Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gut priming with bovine colostrum and T regulatory cells in preterm neonates: a randomized controlled trial

Pediatric Research volume 90, pages 650–656 (2021)Cite this article

Abstract

Background

Necrotizing enterocolitis (NEC) and neonatal sepsis are still considered major problems, especially in formula-fed preterm neonates. This study aimed to investigate the effect of bovine colostrum on T regulatory cells, NEC, and late-onset sepsis in preterm neonates ≤34 weeks.

Methods

This prospective double-blind randomized controlled trial was conducted on 80 preterm infants who were randomly assigned to either the bovine colostrum group (n = 32) or control group (n = 48). T lymphocytes and their subsets, necrotizing enterocolitis, late-onset sepsis (LOS) and its severity, feeding tolerance, growth, length of hospital stay, and mortality were documented.

Results

The bovine colostrum group showed higher follow-up levels of CD4+CD25+ FOXP3+ T lymphocyte % (FOXP3 Tregs). FOXP3 Tregs and its difference in change levels between baseline and follow-up were considered as the most related factors to the bovine colostrum. Bovine colostrum group showed positive trends for reduction of sepsis severity and mortality with no significant difference in the incidence of NEC, LOS, and length of hospital stay.

Conclusions

Preterm neonates who received bovine colostrum showed a higher FOXP3 Treg level.

Impact

  • Bovine colostrum has no significant effect on the incidence of necrotizing enterocolitis.

  • FOXP3 T regulatory cells and their increased level between baseline and follow-up is considered as the most influencing factors related to the bovine colostrum.

  • Positive trends were noted for reduction of sepsis severity and concomitant mortality, but the study lacked the power to assess these outcomes.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: CONSORT flow diagram of the studied neonates.
Fig. 2: FOXP3 expression% in the the nonbovine colostrum group.

References

  1. Menon, G. & Williams, T. C. Human milk for preterm infants: why, what, when and how? Arch. Dis. Child. Fetal Neonatal Ed. 98, F559–F562 (2013).

    Article  Google Scholar 

  2. Davis, T. A. et al. Amino acid composition of the milk of some mammalian species changes with stage of lactation. Br. J. Nutr. 72, 845–853 (1994).

    CAS  Article  Google Scholar 

  3. Playford, R. J., Cattell, M. & Marchbank, T. Marked variability in bioactivity between commercially available bovine colostrum for human use; implications for clinical trials. PLoS ONE 15, e0234719 (2020).

    CAS  Article  Google Scholar 

  4. Li, Y. et al. A stepwise, pilot study of bovine colostrum to supplement the first enteral feeding in preterm infants (Precolos): study protocol and initial results. Front. Pediatr. 5, 42 (2017).

  5. Rasmussen, S. O. et al. Bovine colostrum improves neonatal growth, digestive function, and gut immunity relative to donor human milk and infant formula in preterm pigs. Am. J. Physiol. Gastrointest. Liver Physiol. 311, G480–G491 (2016).

    Article  Google Scholar 

  6. Jensen, M. L. et al. Similar efficacy of human banked milk and bovine colostrum to decrease incidence of necrotizing enterocolitis in preterm piglets. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R4–R12 (2013).

    CAS  Article  Google Scholar 

  7. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nat. Immunol. 2, 816–822 (2001).

    CAS  Article  Google Scholar 

  8. Li, H. B. et al. Foxp3+ T regulatory cells (Tregs) are increased in nasal polyps (NP) after treatment with intranasal steroid. Clin. Immunol. 129, 394–400 (2008).

    CAS  Article  Google Scholar 

  9. Akin, I. M. et al. Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells. Am. J. Perinatol. 31, 1111–1120 (2014).

    Article  Google Scholar 

  10. Banham, A. H., Powrie, F. M. & Suri-Payer, E. FOXP3+ regulatory T cells: current controversies and future perspectives. Eur. J. Immunol. 36, 2832–2836 (2006).

    CAS  Article  Google Scholar 

  11. Melnik, B. C., John, S. M., Carrera-Bastos, P. & Schmitz, G. Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation. Clin. Transl. Allergy 6, 1–9 (2016).

    Article  Google Scholar 

  12. Schulz, K. F., Altman, D. G. & Moher, D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 340, 698–702 (2010).

    Article  Google Scholar 

  13. Barney, C. K. et al. Treating feeding intolerance with an enteral solution patterned after human amniotic fluid: a randomized, controlled, masked trial. J. Perinatol. 27, 28–31 (2007).

    CAS  Article  Google Scholar 

  14. Ballard, J. L. et al. New Ballard Score, expanded to include extremely premature infants. J. Pediatr. 119, 417–423 (1991).

    CAS  Article  Google Scholar 

  15. Boghossian, N. S. et al. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J. Pediatr. 162, 1120.e1–1124.e1 (2013).

    Article  Google Scholar 

  16. Tröger, B. et al. Risk for late-onset blood-culture proven sepsis in very-low-birth weight infants born small for gestational age: a large multicenter study from the German Neonatal Network. Pediatr. Infect. Dis. J. 33, 238–243 (2014).

    Article  Google Scholar 

  17. Töllner, U. Early diagnosis of septicemia in the newborn - clinical studies and sepsis score. Eur. J. Pediatr. 138, 331–337 (1982).

    Article  Google Scholar 

  18. Rodwell, R. L., Leslie, A. L. & Tudehope, D. I. Early diagnosis of neonatal sepsis using a hematologic scoring system. J. Pediatr. 112, 761–767 (1988).

    CAS  Article  Google Scholar 

  19. Goldstein, B., Giroir, B., Randolph, A. & International Consensus Conference on Pediatric Sepsis. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr. Crit. Care Med. 6, 2–8 (2005).

  20. Harris, M. C. et al. Cytokine elaboration in critically ill infants with bacterial sepsis, necrotizing entercolitis, or sepsis syndrome: correlation with clinical parameters of inflammation and mortality. J. Pediatr. 147, 462–468 (2005).

    CAS  Article  Google Scholar 

  21. Richardson, D. K., Gray, J. E., McCormick, M. C., Workman, K. & Goldmann, D. A. Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care. Pediatrics 91, 617–623 (1993).

    CAS  PubMed  Google Scholar 

  22. Helal, N. F. Can the Score for Neonatal Acute Physiology II (SNAPII) predict morbidity and mortality in neonates with sepsis? J. Neonatal Biol. 2, 2 (2013).

  23. Akanni, E. O. & Palini, A. Immunophenotyping of peripheral blood and bone marrow cells by flow cytometry. EJIFCC 17, 17–21 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Steinborn, A. et al. Small for gestational age (SGA) neonates show reduced suppressive activity of their regulatory T cells. Clin. Immunol. 134, 188–197 (2010).

    CAS  Article  Google Scholar 

  25. Buccigrossi, V. et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr. Res. 61, 410–414 (2007).

    CAS  Article  Google Scholar 

  26. Fhölenhag, K., Arrhenius-Nyberg, V., Sjögren, I. & Malmlöf, K. Effects of insulin-like growth factor I (IGF-I) on the small intestine: a comparison between oral and subcutaneous administration in the weaned rat. Growth Factors 14, 81–88 (1997).

    Article  Google Scholar 

  27. Juhl, S. M. et al. Bovine colostrum for preterm infants in the first days of life: a randomized controlled pilot trial. J. Pediatr. Gastroenterol. Nutr. 66, 471–478 (2018).

    Article  Google Scholar 

  28. Sadeghirad, B. et al. Human and bovine colostrum for prevention of necrotizing enterocolitis: a meta-analysis. Pediatrics 142, e20180767 (2018).

  29. Balachandran, B., Dutta, S., Singh, R., Prasad, R. & Kumar, P. Bovine colostrum in prevention of necrotizing enterocolitis and sepsis in very low birth weight neonates: a randomized, double-blind, placebo-controlled pilot trial. J. Trop. Pediatr. 63, 10–17 (2017).

    Article  Google Scholar 

  30. Manzoni, P. et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 302, 1421–1428 (2009).

    CAS  Article  Google Scholar 

  31. Solomons, N. W. Modulation of the immune system and the response against pathogens with bovine colostrum concentrates. Eur. J. Clin. Nutr. 56, S24–S28 (2002).

    CAS  Article  Google Scholar 

  32. Stelwagen, K., Carpenter, E., Haigh, B., Hodgkinson, A. & Wheeler, T. T. Immune components of bovine colostrum and milk. J. Anim. Sci. 87, 3–9 (2009).

    CAS  Article  Google Scholar 

  33. Orsi, N. The antimicrobial activity of lactoferrin: current status and perspectives. Biometals 17, 189–196 (2004).

    CAS  Article  Google Scholar 

  34. Lluis, A. et al. Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood. J. Allergy Clin. Immunol. 133, 551–559 (2014).

  35. Samuel, M. et al. Bovine milk-derived exosomes from colostrum are enriched with proteins implicated in immune response and growth. Sci. Rep. 7, 1–10 (2017).

    CAS  Article  Google Scholar 

  36. Weitkamp, J. H. et al. Ontogeny of FOXP3+ regulatory T cells in the postnatal human small intestinal and large intestinal lamina propria. Pediatr. Dev. Pathol. 12, 443–449 (2009).

    Article  Google Scholar 

  37. Weitkamp, J. H. et al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut 62, 73–82 (2013).

    CAS  Article  Google Scholar 

  38. Himmel, M. E., Yao, Y., Orban, P. C., Steiner, T. S. & Levings, M. K. Regulatory T-cell therapy for inflammatory bowel disease: more questions than answers. Immunology 136, 115–122 (2012).

    CAS  Article  Google Scholar 

  39. Ochoa, T. J. et al. Randomized controlled trial of lactoferrin for prevention of sepsis in peruvian neonates less than 2500 g. Pediatr. Infect. Dis. J. 34, 571–576 (2015).

    Article  Google Scholar 

Download references

Author information

Affiliations

  1. Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Rania I. H. Ismail, Hisham A. Awad, Safaa S. Imam, Ghada I. Gad, Nancy M. Aboushady, Rania M. Abdou, Nesmahar T. Azzam & Noha M. Barakat

  2. Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Deena S. Eissa

  3. Ministry of Health, Cairo, Egypt

    Maha M. Barakat & Mostafa M. Yassin

Authors
  1. Rania I. H. Ismail
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hisham A. Awad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Safaa S. Imam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ghada I. Gad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nancy M. Aboushady
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rania M. Abdou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Deena S. Eissa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nesmahar T. Azzam
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maha M. Barakat
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mostafa M. Yassin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Noha M. Barakat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to data interpretation and manuscript writing and have read and approved the final submission. R.I.H.I. and H.A.A. conceptualized and designed the study. S.S.E. and G.I.G. supervised data collection, reviewed manuscript, and approved the final manuscript as submitted. N.M.A. and R.M.A. contributed to data collection and performed data analysis. D.S.E. contributed to the flow cytometric analysis. N.T.A., M.B.M., and M.M.Y. followed up the implementation of bovine colostrum intervention. N.M.B. drafted the initial manuscript and analyzed and interpreted the data.

Corresponding author

Correspondence to Noha M. Barakat.

Ethics declarations

Competing interests

The authors declare no competing interests.

Informed consent

Informed consent was provided by parents or caregivers of each participant before enrollment.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ismail, R.I.H., Awad, H.A., Imam, S.S. et al. Gut priming with bovine colostrum and T regulatory cells in preterm neonates: a randomized controlled trial. Pediatr Res 90, 650–656 (2021). https://doi.org/10.1038/s41390-020-01344-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-020-01344-y

Search

Advanced search

Quick links