indicated) that showed that bovine lactoferrin supplementation:

  • Reduced incidence of lower respiratory tract illnesses (healthy babies)
  • Reduced infection-related mortality
  • Reduced the incidence of stage 2 or greater necrotizing enterocolitis and death
  • Decreased episodes of sepsis

A review24 described that other clinical trials (adults unless otherwise specified) showed that bovine lactoferrin supplementation:

  • Inhibited Helicobacter pylori colonization
  • Inhibited hepatic inflammation in patients with chronic hepatitis C
  • Decreased oxidative stress and inflammation in chronic hepatitis C virus patients who did not respond to antiviral therapy
  • Decreased visceral fat and total adiposity accumulation in subjects with obesity
  • Increased iron absorption in female long-distance runners
  • Increased iron absorption in infants
  • Increased iron nutritional status in anemic pregnant women
  • Decreased serum IL-6 and improved iron levels in women

A meta-analysis found that oral lactoferrin performed better than oral ferrous sulphate in daily supplementation for four weeks at improving hemoglobin with significantly fewer gastrointestinal side effects.25

Finally, lactoferrin has demonstrated its immune effects for the common cold. A double blind, randomized placebo controlled clinical trial demonstrated that 600 mg of bovine lactoferrin/immunoglobulin-rich whey protein combination for 90 days resulted in a significantly lower number of total colds in the treatment group vs. the placebo group, and the total number of symptoms associated with the cold were also significantly lower with the treatment.26 Supporting evidence comes from a study which demonstrated that a supplement also containing lactoferrin decreased symptoms associated with the cold and gastroenteritis according to the English abstract of an article in Japanese.27

Summary

The potential benefit for lactoferrin to protect infants to adults with immune development and basic defense systems as well as iron absorption and counterinflammatory mechanisms make it an attractive therapeutic for multiple applications. As part of the body’s natural defense mechanisms, elevated lactoferrin is a biomarker for IBS when in feces and through blood or tears may indicate other diseases. Therapeutic applications of lactoferrin include oral health, skin health particularly for wound healing, allergies, lung health, iron metabolism, vaginal health, newborn health, gastrointestinal health, respiratory health, and overall immune health.

Citations

  1. Rosa L et al. Lactoferrin: a natural glycoprotein involved in iron and inflammatory homeostasis. Int J Mol Sci. 2017;18(9).
  2. Ganz T. Iron and infection. Int J Hematol. 2018;107(1):7-15.
  3. Lepanto MS et al. Lactoferrin in aseptic and septic inflammation. Molecules. 2019;24(7).
  4. Inoue H et al. Blood lactoferrin release induced by running exercise in normal volunteers: antibacterial activity. Clinica Chimica Acta. 2004;341(1):165-172.
  5. Gillum TL et al. Exercise, but not acute sleep loss, increases salivary antimicrobial protein secretion. J Strength Cond Res. 2015;29(5):1359–1366.
  6. Gillum T et al. The effects of exercise, sex, and menstrual phase on salivary antimicrobial proteins. Published online 2014:16.
  7. Gillum T et al. Exercise increases lactoferrin, but decreases lysozyme in salivary granulocytes. Eur J Appl Physiol. 2017;117(5):1047-1051.
  8. Zhou X et al. Fecal lactoferrin in discriminating inflammatory bowel disease from irritable bowel syndrome: a diagnostic meta-analysis. BMC Gastroenterol. 2014;14:121.
  9. Ponzini E et al. Lactoferrin concentration in human tears and ocular diseases: a meta-analysis. Invest Ophthalmol Vis Sci. 2020;61(12):9.
  10. Adlerova L et al. Lactoferrin: a review. Veterinarni Medicina. 2008;53(9):457-468.
  11. Kell DB et al. The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria. Front Immunol. 2020;11.
  12. Chang R et al. Lactoferrin as potential preventative and adjunct treatment for COVID-19. Int J Antimicrob Agents. 2020;56(3):106118.
  13. Berlutti F et al. Antiviral properties of lactoferrin–a natural immunity molecule. Molecules. 2011;16(8):6992-7018.
  14. Lepanto MS et al. Efficacy of lactoferrin oral administration in the treatment of anemia and anemia of inflammation in pregnant and non-pregnant women: an interventional study. Front Immunol. 2018;9.
  15. Siqueiros-Cendón T et al. Immunomodulatory effects of lactoferrin. Acta Pharmacol Sin. 2014;35(5):557-566.
  16. He S-H et al. Modulation of histamine release from human colon mast cells by protease inhibitors. World J Gastroenterol. 2004;10(3):337-341.
  17. Bruni N et al. Antimicrobial activity of lactoferrin-related peptides and applications in human and veterinary medicine. Molecules. 2016;21(6).
  18. Ammons MC et al. Lactoferrin: A bioinspired, anti-biofilm therapeutic. Biofouling. 2013;29(4):443.
  19. Wakabayashi H et al. Inhibitory effects of lactoferrin on growth and biofilm formation of Porphyromonas gingivalis and Prevotella intermedia. Antimicrob Agents Chemother. 2009;53(8):3308-3316.
  20. Masci JR. Complete response of severe, refractory oral candidiasis to mouthwash containing lactoferrin and lysozyme. AIDS. 2000;14(15):2403–2404.
  21. Gil-Montoya JA et al. Evaluation of the clinical efficacy of a mouthwash and oral gel containing the antimicrobial proteins lactoperoxidase, lysozyme and lactoferrin in elderly patients with dry mouth–a pilot study. Gerodontology. 2008;25(1):3-9.
  22. Brouwer CPJM et al. Discovery and development of a synthetic peptide derived from lactoferrin for clinical use. Peptides. 2011;32(9):1953-1963.
  23. Telang S. Lactoferrin: a critical player in neonatal host defense. Nutrients. 2018;10(9).
  24. Superti F. Lactoferrin from bovine milk: a protective companion for life. Nutrients. 2020;12(9).
  25. Hashim HA et al. Lactoferrin or ferrous salts for iron deficiency anemia in pregnancy: A meta-analysis of randomized trials. Eur J Obstet and Gynecol Reprod Biol. 2017;219:45-52.
  26. 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. Complem Ther Med. 2013;21(3):164-171.
  27. Oda H et al. Questionnaire survey on the subjective effects of a lactoferrin supplement. Jpn J Complem Altern Med. 2012;9(2):121-128.

 

Noelle Patno, PhD is the Nutrition Scientist for Digestive Health at Metagenics. Dr. Patno received her PhD in Molecular Metabolism and Nutrition and Masters in Translational Science from the University of Chicago, studying the role of microbial components in intestinal epithelial cell survival related to inflammatory bowel disease. Prior to her graduate studies, Dr. Patno received a chemical engineering degree from Stanford University and worked as an engineer. She has personal experience and interest in preventive nutrition and nutritional therapies for chronic disease, and her current role involves researching and developing probiotics, prebiotics, and other nutritional programs for the promotion of digestive and overall health.

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