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The effects of probiotic supplementation on the gene expressions of immune cell surface markers and levels of antibodies and pro-inflammatory cytokines in human milk

Journal of Perinatology volume 41, pages 1083–1091 (2021)Cite this article

Subjects

Abstract

Objective

This study investigated the impact of probiotic supplementation on the gene expressions of cluster of differentiation (CD) as cell markers and the concentrations of antibodies and cytokines in human milk.

Study design

Gene expressions of CD28, CD19, and CD38 were determined in milk from 15 women ingesting daily probiotics (from Greek yogurt) and 12 women who do not consume probiotics. Concentrations of antibodies and cytokines were measured using ELISA.

Results

Gene expression of CD28 tended to be higher in milk from mothers ingesting daily probiotics than mothers who did not take probiotics. Interleukin-6 (IL-6) concentration in milk was higher in mothers ingesting probiotics than those who do not consume probiotics. The increase of IL-6 level in human milk was positively correlated with total IgA and IgG concentrations.

Conclusions

Probiotic supplementation could enhance the secretion of IL-6 in human milk. Human milk IL-6 may improve neonatal immunity due to its stimulation of total IgA and IgG.

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Fig. 1: Overall gene expression of the cluster of differentiation (CD) as cell markers and concentration of antibodies and pro-inflammatory cytokines in human milk.
Fig. 2: Effects of probiotic supplementation (at least one billion of probiotic bacteria per day from Greek yogurt) on the gene expressions of the cluster of differentiation (CD) as cell markers and the concentrations of antibodies and pro-inflammatory cytokines in human milk.
Fig. 3: Correlation between the gene expression of the cluster of differentiation (CD) as cell markers and the concentrations of antibodies and pro-inflammatory cytokines in human milk.

References

  1. Brandtzaeg P. Mucosal immunity: integration between mother and the breast-fed infant. Vaccine 2003;21:3382–8.

    Article  CAS  PubMed  Google Scholar 

  2. Brandtzaeg P, Nilssen DE, Rognum TO, Thrane PS. Ontogeny of the mucosal immune system and IgA deficiency. Gastroenterol Clin N Am. 1991;20:397–439.

    Article  CAS  Google Scholar 

  3. Brandtzaeg P. The mucosal immune system and its integration with the mammary glands. J Pediatr. 2010;156:S8–S15.

    Article  CAS  PubMed  Google Scholar 

  4. Khan J, Vesel L, Bahl R, Martines JC. Timing of breastfeeding initiation and exclusivity of breastfeeding during the first month of life: effects on neonatal mortality and morbidity—a systematic review and meta-analysis. Matern Child Health J. 2015;19:468–79.

    Article  PubMed  Google Scholar 

  5. Longet S, Vonarburg C, Lötscher M, Miescher S, Zuercher A, Corthésy B. Reconstituted human polyclonal plasma-derived secretory-like IgM and IgA maintain the barrier function of epithelial cells infected with an enteropathogen. J Biol Chem. 2014;289:21617–26.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Quan CP, Berneman A, Pires R, Avrameas S, Bouvet JP. Natural polyreactive secretory immunoglobulin A autoantibodies as a possible barrier to infection in humans. Infect Immun. 1997;65:3997–4004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wirt DP, Adkins LT, Palkowetz KH, Schmalstieg FC, Goldman AS. Activated and memory T lymphocytes in human milk. Cytometry 1992;13:282–90.

    Article  CAS  PubMed  Google Scholar 

  8. Tuaillon E, Valea D, Becquart P, Al Tabaa Y, Meda N, Bollore K, et al. Human milk-derived B cells: a highly activated switched memory cell population primed to secrete antibodies. J Immunol. 2009;182:7155–62.

    Article  CAS  PubMed  Google Scholar 

  9. Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol. 1993;11:191–212.

    Article  CAS  PubMed  Google Scholar 

  10. Jourdan M, Caraux A, Caron G, Robert N, Fiol G, Rème T, et al. Characterization of a transitional preplasmablast population in the process of human B cell to plasma cell differentiation. J Immunol. 2011;187:3931–41.

    Article  CAS  PubMed  Google Scholar 

  11. Tarte K, Zhan F, De Vos J, Klein B, Shaughnessy J. Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. Blood 2003;102:592–600.

    Article  CAS  PubMed  Google Scholar 

  12. Jego G, Robillard N, Puthier D, Amiot M, Accard F, Pineau D, et al. Reactive plasmacytoses are expansions of plasmablasts retaining the capacity to differentiate into plasma cells. Blood J Am Soc Hematol. 1999;94:701–12.

    CAS  Google Scholar 

  13. Akira SH, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990;4:2860–7.

    Article  CAS  PubMed  Google Scholar 

  14. Jelinek DF, Lipsky PE. Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol. 1987;139:2970–6.

    CAS  PubMed  Google Scholar 

  15. Palkowetz KH, Royer CL, Garofalo R, Rudloff HE, Schmalstieg FC Jr, Goldman AS. Production of interleukin-6 and interleukin-8 by human mammary gland epithelial cells. J Reprod Immunol. 1994;26:57–64.

    Article  CAS  PubMed  Google Scholar 

  16. de Araújo-Souza PS, Hanschke SC, Viola JP. Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res. 2015. https://doi.org/10.1155/2015/849573.

  17. Zhao Y, Lin L, Xiao Z, Li M, Wu X, Li W, et al. Protective role of γδ T cells in different pathogen infections and its potential clinical application. J Immunol Res. 2018. https://doi.org/10.1155/2018/5081634.

  18. Bourges D, Meurens F, Berri M, Chevaleyre C, Zanello G, Levast B, et al. New insights into the dual recruitment of IgA+ B cells in the developing mammary gland. Microbiol Immunol. 2008;45:3354–62.

    CAS  Google Scholar 

  19. Johnson S, Bourges D, Wijburg O, Strugnell RA, Lew AM. Milk IgA responses are augmented by antigen delivery to the mucosal addressin cellular adhesion molecule 1. Vaccine 2006;24:5552–8.

    Article  CAS  PubMed  Google Scholar 

  20. Lindner C, Thomsen I, Wahl B, Ugur M, Sethi MK, Friedrichsen M, et al. Diversification of memory B cells drives the continuous adaptation of secretory antibodies to gut microbiota. Nat immunol. 2015;16:880–8.

    Article  CAS  PubMed  Google Scholar 

  21. Vorbach C, Capecchi MR, Penninger JM. Evolution of the mammary gland from the innate immune system? Bioessays 2006;28:606–16.

    Article  CAS  PubMed  Google Scholar 

  22. Boumahrou N, Chevaleyre C, Berri M, Martin P, Bellier S, Salmon H. An increase in milk IgA correlates with both pIgR expression and IgA plasma cell accumulation in the lactating mammary gland of PRM/Alf mice. J Reprod Immunol. 2012;96:25–33.

    Article  CAS  PubMed  Google Scholar 

  23. Prescott SL, Wickens K, Westcott L, Jung W, Currie H, Black PN, et al. Supplementation with Lactobacillus rhamnosus or Bifidobacterium lactis probiotics in pregnancy increases cord blood interferon‐γ and breast milk transforming growth factor‐β and immunoglobin A detection. Clin Exp Allergy. 2008;38:1606–14.

    Article  CAS  PubMed  Google Scholar 

  24. Demers-Mathieu V, Mathijssen G, Dapra C, Do DM, Medo E. Active free secretory component and secretory IgA in human milk: do maternal vaccination, allergy, infection, mode of delivery, nutrition and active lifestyle change their concentrations? Pediatr Res. 2020:1–8. https://doi.org/10.1038/s41390-020-0966-7.

  25. Demers-Mathieu V, Underwood MA, Beverly RL, David DC. Survival of immunoglobulins from human milk to preterm infant gastric samples at 1, 2, and 3 h postprandial. Neonatology 2018;114:242–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Demers-Mathieu V, Underwood MA, Beverly RL, Nielsen SD, Dallas DC. Comparison of human milk immunoglobulin survival during gastric digestion between preterm and term infants. Nutrients 2018;10:631.

    Article  PubMed Central  Google Scholar 

  27. Demers-Mathieu V, Huston RK, Markell AM, McCulley EA, Martin RL, Spooner M, et al. Differences in maternal immunoglobulins within mother’s own breast milk and donor breast milk and across digestion in preterm infants. Nutrients 2019;11:920.

    Article  CAS  PubMed Central  Google Scholar 

  28. Morteau O, Gerard C, Lu B, Ghiran S, Rits M, Fujiwara Y, et al. An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation. J Immunol. 2008;18:6309–15.

    Article  Google Scholar 

  29. Wilson E, Butcher EC. CCL28 controls immunoglobulin (Ig) A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate. J Exp Med. 2004;200:805–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fujihashi K, McGhee JR, Lue C, Beagley KW, Taga T, Hirano T, et al. Human appendix B cells naturally express receptors for and respond to interleukin 6 with selective IgA1 and IgA2 synthesis. J Clin Investig. 1991;88:248–52.

    Article  CAS  PubMed  Google Scholar 

  31. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1–78.

    Article  CAS  PubMed  Google Scholar 

  32. Saito S, Maruyama M, Kato Y, Moriyama I, Ichijo M. Detection of IL-6 in human milk and its involvement in IgA production. J Reprod Immunol 1991;20:267–76.

    Article  CAS  PubMed  Google Scholar 

  33. Ustundag B, Yilmaz E, Dogan Y, Akarsu S, Canatan H, Halifeoglu I, et al. Levels of cytokines (IL-1β, IL-2, IL-6, IL-8, TNF-α) and trace elements (Zn, Cu) in breast milk from mothers of preterm and term infants. Mediat Inflamm. 2005;2005. https://doi.org/10.1155/MI.2005.331.

  34. Basolo F, Conaldi PG, Fiore L, Calvo S, Toniolo A. Normal breast epithelial cells produce interleukins 6 and 8 together with tumor‐necrosis factor: defective IL6 expression in mammary carcinoma. Int J Cancer. 1993;55:926–30.

    Article  CAS  PubMed  Google Scholar 

  35. Dawod B, Marshall JS. Cytokines and soluble receptors in breast milk as enhancers of oral tolerance development. Front Immunol. 2019;10:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dann SM, Spehlmann ME, Hammond DC, Limura M, Hase K, Choi LJ, et al. IL-6-dependent mucosal protection prevents establishment of a microbial niche for attaching/effacing lesion-forming enteric bacterial pathogens. J Immunol. 2008;180:6816–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS ONE. 2014;9:e114195.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bloomfield M, Parackova Z, Cabelova T, Pospisilova I, Kabicek P, Houstkova H, et al. Anti-IL6 autoantibodies in an infant with CRP-less septic shock. Front Immunol. 2019;10:2629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shive CL, Jiang W, Anthony DD, Lederman MM. Soluble CD14 is a nonspecific marker of monocyte activation. AIDS 2015;29:1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all study participants for their valuable contributions.

Funding

The authors (VD-M, GBM, CD, and ED) disclosed receipt of the financial support from Medolac Laboratories A Public Benefit Corporation for the conduct of the study.

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Authors and Affiliations

  1. Department of Neonatal Immunology and Microbiology, Medolac Laboratories A Public Benefit Corporation, Boulder City, NV, USA

    Veronique Demers-Mathieu, Gabrielle B. Mathijssen, Ciera DaPra & Elena Medo

Authors
  1. Veronique Demers-Mathieu
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  2. Gabrielle B. Mathijssen
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  3. Ciera DaPra
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  4. Elena Medo
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Contributions

VD-M conceptualized and designed the study, carried out the RT-qPCR of immune cells, cytokine ELISA, the statistical analysis, and drafted the manuscript. GBM and CD performed antibody ELISA. VD-M have primary responsibility for the final content. EM have obtained the funding acquisition of this study. GBM, CD, and EM approved the final paper as submitted.

Corresponding author

Correspondence to Veronique Demers-Mathieu.

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Conflict of interest

VD-M, GBM, CD, and EM are employees of Medolac Laboratories.

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Demers-Mathieu, V., Mathijssen, G.B., DaPra, C. et al. The effects of probiotic supplementation on the gene expressions of immune cell surface markers and levels of antibodies and pro-inflammatory cytokines in human milk. J Perinatol 41, 1083–1091 (2021). https://doi.org/10.1038/s41372-020-00875-w

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  • DOI: https://doi.org/10.1038/s41372-020-00875-w

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