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.

  • Clinical Research Article
  • Published:

Bifidobacteria modulate immune response in pediatric patients with cow’s milk protein allergy

Pediatric Research volume 94, pages 1111–1118 (2023)Cite this article

Abstract

Background

In children with an allergy to cow’s milk proteins (CMA), the altered composition of intestinal microbiota influences the immune tolerance to milk proteins (CMP). This study aims to investigate the effect of probiotics on the phenotype and activation status of peripheral basophils and lymphocytes in a pediatric CMA cohort.

Methods

CMA children underwent 45 days of treatment with Bifidobacteria. The basophil degranulation and the immune phenotype of B cells, T helper cells, and regulatory T cells were analyzed in peripheral blood at diagnosis (T0), after a 45-day probiotic treatment (T1), and 45 days after the probiotic wash-out (T2).

Results

We observed in probiotic-treated CMA patients a decrease in naive T lymphocytes. Among the CD3+ cell subsets, both naive and activated CD4+ cells resulted markedly reduced after taking probiotics, with the lowest percentages at T2. A decreased basophil degranulation was observed in response to all analyzed CMP at T1 compared to T0.

Conclusions

The probiotic treatment resulted in a decrease of circulating naive and activated CD4+ T cells, as well as degranulating basophils. These data suggest that the Bifidobacteria could have a beneficial effect in the modulation of oral tolerance to CMP.

Trial registration

ISRCTN69069358. URL of registration: https://www.isrctn.com/ISRCTN69069358.

Impact

  • Probiotic treatment with Bifidobacteria induces a reduction of both naive and activated circulating CD4+ T cells in pediatric patients with cow’s milk allergy (CMA).

  • The probiotic supplementation induces a decreased basophil degranulation.

  • The immunological tolerance persists even after 45 days of the probiotic wash-out.

  • Bifidobacteria in vivo supplementation down-modulates the activation of innate and adaptive immunity in pediatric patients with cow’s milk allergy.

  • Bifidobacteria contribute to the development of immune tolerance in CMA patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cell population percentages analyzed by flow cytometry.
Fig. 2: The effect of probiotic treatment on the frequency of circulating T and B cell subsets.
Fig. 3: Effect of probiotic treatment on the percentage of degranulating basophils in response to cow’s milk proteins.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the study will be available upon request to the authors.

References

  1. Boyce, J. A. et al. Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report. J. Allergy Clin. Immunol. 126, 1105–1118 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sicherer, S. H. Epidemiology of food allergy. J. Allergy Clin. Immunol. 127, 594–602 (2011).

    Article  PubMed  Google Scholar 

  3. Høst, A. et al. Clinical course of cow’s milk protein allergy/intolerance and atopic diseases in childhood. Pediatr. Allergy Immunol. 13, 23–28 (2002).

    Article  PubMed  Google Scholar 

  4. Basturk, A., Isik, İ., Atalay, A. & Yılmaz, A. Investigation of the efficacy of Lactobacillus rhamnosus GG in infants with cow’s milk protein allergy: a randomised double-blind placebo-controlled trial. Probiotics Antimicrob. Proteins 12, 138–143 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nakayama, J. et al. Aberrant structures of fecal bacterial community in allergic infants profiled by 16S rRNA gene pyrosequencing. FEMS Immunol. Med. Microbiol. 63, 397–406 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Plunkett, C. H. & Nagler, C. R. The influence of the microbiome on allergic sensitization to food. J. Immunol. 198, 581–589 (2017).

    Article  CAS  PubMed  Google Scholar 

  8. Osborn, D. A. & Sinn, J. K. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst. Rev. 17, CD006475 (2007).

    Google Scholar 

  9. Boyle, R. J., Bath-Hextall, F. J., Leonardi-Bee, J., Murrell, D. F. & Tang, M. L.-K. Probiotics for the treatment of eczema: a systematic review. Clin. Exp. Allergy 39, 1117–1127 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Martínez-Cañavate, A. et al. A probiotic dairy product containing L. gasseri CECT5714 and L. coryniformis CECT5711 induces immunological changes in children suffering from allergy. Pediatr. Allergy Immunol. 20, 592–600 (2009).

    Article  PubMed  Google Scholar 

  11. Vliagoftis, H., Kouranos, V. D., Betsi, G. I. & Falagas, M. E. Probiotics for the treatment of allergic rhinitis and asthma: systematic review of randomized controlled trials. Ann. Allergy Asthma Immunol. 101, 570–579 (2008).

    Article  PubMed  Google Scholar 

  12. Peluso, I. et al. Lactobacillus paracasei subsp. paracasei B21060 suppresses human T-cell proliferation. Infect. Immun. 75, 1730–1737 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Majamaa, H. & Isolauri, E. Probiotics: a novel approach in the management of food allergy. J. Allergy Clin. Immunol. 99, 179–185 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Viljanen, M. et al. Probiotic effects on faecal inflammatory markers and on faecal IgA in food allergic atopic eczema/dermatitis syndrome infants. Pediatr. Allergy Immunol. 16, 65–71 (2005).

    Article  PubMed  Google Scholar 

  15. Sackesen, C. et al. Current trends in tolerance induction in cow’s milk allergy: from passive to proactive strategies. Front. Pediatr. 7, 372 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Nucera, E. et al. Utility of basophil activation test for monitoring the acquisition of clinical tolerance after oral desensitization to cow’s milk: pilot study. U. Eur. Gastroenterol. J. 3, 272–276 (2015).

    Article  CAS  Google Scholar 

  17. Berni Canani, R. et al. Effect of Lactobaccillus GG on tollerance acquisition in infants with cow’s milk allergy: a randomized trial. J. Allergy Clin. Immunol. 129, 580–582.e5 (2012).

    Article  PubMed  Google Scholar 

  18. Camarca, A. et al. Human peripheral blood mononuclear cell function and dendritic cell differentiation are affected by bisphenol-A exposure. PLoS ONE 11, e0161122 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bates, D., Mächler, M., Bolker, B. & Walker, S. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1–48 (2015).

    Article  Google Scholar 

  20. Strisciuglio, C. et al. Bifidobacteria enhance antigen sampilng and processing by dendtritic cells in pediatric inflammatory bowel disease. Inflamm. Bowel Dis. 21, 1491–1498 (2015).

    Article  PubMed  Google Scholar 

  21. Fiorentini, S. et al. CD11b expression identifies CD8+CD28+ T lymphocytes with phenotype and function of both naive/memory and effector cells. J. Immunol. 166, 900–907 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Järvinen, K. M., Aro, A., Juntunen-Backman, K. & Suomalainen, H. Large number of CD19+/CD23+ B cells and small number of CD8+ T cells as early markers for cow’s milk allergy (CMA). Pediatr. Allergy Immunol. 9, 139–142 (1998).

    Article  PubMed  Google Scholar 

  23. Perezabad, L. et al. The establishment of cow’s milk protein allergy in infants is related with a deficit of regulatory T cells (Treg) and vitamin D. Pediatr. Res. 81, 722–730 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Mowat, A. M. The regulation of immune responses to dietary protein antigens. Immunol. Today 8, 93–98 (1987).

    Article  CAS  PubMed  Google Scholar 

  25. Suomalainen, H., Soppi, E., Laine, S. & Isolauri, E. Immunologic disturbances in cow’s milk allergy, 2: evidence for defective interferon-gamma generation. Pediatr. Allergy Immunol. 4, 203–207 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Huber, M. & Lohoff, M. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. Allergo J. Int. 24, 8–15 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Osterlund, P. & Suomalainen, H. Low frequency of CD4+, but not CD8+, T cells expressing interferon-gamma is related to cow’s milk allergy in infancy. Pediatr. Allergy Immunol. 13, 262–268 (2002).

    Article  PubMed  Google Scholar 

  28. Curotto de Lafaille, M. A. et al. Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29, 114–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Hol, J. et al. The acquisition of tolerance toward cow’s milk through probiotic supplementation: a randomized, controlled trial. J. Allergy Clin. Immunol. 121, 1448–1454 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Ciepiela, O. et al. Basophil activation test based on the expression of CD203c in the diagnostics of cow milk allergy in children. Eur. J. Med. Res. 15, 21–26 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hemmings, O., Kwok, M., McKendry, R. & Santos, A. F. Basophil activation test: old and new applications in allergy. Curr. Allergy Asthma Rep. 18, 77 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Shreffler, W. G. Evaluation of basophil activation in food allergy: present and future applications. Curr. Opin. Allergy Clin. Immunol. 6, 226–233 (2006).

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. These authors contributed equally: Caterina Strisciuglio, Alessandra Vitale.

Authors and Affiliations

  1. Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy

    Caterina Strisciuglio, Alessandra Vitale & Michele Miraglia del Giudice

  2. Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy

    Francesco Perna

  3. U.O.C Clinical Biochemistry, A.O.R.N. Ospedale dei Colli, Naples, Italy

    Federica Garziano

  4. Department of Public Health, University of Naples “Federico II”, Naples, Italy

    Pasquale Dolce

  5. Institute of Biochemistry and Cell Biology, CNR, Naples, Italy

    Serena Vitale & Carmen Gianfrani

  6. Neuroimmunology Unit, IRCCS Fondazione Santa Lucia, Rome, Italy

    Teresa Micillo

  7. Department of Translational Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy

    Franca Oglio

  8. Department of Molecular Medicine and Biotechnology Science, University of Naples “Federico II”, Naples, Italy

    Giuseppe Matarese

Authors
  1. Caterina Strisciuglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandra Vitale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francesco Perna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federica Garziano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pasquale Dolce
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Serena Vitale
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teresa Micillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Franca Oglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michele Miraglia del Giudice
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giuseppe Matarese
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carmen Gianfrani
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.S. and A.V. contributed to the conception and design of the study, sample collection, analysis and interpretation of data, and drafted the article; F.P. performed the BAT experiments; F.G. contributed to sample collection and performed BAT experiments. P.D. performed the statistical and correlation analysis; S.V., T.M., and F.O. contributed to sample collection and analysis; M.M.d.G. contributed to the conception, design, and intellectual content of the study; G.M. and C.G. contributed to the conception, design and intellectual content of the study, revised the data, and drafted the article.

Corresponding author

Correspondence to Caterina Strisciuglio.

Ethics declarations

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of the University of Campania “Luigi Vanvitelli” (registration number 07/2016). Written informed consent for participation in the study and publishing of individual patient data were obtained from the parents of all children.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strisciuglio, C., Vitale, A., Perna, F. et al. Bifidobacteria modulate immune response in pediatric patients with cow’s milk protein allergy. Pediatr Res 94, 1111–1118 (2023). https://doi.org/10.1038/s41390-023-02534-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41390-023-02534-0

Search

Advanced search

Quick links