Lactoferrin

Overview

Lactoferrin (LF) is a naturally occurring iron-binding glycoprotein classified as a postbiotic with immunomodulatory, antimicrobial, and prebiotic-like properties. Found abundantly in human and bovine milk, as well as in mucosal secretions and neutrophil granules, lactoferrin plays a critical role in host defense and mucosal immunity. Its relevance to microbiome-targeted therapy lies in its dual ability to inhibit pathogenic microorganisms by sequestering iron and disrupting microbial membranes, while supporting the growth of beneficial commensals such as Lactobacillus and Bifidobacterium.^[1][2]

Mechanisms of Action

Mechanistically, LF suppresses inflammation by modulating cytokine signaling (e.g., lowering TNF-α, IL-6, and IL-1β while increasing IL-10), blocks pathogen adhesion, and disrupts biofilm formation.^[3][4] It also interacts with immune cells—enhancing NK cell cytotoxicity, regulating dendritic cell function, and promoting epithelial barrier stability.^[5] Clinically, LF has demonstrated utility as a biomarker in feces (for IBD), saliva (for Alzheimer’s disease), and tears (for dry eye disease). These diagnostic links reflect its consistent association with microbial balance and host immune responses. Lactoferrin also exhibits broad antiviral properties, blocking host cell entry of viruses like HSV, CMV, HIV, and SARS-CoV-2 through interactions with heparan sulfate receptors.^[6] Its anticancer and bone-supporting effects are connected to immunomodulatory and microbiome-mediated pathways, including apoptosis induction and osteoblast activation.^[7]

Mechanism of Action	Overview
Antibacterial	Lactoferrin exerts broad-spectrum antibacterial activity through iron chelation, membrane disruption, and inhibition of adhesion and biofilm formation. It is particularly effective against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Salmonella spp. It shows synergy with antibiotics and spares beneficial microbiota such as Lactobacillus and Bifidobacterium species.[8][9][10][11]
Antifungal	Lactoferrin and its derived peptides (e.g., lactoferricin, lactoferrampin) inhibit Candida albicans, Cryptococcus neoformans, and biofilm-forming fungi. Mechanisms include membrane permeabilization, ROS generation, and interference with ergosterol pathways. Synergy with amphotericin B enhances fungicidal effects and reduces virulence traits such as hyphal elongation and capsule size.[12][13]
Antiviral	Lactoferrin prevents viral attachment and entry by binding host cell glycosaminoglycans or viral envelope proteins. It is active against HSV-1/2, HIV, Rotavirus, Norovirus, RSV, and SARS-CoV-2. Additional effects include interferon induction and NK cell activation.[14][15][16]
Anti-inflammatory	Lactoferrin reduces inflammation by inhibiting TLR4-mediated NF-κB activation, leading to decreased levels of TNF-α, IL-1β, and IL-6. It also increases IL-10 and promotes regulatory immune profiles, helping to resolve dysbiosis-induced inflammation and restore microbial-epithelial homeostasis.[17][18]
Immunomodulatory	Lactoferrin shapes immune responses by modulating dendritic cells and promoting Th1/Th2 balance. It supports tolerance toward commensals like Lactobacillus while suppressing excessive responses to pathobionts, stabilizing the immune-microbiome interface. [19][20][21]
Prebiotic	Lactoferrin selectively promotes Lactobacillus and Bifidobacterium while suppressing pathogens through iron restriction and immune signaling modulation. This fosters a more resilient microbiome, especially under inflammatory or antibiotic stress[22][23][24]

Microbial Implications

Lactoferrin modulates the microbiome through selective antimicrobial and prebiotic actions. It consistently increases beneficial taxa such as Lactobacillus rhamnosus, L. crispatus, L. jensenii, and Bifidobacterium longum, which are critical for maintaining mucosal integrity, lowering pH, and promoting immune tolerance.^[25][26] Simultaneously, lactoferrin suppresses overgrowth of pathogenic or dysbiosis-associated microbes, which are commonly elevated in bacterial vaginosis, sepsis, and inflammatory gut conditions.^[27] In fungal ecosystems, lactoferrin and its peptides inhibit Candida albicans and Cryptococcus neoformans by targeting cell walls, inducing oxidative stress, and blocking hyphal transition and biofilm development.^[28][29] In viral infections, lactoferrin prevents epithelial entry of HSV-1/2, rotavirus, norovirus, and SARS-CoV-2 by binding to viral particles or host receptors, while modulating antiviral immune responses such as interferon activation and NK cell recruitment. ^[30][31] This immune-epithelial stabilization helps maintain microbial balance during acute viral illness. These microbial shifts are associated with clinical improvements in conditions like bacterial vaginosis (BV), candidiasis, neonatal infections, and viral gastroenteritis, making lactoferrin a compelling microbiome-aligned therapeutic tool.

Conditions

Conditions	Status
Bacterial Vaginosis	Validated
Endometriosis	In Progress

Clinical Evidence

Clinical and preclinical studies show that lactoferrin exerts antimicrobial activity. In women with vaginal dysbiosis, LF promoted Lactobacillus dominance and suppressed pathogens like Gardnerella vaginalis and Atopobium vaginae^[32]. LF-derived peptides impaired fungal virulence in Candida albicans and Cryptococcus neoformans while enhancing antifungal synergy.^[33] In viral contexts, LF shortened symptom duration and modulated immune responses without disrupting the microbiome. ^[34]

Dosage

Typical clinical doses of oral lactoferrin range from 100 mg to 1,000 mg daily, depending on the indication and population in viral prevention studies, in capsule or powder form.^[35] Vaginal applications often involved local formulations (e.g., ovules or suppositories) delivering 20–300 mg per dose, used alone or with probiotics for synergy.^[36] For enhanced efficacy, some studies recommend apo-lactoferrin or enteric-coated capsules, which protect LF from gastric degradation and improve delivery to the intestine or urogenital tract.^[37][38]

Safety

For years, clinical trials have been underway based on the use of lactoferrin in the treatment of children, and even premature babies. An important aspect is the lack of reported side effects, which makes lactoferrin a safe protein even for the youngest patients.^{[39][40][41][42]}

FAQs

How does lactoferrin preserve microbial homeostasis while exhibiting antimicrobial activity?

Lactoferrin acts through iron sequestration and membrane destabilization, which primarily affect iron-dependent pathogens, sparing commensals like Lactobacillus and Bifidobacterium. These beneficial microbes are often resistant to LF’s effects and may even use LF-bound glycans for growth^[43][44].

Can lactoferrin shift microbial virulence without eliminating the pathogen?

LF and its peptides modulate pathogenicity by inhibiting key virulence mechanisms, biofilm formation, toxin release, capsule formation, and adhesion—even when full eradication isn’t achieved. In Candida albicans and Cryptococcus neoformans, LF disrupts hyphal growth and capsule integrity, thereby reducing pathogenic potential without sterilizing the niche^[45][46].

Is there evidence that lactoferrin modulates immune-microbiome crosstalk at mucosal surfaces?

Lactoferrin supports immune tolerance by downregulating NF-κB and inflammatory cytokines, while enhancing anti-inflammatory mediators. These effects reduce immune-mediated disruption of commensals and maintain epithelial barrier integrity. In viral and bacterial infections, this dual action stabilizes the microbiome-immune axis, especially in the gut and vaginal mucosa^[47][48][49].

Research Feed

Update History

References

1. Lactoferrin: A review. Adlerova, L. & Bartoskova, Alena & Martin, Faldyna.. (Veterinarni Medicina, 53, 2008 (9): 457–468)
2. Lactoferrin: A glycoprotein that plays an active role in human health.. Cao X, Ren Y, Lu Q, Wang K, Wu Y, Wang Y, Zhang Y, Cui X, Yang Z and Chen Z. (Front. Nutr. 9:1018336.)
3. Lactoferrin: A review. Adlerova, L. & Bartoskova, Alena & Martin, Faldyna.. (Veterinarni Medicina, 53, 2008 (9): 457–468)
4. The Lactoferrin Phenomenon—A Miracle Molecule. Kowalczyk, P.; Kaczy ´nska, K.; Kleczkowska, P.; Bukowska-O´sko, I.; Kramkowski, K.; Sulejczak, D.. (Molecules 2022, 27, 2941.)
5. Lactoferrin: A review. Adlerova, L. & Bartoskova, Alena & Martin, Faldyna.. (Veterinarni Medicina, 53, 2008 (9): 457–468)
6. Lactoferrin: A review. Adlerova, L. & Bartoskova, Alena & Martin, Faldyna.. (Veterinarni Medicina, 53, 2008 (9): 457–468)
7. Lactoferrin: A glycoprotein that plays an active role in human health.. Cao X, Ren Y, Lu Q, Wang K, Wu Y, Wang Y, Zhang Y, Cui X, Yang Z and Chen Z. (Front. Nutr. 9:1018336.)
8. Antibacterial properties of lactoferrin: A bibliometric analysis from 2000 to early 2022. Xu, Y., Wang, Y., He, J., & Zhu, W.. (Frontiers in Microbiology, 2022, 13, 947102.)
9. The Antimicrobial Effect of Lactoferrin on Gram-Negative and Gram-Positive Bacteria. Somayeh JahaniAmin ShakibaLeila Jahani. (Int J Infect. 2015 July; 2(3): e27954.)
10. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
11. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
12. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
13. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Fernandes, K. E., & Carter, D. A. (.. (Frontiers in Microbiology,2017) 8, 2.)
14. Antiviral properties of lactoferrin–a natural immunity molecule. Berlutti F, Pantanella F, Natalizi T, Frioni A, Paesano R, Polimeni A, Valenti P.. (Molecules. 2011 Aug 16;16(8):6992-7018.)
15. The effects of orally administered lactoferrin in the prevention and management of viral infections: a systematic review.. Sinopoli A , Isonne C , Santoro MM , Baccolini V.. (Rev Med Virol. 2022; 32(1):e2261.)
16. 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, ISSN 1341-321X)
17. Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections. Drago-Serrano ME, Campos-Rodríguez R, Carrero JC, de la Garza M.. (Int J Mol Sci. 2017 Mar 1;18(3):501.)
18. Lactoferrin and Its Potential Impact for the Relief of Pain: A Preclinical Approach. Godínez-Chaparro, B.; Guzmán-Mejía, F.; Drago-Serrano, M.E.. (Pharmaceuticals 2021, 14, 868.)
19. Lactoferrin as a natural immune modulator. Actor JK, Hwang SA, Kruzel ML.. (Curr Pharm Des. 2009;15(17):1956-73.)
20. Immunomodulatory effects of lactoferrin. Siqueiros-Cendón, T., Arévalo-Gallegos, S., Iglesias-Figueroa, B. et al.. (Acta Pharmacol Sin 35, 557–566 (2014))
21. Overview of Lactoferrin as a Natural Immune Modulator. Dominique Legrand. (The Journal of Pediatrics, Volume 173, Supplement, 2016, Pages S10-S15, ISSN 0022-3476)
22. Prebiotic and modulatory evidence of lactoferrin on gut health and function. Zhao, C., Chen, N., & Ashaolu, T. J.. (Journal of Functional Foods, 108, 105741)
23. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
24. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
25. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
26. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
27. The Antimicrobial Effect of Lactoferrin on Gram-Negative and Gram-Positive Bacteria. Somayeh JahaniAmin ShakibaLeila Jahani. (Int J Infect. 2015 July; 2(3): e27954.)
28. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
29. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Fernandes, K. E., & Carter, D. A. (.. (Frontiers in Microbiology,2017) 8, 2.)
30. Antiviral properties of lactoferrin–a natural immunity molecule. Berlutti F, Pantanella F, Natalizi T, Frioni A, Paesano R, Polimeni A, Valenti P.. (Molecules. 2011 Aug 16;16(8):6992-7018.)
31. 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, ISSN 1341-321X)
32. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
33. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
34. 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, ISSN 1341-321X)
35. 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, ISSN 1341-321X)
36. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
37. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
38. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
39. The Lactoferrin Phenomenon—A Miracle Molecule. Kowalczyk, P.; Kaczy ´nska, K.; Kleczkowska, P.; Bukowska-O´sko, I.; Kramkowski, K.; Sulejczak, D.. (Molecules 2022, 27, 2941.)
40. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
41. The effects of orally administered lactoferrin in the prevention and management of viral infections: a systematic review.. Sinopoli A , Isonne C , Santoro MM , Baccolini V.. (Rev Med Virol. 2022; 32(1):e2261.)
42. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
43. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
44. Featured Prebiotic Agent: The Roles and Mechanisms of Direct and Indirect Prebiotic Activities of Lactoferrin and Its Application in Disease Control. Liu, Z.-S., & Chen, P.-W.. (Nutrients, 15(12), 2759.)
45. Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B. Fernandes KE, Weeks K, Carter DA.. (Antimicrob Agents Chemother 64:10.1128/aac.02284-19.)
46. The Antifungal Activity of Lactoferrin and Its Derived Peptides: Mechanisms of Action and Synergy with Drugs against Fungal Pathogens. Fernandes, K. E., & Carter, D. A. (.. (Frontiers in Microbiology,2017) 8, 2.)
47. Antimicrobial and Prebiotic Activity of Lactoferrin in the Female Reproductive Tract: A Comprehensive Review. Artym, J.; Zimecki, M.. (Biomedicines 2021, 9, 1940)
48. 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, ISSN 1341-321X)
49. Antiviral properties of lactoferrin–a natural immunity molecule. Berlutti F, Pantanella F, Natalizi T, Frioni A, Paesano R, Polimeni A, Valenti P.. (Molecules. 2011 Aug 16;16(8):6992-7018.)