Lactoferrin is able to bind iron and regulate the iron balance in the body. Through this ability, Lactoferrin can reduce inflammation and support the immune system by depriving microorganisms of something essential for their growth. 

Specifically, Lactoferrin helps ensure that the correct concentration of free iron is maintained in human fluids. This prevents iron deficiency, release of free radicals and microbial colonisation [1-4].

In 2017, Rosa et al. published an interesting overview article about the modes of action in iron homeostasis [5].

Iron is an essential element for cell growth and proliferation, and essential for DNA replication and energy production. However, it can also have a toxic effect on the body if it is present in excess. Then the delivery of electrons to oxygen can result in the creation of free radicals [6]. These can cause tissue injury and organ damage [7].

Under normal circumstances, there is so little free iron in the body that there is no risk of free radicals forming, inflammatory processes arising or microorganisms using iron for reproduction [8,9]. However, if the balance is disturbed and too much free iron is available, the risk of infection and the formation of free radicals increases, as well as the development of inflammation [9].

The equilibrium between the iron present in the blood and that present in tissue is called iron homeostasis. This is strictly controlled by various mechanisms to prevent iron deficiency and excess iron.

Ferroportin , a transmembrane portein that transports divalent iron ions (Fe2+) from the cell interior into the extracellular space, plays an important role here. In the case of an inflammatory reaction or infection, ferroportin is down-regulated. This is caused by the proinflammatory cytokine interleukin-6 (IL-6) [10,11] and by binding ferroportin to hepcidin, a protein from the liver. Thus the iron remains in the cell.

As a result, there is an iron overload at the cellular level, while at the systemic level, iron deficiency, iron deficiency anaemia and anaemia of inflammation may occur [4,12].

The usual intervention in iron deficiency consists of iron supplementation, based on the assumption that this should increase the haematological parameters again. However, iron homeostasis often cannot be restored in this way, because of undesirable gastrointestinal side-effects during therapy, such as nausea, vomitting, diarrhoea and constipation [7,13-16].

Studies in rats showed increased production of free radicals [8] and severe progression of inflammatory status in the intestine after administration of an iron rich diet [9].

In the case of anaemia of inflammation, the most severe iron homeostasis disorder, the great difficulty of the therapy lies in the high IL-6 levels, with which it is associated [17]. For a long time it has been assumed that the reduction of iron availability in the blood is a defence mechanism against extracellular pathogens [17-19]. However, Rosa et al recommend rethinking classical therapy.  There are bacteria that can penetrate the cell and cause inflammation within. These could benefit from the iron overload within the cell and cause an even stronger reaction [20,21].

It is therefore of the utmost importance to counteract the persistence of the inflammatory state,

to balance iron levels between tissues/secretions and blood, thereby avoiding intracellular iron accumulation, and thus reducing the severity of the infection.

Lactoferrin has a molecular structure that offers various binding possibilities for cells, pathogens, iron and other substances. It belongs to the group of the transferrins and is able to pick up, distribute and dispense tri-valent iron.

During infection and/or inflammation processes, the concentration of Lactoferrin in the body increases, as it is produced and released by immune cells (neutrophil granulocytes).   This ensures that the freely available iron does not become too high, thus preventing microbial growth and the formation of free radicals. In infected/inflamed host cells, Lactoferrin also exerts an anti-inflammatory effect against interleukin-6 (IL-6) which again prevents intracellular iron overload.

At the same time, lactoferrin shows bacteriostatic activity, because the binding of iron also strongly inhibits bacterial growth and the expression of virulence factors [22,23].

With regard to anaemia of inflammation and the clinical effect of Lactoferrin, a 2006 study in pregnant women [13], showed oral administration of Lactoferrin in combination with iron demonstrated an increase in haematological parameters after 30 days.

Lactoferrin shows great anti-inflammatory potential in its ability to modulate the inflammatory response regardless of whether it is caused by intracellular bacteria [21,24-26] or triggered via toll-like receptors on the surface of the immune cells [27,28].

Lactoferrin therefore appears to be a key element, not only in the defence system against microorganisms [2,29,30], but also as a central component in inhibiting an inflammatory reaction [31].

The fact that the administration of iron in anaemia of inflammation does not reduce inflammatory processes is not surprising, because iron is itself an amplifier of inflammation [32-34].  From this viewpoint, the authors of the review article mentioned before describe the new approach of treating anaemia of inflammation with lactoferrin instead, as an extremely significant innovation.

They underline in their approach that, in vivo, the anaemia of inflammation state arises from the delocalisation of iron, i.e. iron overload in cells/tissues and iron deficiency in the blood, rather than from a general lack of iron.


1        Bullen JJ, Rogers HJ, Spalding PB, Ward CG. Iron and infection: the heart of the matter. FEMS immunology and medical microbiology 2005; 43: 325–330.

2        Valenti P, Antonini G. Lactoferrin: an important host defence against microbial and viral attack. Cellular and molecular life sciences : CMLS 2005; 62: 2576–2587.

3        Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proceedings of the National Academy of Sciences of the United States of America 2005; 102: 1906–1910.

4        Andrews NC. Iron metabolism: iron deficiency and iron overload. Annual review of genomics and human genetics 2000; 1: 75–98.

5        Rosa L, Cutone A, Lepanto MS, Paesano R, Valenti P. Lactoferrin: A Natural Glycoprotein Involved in Iron and Inflammatory Homeostasis. International Journal of Molecular Sciences 2017; 18.

6        Andrews NC. Disorders of iron metabolism. The New England journal of medicine 1999; 341: 1986–1995.

7        Zaim M, Piselli L, Fioravanti P, Kanony-Truc C. Efficacy and tolerability of a prolonged release ferrous sulphate formulation in iron deficiency anaemia: a non-inferiority controlled trial. European journal of nutrition 2012; 51.

8        Kadiiska MB, Burkitt MJ, Xiang QH, Mason RP. Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation. Journal of Clinical Investigation 1995; 96: 1653–1657.

9        Reifen R, Matas Z, Zeidel L, Berkovitch Z, Bujanover Y. Iron supplementation may aggravate inflammatory status of colitis in a rat model. Digestive diseases and sciences 2000; 45.

10     Cutone A, Frioni A, Berlutti F, Valenti P, Musci G, Di Bonaccorsi Patti MC. Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014; 27: 807–813.

11     Cutone A, Rosa L, Lepanto MS, Scotti MJ, Berlutti F, Di Bonaccorsi Patti MC, Musci G, Valenti P. Lactoferrin Efficiently Counteracts the Inflammation-Induced Changes of the Iron Homeostasis System in Macrophages. Frontiers in immunology 2017; 8: 705.

12     Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells, Molecules, and Diseases 2003; 30: 288–297.

13     Paesano R, Torcia F, Berlutti F, Pacifici E, Ebano V, Moscarini M, Valenti P. Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women. Biochemistry and cell biology = Biochimie et biologie cellulaire 2006; 84: 377–380.

14     Palacios S. The management of iron deficiency in menometrorrhagia. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 2011; 27 Suppl 1: 1126–1130.

15     Rizvi S, Schoen RE. Supplementation with oral vs. intravenous iron for anemia with IBD or gastrointestinal bleeding: is oral iron getting a bad rap? The American journal of gastroenterology 2011; 106: 1872–1879.

16     Ortiz R, Toblli JE, Romero JD, Monterrosa B, Frer C, Macagno E, Breymann C. Efficacy and safety of oral iron(III) polymaltose complex versus ferrous sulfate in pregnant women with iron-deficiency anemia: a multicenter, randomized, controlled study. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 2011; 24: 1347–1352.

17     De Domenico I, McVey WD, Kaplan J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nature reviews. Molecular cell biology 2008; 9.

18     Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annual review of nutrition 2006; 26: 323–342.

19     Mackenzie EL, Iwasaki K, Tsuji Y. Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications. Antioxidants & Redox Signaling 2008; 10: 997–1030.

20     Ajello M, Greco R, Giansanti F, Massucci MT, Antonini G, Valenti P. Anti-invasive activity of bovine lactoferrin towards group A streptococci. Biochemistry and cell biology = Biochimie et biologie cellulaire 2002; 80.

21     Sessa R, Di Pietro M, Filardo S, Bressan A, Rosa L, Cutone A, Frioni A, Berlutti F, Paesano R, Valenti P. Effect of bovine lactoferrin on Chlamydia trachomatis infection and inflammation. Biochemistry and cell biology = Biochimie et biologie cellulaire 2017; 95: 34–40.

22     Weinberg ED. Iron availability and infection. Biochimica et biophysica acta 2009; 1790: 600–605.

23     Bullen JJ, Rogers HJ, Leigh L. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. British medical journal 1972; 1: 69–75.

24     Frioni A, Conte MP, Cutone A, Longhi C, Musci G, di PMC, Natalizi T, Marazzato M, Lepanto MS, Puddu P, Paesano R, Valenti P, Berlutti F. Lactoferrin differently modulates the inflammatory response in epithelial models mimicking human inflammatory and infectious diseases. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014; 27.

25     Berlutti F, Schippa S, Morea C, Sarli S, Perfetto B, Donnarumma G, Valenti P. Lactoferrin downregulates pro-inflammatory cytokines upexpressed in intestinal epithelial cells infected with invasive or noninvasive Escherichia coli strains. Biochemistry and cell biology = Biochimie et biologie cellulaire 2006; 84: 351–357.

26     Valenti P, Catizone A, Pantanella F, Frioni A, Natalizi T, Tendini M, Berlutti F. Lactoferrin decreases inflammatory response by cystic fibrosis bronchial cells invaded with Burkholderia cenocepacia iron-modulated biofilm. International journal of immunopathology and pharmacology 2011; 24.

27     Puddu P, Valenti P, Gessani S. Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie 2009; 91: 11–18.

28     Puddu P, Latorre D, Carollo M, Catizone A, Ricci G, Valenti P, Gessani S. Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells. PloS one 2011; 6: e22504.

29     Ward PP, Paz E, Conneely OM. Multifunctional roles of lactoferrin: a critical overview. Cellular and molecular life sciences : CMLS 2005; 62: 2540–2548.

30     Legrand D, Elass E, Carpentier M, Mazurier J. Lactoferrin: a modulator of immune and inflammatory responses. Cellular and molecular life sciences : CMLS 2005; 62: 2549–2559.

31     Paesano R, Pacifici E, Benedetti S, Berlutti F, Frioni A, Polimeni A, Valenti P. Safety and efficacy of lactoferrin versus ferrous sulphate in curing iron deficiency and iron deficiency anaemia in hereditary thrombophilia pregnant women: an interventional study. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014; 27.

32     Paesano R, Berlutti F, Pietropaoli M, Goolsbee W, Pacifici E, Valenti P. Lactoferrin efficacy versus ferrous sulfate in curing iron disorders in pregnant and non-pregnant women. International journal of immunopathology and pharmacology 2010; 23: 577–587.

33     Khalafallah AA, Dennis AE. Iron deficiency anaemia in pregnancy and postpartum: pathophysiology and effect of oral versus intravenous iron therapy. Journal of pregnancy 2012; 2012: 630519.

34     Paesano R, Berlutti F, Pietropaoli M, Pantanella F, Pacifici E, Goolsbee W, Valenti P. Lactoferrin efficacy versus ferrous sulfate in curing iron deficiency and iron deficiency anemia in pregnant women. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2010; 23: 411–417.