Clinical use of lactoferrin in neonates. A review of literature

• Olga A. Krogh-Jensen
• Magnitskaya E.A.

Abstract

Hospital-acquired infections represent the majority of diseases affecting preterm infants in NICUs. Among multiple strategies that have been designed to reduce infant mortality is the search for safe and effective drugs that target the underlying immaturity of immune system in premature infants. It is known that breast milk reduces the incidence of bacteremia and necrotizing enterocolitis. It is suggested that the breast milk biomolecules modify the intestinal microbiome, protecting the intestinal mucosa and promoting its growth, have a positive effect on the development of local immunity. One of these bioactive molecules, partLy expLaining the properties of breast miLk, is the protein of Lactoferrin (LF). LF protects against pathogens in muLtipLe ways: it sequesters iron essentiaL for bacteriaL growth and prevents forming bacteriaL biofiLms; binds to LipopoLysaccharide on the ceLL surface of Gram negative bacteria, disrupting the bacteriaL ceLL membrane; has immunomoduLatory properties. We anaLyzed internationaL Literature in the databases PubMed, CLinicaLKey, MEDLINE. The purpose of oursearch was the use of Lactoferrin in neonates. In this review, we incLuded reports on randomized, bLind, pLacebo-controLLed triaLs. CurrentLy, the resuLts of bLind randomized pLacebo-controLLed triaLs indicate that suppLementaL Lactoferrin (in combination or without probiotics) reduces the incidence of Late-onset sepsis and necrotizing enterocoLitis (>II stage according to BeLL's cLassification) in premature infants. Its use is safe and does not cause side effects.

Keywords:lactoferrin, hospital-acquired infections, late-onset sepsis, necrotizing enterocoliti, newborn, preterm, infant, very low birth weight, extreme low birth weight

References

1. Polin R.A., Denson S., Brady M.T.; Committee on Fetus and Newborn; Committee on Infectious Diseases. Epidemiology and diagnosis of health care associated infections in the NICU. Pediatrics. 2012; 129: e1104-9.

2. Polin R.A., Denson S., Brady M.T.; Committee on Fetus and Newborn; Committee on Infectious Diseases. Epidemiology and diagnosis of health care associated infections in the NICU. Pediatrics. 2012; 129: e1085-93.

3. Collado M.C., Cernada M., Neu J., Perez-Martinez G., et al. Factors influencing gastrointestinal tract and microbiota immune interaction in preterm infants. Pediatr Res. 2015; 77: 726-31.

4. Patel A.L., Johnson T.J., Engstrom J.L., Fogg L.F., et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatol. 2013; 33: 514-9.

5. Sullivan S., Schanler R.J., Kim J.H., Patel A.L., et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010; 156: 562.e1-7.e1.

6. Neu J., Mihatsch W.A., Zegarra J., Supapannachart S., et al. Intes­tinal mucosal defense system. Part 1. Consensus recommendations for immunonutrients. J Pediatr. 2013; 162: S56-63.

7. Benjamin J.T., Mezu-Ndubuisi O.J., Maheshwari A. Fanaroff and Martin's Neonatal-Perinatal Medicine. Philadelphia, PA: Elsevier, 2014; Ch. 54. Developmental Immunology: 696-733

8. Embleton N.D., Berrington J.E., McGuire W., et al. Lactoferrin: an­timicrobial activity and therapeutic potential. Semin Fetal Neonatal Med. 2013; 18 (3): 143-9.

9. Turin C.G., Zea-Vera A., Rueda M.S., Mercado E., et al. Lactoferrin concentration in breast milk of mothers of low-birth-weight newborns. J Perinatol. 2017; 37 (5): 507-12.

10. Anderson B.F., Baker H.M., Norris G.E., Rice D.W., et al. Structure of human lactoferrin: crystallographic structure analysis and refinement at 2·8 A resolution. J Mol Biol. 1989; 209: 711-34.

11. Fransson G.-B., Lonnerdal B. Iron in human milk. J Pediatr. 1980; 96 (3, Pt 1): 380-4.

12. Levay P.F., Viljoen M. Lactoferrin: a general review. Haematologica. 1995; 80: 252-67.

13. Singh P.K., Parsek M.R., Greenberg E.P., et al. A component of innate immunity prevents bacterial biofilm development. Nature. 2002; 417: 552-5.

14. Legrand D. Lactoferrin, a key moLecuLe in immune and infLamma­tory processes. Biochem CeLL BioL. 2012; 90: 252-68.

15. De La Rosa G., Yang D., Tewary P., et aL. Lactoferrin acts as an aLarmin to promote the recruitment and activation of APCs and antigen-specific immune responses. J ImmunoL. 2008; 180: 6868-76.

16. Sherman M.P., Adamkin D.H., Radmacher P.G., et aL. Protective proteins in mammaLian miLks: Lactoferrin steps forward. Neoreviews. 2012; 13: e293-300.

17. Kuwata H., Yip T.T., Tomita M., et aL. Direct evidence of the gen­eration in human stomach of an antimicrobiaL peptide domain (Lactoferricin) from ingested Lactoferrin. Biochim Biophys Acta. 1998; 1429: 129-41.

18. GonzaLez-Chavez S.A., ArevaLo-GaLLegos S., Rascon-Cruz Q. Lactoferrin: structure, function and appLications. Int J Antimicrob Agents. 2009; 33: 301.e1-8.

19. VogeL H.J. Lactoferrin, a bird's eye view. Biochem CeLL BioL. 2012; 90: 233-44.

20. Kuwata H., Yamauchi K., Teraguchi S., et aL. FunctionaL fragments of ingested Lactoferrin are resistant to proteoLytic degradation in the gas­trointestinaL tract of aduLt rats. J Nutr. 2001; 131: 2121-7.

21. Sherman M.P. New concepts of microbiaL transLocation in the neonataL intestine: mechanisms and prevention. CLin PerinatoL. 2010; 37: 565-79.

22. Bevins C.L., SaLzman N.H. Paneth ceLLs, antimicrobiaL peptides and maintenance of intestinaL homeostasis. Nat Rev MicrobioL. 2011; 9: 356-68.

23. De Araujo A.N., GiugLiano L.G. Lactoferrin and free secretory com­ponent of human miLk inhibit the adhesion of enteropathogenic Esche­richia coLi to HeLa ceLLs. BMC MicrobioL. 2001; 1: 25.

24. Zaghouani H., Hoeman C.M., Adkins B. NeonataL immunity: fauLty T-heLpers and the shortcomings of dendritic ceLLs. Trends ImmunoL. 2009; 30: 585-91.

25. Baker H.M., Baker E.N. A structuraL perspective on Lactoferrin function. Biochem CeLL BioL. 2012; 90: 320-8.

26. Sherman M.P., Petrak K. Lactoferrin-enhanced anoikis: a defense against neonataL necrotizing enterocoLitis. Med Hypotheses. 2005; 65: 478-82.

27. Fischer R., Debbabi H., Dubarry M., et aL. ReguLation of physioLog­icaL and pathoLogicaL Th1 and Th2 responses by Lactoferrin. Biochem CeLL BioL. 2006; 84: 303-11.

28. Chodaczek G., Zimecki M., Lukasiewicz J., et aL. A compLex of Lacto­ferrin with monophosphoryL Lipid A is an efficient adjuvant of the humoraL and ceLLuLar immune response in mice. Med MicrobioL ImmunoL. 2006; 195: 207-16.

29. Prgomet C., Prenner M.L., Schwarz F.J., et aL. Effect of Lactoferrin on seLected immune system parameters and the gastrointestinaL morphoLogy in growing caLves. J Anim PhysioL Anim Nutr (BerL). 2007; 91: 109-19.

30. Sherman M.P., Bennett S.H., Hwang F.F., et aL. NeonataL smaLL boweL epitheLia: enhancing anti-bacteriaL defense with Lactoferrin and LactobaciLLus GG. BiometaLs. 2004; 17: 285-9.

31. De Moreno de LeBLanc A., Dogi C.A., GaLdeano C.M., et aL. Effect of the administration of a fermented miLk containing LactobaciLLus casei DN-114001 on intestinaL microbiota and gut associated immune ceLLs of nursing mice and after weaning untiL immune maturity. BMC ImmunoL. 2008; 9: 27.

32. Manzoni P., RinaLdi M., Cattani S., et aL. Bovine Lactoferrin suppLe­mentation for prevention of Late-onset sepsis in very Low-birth-weight neonates: a randomized triaL. JAMA. 2009; 302: 1421-8.

33. Manzoni P., StoLfi I., Messner H., et aL. Bovine Lactoferrin prevents invasive fungaL infections in very Low birth weight infants: a random­ized controLLed triaL. Pediatrics. 2012; 129 (1): 116-23. doi: 10.1542/peds.2011-0279.

34. Manzoni P., Meyer M., StoLfi I., et aL. Bovine Lactoferrin suppLemen­tation for prevention of necrotizing enterocoLitis in very-Low-birth-weight neonates: a randomized cLinicaL triaL. EarLy Hum Dev. 2014; 90 (1): S60-5.

35. Sherman M.P., Adamkin D.H., NikLas V., Radmacher P., et aL. Ran­domized controLLed triaL of taLactoferrin oraL soLution in preterm infants. J Pediatr. 2016; 175: 68-73.e3. doi: 10.1016/j.jpeds.2016.04.084.

36. Akin I.M., Atasay B., Dogu F., OkuLu E., et aL. OraL Lactoferrin to prevent nosocomiaL sepsis and necrotizing enterocoLitis of premature neonates and effect on T-reguLatory ceLLs. Am J PerinatoL. 2014; 31 (12): 1111-20. doi: 10.1055/s-0034-1371704.

37. Ochoa T.J., Zegarra J., Cam L., LLanos R., et aL.; NEOLACTO Research Group. Randomized controLLed triaL of Lactoferrin for prevention of sepsis in peruvian neonates Less than 2500 g. Pediatr Infect Dis J. 2015; 34 (6): 571-6. doi: 10.1097/INF.0000000000000593.

38. Barrington K.J., Assaad M.A., Janvier A. The Lacuna TriaL: a doubLe-bLind randomized controLLed piLot triaL of Lactoferrin suppLe­mentation in the very preterm infant. J PerinatoL. 2016; 36 (8): 666-9. doi: 10.1038/jp.2016.24.

39. Kaur G., GathwaLa G. Efficacy of bovine Lactoferrin suppLementa­tion in preventing Late-onset sepsis in Low birth weight neonates: a ran­domized pLacebo-controLLed cLinicaL triaL. J Trop Pediatr. 2015; 61 (5): 370-6. doi: 10.1093/tropej/fmv044.

40. Pammi M., Suresh G. EnteraL Lactoferrin suppLementation for prevention of sepsis and necrotizing enterocoLitis in preterm infants. Cochrane Database Syst Rev. 2017: CD007137. doi: 10.1002/14651858.CD007137.pub5.

41. BeLL M.J., Ternberg J.L., Feigin R.D., et aL. NeonataL necrotizing enterocoLitis: therapeutic decisions based upon cLinicaL staging. Ann Surg. 1978; 187: 1-7.

42. Weitkamp J.H., Rudzinski E., Koyama T., et aL. Ontogeny of FOXP3(p)reguLatory T ceLLs in the postnataL human smaLL intestinaL and Large intestinaL Lamina propria. Pediatr Dev PathoL. 2009; 12 (6): 443-9.

43. Weitkamp J.H., Koyama T., Rock M.T., et aL. Necrotising enterocoLitis is characterised by disrupted immune reguLation and diminished mucosaL reguLatory (FOXP3)/effector (CD4, CD8) T ceLL ratios. Gut. 2013; 62 (1): 73-82.

44. MauL J., Loddenkemper C., Mundt P., et aL. PeripheraL and intestinaL reguLatory CD4CD25(high) T ceLLs in inflammatory boweL disease. Gastroen-teroLogy. 2005; 128 (7): 1868-78.

45. Rueda C.M., Moreno-Fernandez M.E., Jackson C.M., KaLLapur S.G., et aL. NeonataL reguLatory T ceLLs have reduced capacity to suppress den­dritic ceLL function. Eur J ImmunoL. 2015; 45: 2582-92.

46. Davidson T.S., Shevach E.M. PoLycLonaL Treg ceLLs moduLate T ef­fector ceLL trafficking. Eur J ImmunoL. 2011; 41: 2862-70.

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)