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.

  • Basic Science Article
  • Published:

Multi-strain probiotic administration decreases necrotizing enterocolitis severity and alters the epigenetic profile in mice

Pediatric Research (2024)Cite this article

Abstract

Background

Probiotic administration may decrease the incidence of necrotizing enterocolitis (NEC) through mechanisms that are largely unknown. We investigated the effects of probiotics on intestinal epigenetics and assessed their effects on intestinal inflammation and motility using both ileum-predominant and combined ileo-colitis mouse NEC models.

Methods

C57BL/6 J mice were gavage-fed a multi-strain probiotic from postnatal days 3-11, consisting of B. infantis, B. lactis, and S. thermophilus. From p8, mice were exposed to ileo-colitis NEC involving formula containing NEC bacteria and 0.5% DSS. DNA methylation was measured using the Infinium Methylation Assay. Gastrointestinal motility was assessed by 70 Kd FITC-dextran transit time. Probiotic colonization was measured in probiotic-fed mice by qPCR.

Results

Probiotic administration caused significant changes in the small intestine’s epigenetic signature, a reduction in NEC severity, and improved intestinal motility. The effects of probiotics were more pronounced in the ileo-colitis NEC model.

Conclusions

These findings shed light on the role of probiotics in two clinically relevant models of NEC, add additional insights into their underlying mechanism of action, and reveal unanticipated epigenetic modifications to the intestinal mucosa after their use.

Impact

  • These findings shed light on the role of multi-strain probiotics in two clinically relevant animal models of NEC, and add additional insights into their underlying mechanism of action

  • This study provides a new, clinically relevant model for the study of NEC including administration of 0.5% DSS, to include ileal dominant and ileo-colonic dominant phenotypes of the disease.

  • These results reveal that clinically relevant strains of probiotic bacteria can exert epigenetic effects on the small intestine in mice, and can attenuate the epigenetic changes induced by NEC.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Establishment of a clinically relevant murine NEC model with the administration of a multi-strain probiotic.
Fig. 2: The administration of probiotics reduces inflammation in an ileo-colitis NEC model.
Fig. 3: Administration of a multi-strain probiotic promotes small intestinal motility in experimental NEC.
Fig. 4: Probiotic administration reduces TLR4-induced inflammation in cells and mice.
Fig. 5: Probiotic administration induces significant epigenetic changes in the iileum of mice.

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are partially available in the supplementary material, additional information is available from the corresponding author on reasonable request. The R-scripts used for DNA methylation analyses are available on Github https://github.com/hannahmoore6/Multi-strain-Probiotic-Administration-Methylation-Assay.

References

  1. Hackam, D. J. & Sodhi, C. P. Bench to bedside—new insights into the pathogenesis of necrotizing enterocolitis. Nat. Rev. Gastroenterol. Hepatol. 19, 468–479 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Lin, P. W. & Stoll, B. J. Necrotising enterocolitis. Lancet 368, 1271–1283 (2006).

    Article  PubMed  Google Scholar 

  3. Pammi, M. et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome 5, 31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Scheese, D. J., Sodhi, C. P. & Hackam, D. J. New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics. Semin Pediatr. Surg. 32, 151309 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Singh, D. K. et al. Necrotizing enterocolitis: bench to bedside approaches and advancing our understanding of disease pathogenesis. Front Pediatr. 10, 1107404 (2022).

    Article  PubMed  Google Scholar 

  6. Cilieborg, M. S., Boye, M. & Sangild, P. T. Bacterial colonization and gut development in preterm neonates. Early Hum. Dev. 88, S41–S49 (2012).

    Article  PubMed  Google Scholar 

  7. Yu, D. H. et al. Postnatal epigenetic regulation of intestinal stem cells requires DNA methylation and is guided by the microbiome. Genome Biol. 16, 211 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Good, M. et al. Global hypermethylation of intestinal epithelial cells is a Hallmark feature of neonatal surgical necrotizing enterocolitis. Clin. Epigenet. 12, 190 (2020).

    Article  CAS  Google Scholar 

  9. Good, M. et al. Neonatal necrotizing enterocolitis-associated DNA methylation signatures in the colon are evident in stool samples of affected individuals. Epigenomics 13, 829–844 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tian, B. et al. Epigenetic insights into necrotizing enterocolitis: unraveling methylation-regulated biomarkers. Inflammation (2024).

  11. Liu, Y., Fatheree, N. Y., Mangalat, N. & Rhoads, J. M. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of Tlr4 and Nf-Kappab signaling in the intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G608–G617 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Jilling, T., Lu, J., Jackson, M. & Caplan, M. S. Intestinal epithelial apoptosis initiates gross bowel necrosis in an experimental rat model of neonatal necrotizing enterocolitis. Pediatr. Res. 55, 622–629 (2004).

    Article  PubMed  Google Scholar 

  13. Afrazi, A. et al. Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J. Biol. Chem. 289, 9584–9599 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Werts, A. D. et al. A novel role for necroptosis in the pathogenesis of necrotizing enterocolitis. Cell Mol. Gastroenterol. Hepatol. 9, 403–423 (2020).

    Article  PubMed  Google Scholar 

  15. Sodhi, C. P. et al. Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. Gastroenterology 138, 185–196 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Neal, M. D. et al. Toll-like receptor 4 is expressed on intestinal stem cells and regulates their proliferation and apoptosis via the P53 up-regulated modulator of apoptosis. J. Biol. Chem. 287, 37296–37308 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sodhi, C. P. et al. The human milk oligosaccharides 2’-fucosyllactose and 6’-sialyllactose protect against the development of necrotizing enterocolitis by inhibiting toll-like receptor 4 signaling. Pediatr. Res. 89, 91–101 (2021).

    Article  CAS  PubMed  Google Scholar 

  18. Good, M. et al. Breast milk protects against the development of necrotizing enterocolitis through inhibition of toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor. Mucosal Immunol. 8, 1166–1179 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sodhi, C. P. et al. Intestinal epithelial toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology 143, 708–718 e705 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Egan, C. E. et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J. Clin. Invest 126, 495–508 (2016).

    Article  PubMed  Google Scholar 

  21. Gribar, S. C. et al. Reciprocal expression and signaling of Tlr4 and Tlr9 in the pathogenesis and treatment of necrotizing enterocolitis. J. Immunol. 182, 636–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Tran, L. et al. Necrotizing enterocolitis and cytomegalovirus infection in a premature infant. Pediatrics 131, e318–e322 (2013).

    Article  PubMed  Google Scholar 

  23. Hackam, D. J., Good, M. & Sodhi, C. P. Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis: toll-like receptors throw the switch. Semin Pediatr. Surg. 22, 76–82 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kashif, H., Abuelgasim, E., Hussain, N., Luyt, J. & Harky, A. Necrotizing enterocolitis and congenital heart disease. Ann. Pediatr. Cardiol. 14, 507–515 (2021).

    Article  PubMed  Google Scholar 

  25. Garg, P. M. et al. Intestinal resection is more likely to be effective in necrotizing enterocolitis extending to colon than in disease limited to the small intestine. Newborn (Clarksville) 1, 14–26 (2022).

    Article  PubMed  Google Scholar 

  26. Wang, Y. et al. Probiotics, prebiotics, lactoferrin, and combination products for prevention of mortality and morbidity in preterm infants: a systematic review and network meta-analysis. JAMA Pediatr. 177, 1158–1167 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    Article  PubMed  Google Scholar 

  28. Chi, C. et al. Effects of probiotics in preterm infants: a network meta-analysis. Pediatrics 147, e20200706 (2021).

  29. Sharif, S., Meader, N., Oddie, S. J., Rojas-Reyes, M. X. & McGuire, W. Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst. Rev. 7, CD005496 (2023).

    PubMed  Google Scholar 

  30. Barbian, M. E. & Patel, R. M. Probiotics for prevention of necrotizing enterocolitis: where do we stand? Semin. Perinatol. 47, 151689 (2023).

    Article  PubMed  Google Scholar 

  31. Underwood, M. A. et al. Bifidobacterium longum Subsp. Infantis in experimental necrotizing enterocolitis: alterations in inflammation, innate immune response, and the microbiota. Pediatr. Res. 76, 326–333 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shiou, S. R. et al. Synergistic protection of combined probiotic conditioned media against neonatal necrotizing enterocolitis-like intestinal injury. PLoS One 8, e65108 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Alsharairi, N. A. Therapeutic potential of gut microbiota and its metabolite short-chain fatty acids in neonatal necrotizing enterocolitis. Life (Basel) 13, 561 (2023).

  34. Sadeghpour Heravi, F. & Hu, H. Bifidobacterium: host-microbiome interaction and mechanism of action in preventing common gut-microbiota-associated complications in preterm infants: a narrative review. Nutrients 15, 709 (2023).

  35. Patel, R. M. & Underwood, M. A. Probiotics and necrotizing enterocolitis. Semin. Pediatr. Surg. 27, 39–46 (2018).

    Article  PubMed  Google Scholar 

  36. Luo, Z. et al. Limosilactobacillus reuteri in immunomodulation: molecular mechanisms and potential applications. Front Immunol. 14, 1228754 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Good, M. et al. Lactobacillus rhamnosus Hn001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of Tlr9. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G1021–G1032 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ansari, I. et al. The microbiota programs DNA methylation to control intestinal homeostasis and inflammation. Nat. Microbiol. 5, 610–619 (2020).

    Article  CAS  PubMed  Google Scholar 

  39. Cortese, R., Lu, L., Yu, Y., Ruden, D. & Claud, E. C. Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 11, 205–215 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Plummer, E. L. et al. Gut microbiota of preterm infants supplemented with probiotics: sub-study of the proprems trial. BMC Microbiol. 18, 184 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang, W. et al. Clinical efficacy of probiotics on feeding intolerance in preterm infants: a systematic review and meta-analysis. Transl. Pediatr. 11, 229–238 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kovler, M. L. et al. Toll-like receptor 4-mediated enteric glia loss is critical for the development of necrotizing enterocolitis. Sci. Transl. Med. 13, eabg3459 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. van den Akker, C. H. P. et al. Probiotics and preterm infants: a position paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. J. Pediatr. Gastroenterol. Nutr. 70, 664–680 (2020).

    Article  PubMed  Google Scholar 

  44. Jacobs, S. E. et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 132, 1055–1062 (2013).

    Article  PubMed  Google Scholar 

  45. Miller, M. S., Galligan, J. J. & Burks, T. F. Accurate measurement of intestinal transit in the rat. J. Pharm. Methods 6, 211–217 (1981).

    Article  CAS  Google Scholar 

  46. Zhou, W. et al. DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse. Cell Genom. 2, 100144 (2022).

  47. Zhou, W., Triche, T. J. Jr., Laird, P. W. & Shen, H. Sesame: reducing artifactual detection of DNA methylation by infinium beadchips in genomic deletions. Nucleic Acids Res. 46, e123 (2018).

    PubMed  PubMed Central  Google Scholar 

  48. Triche, T. J. Jr., Weisenberger, D. J., Van Den Berg, D., Laird, P. W. & Siegmund, K. D. Low-level processing of illumina infinium DNA methylation beadarrays. Nucleic Acids Res. 41, e90 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Summarizedexperiment: Summarizedexperiment Container. R Package Version 1.32.0, https://Bioconductor.Org/Packages/Summarizedexperiment (2023).

  50. Viennois, E., Chen, F., Laroui, H., Baker, M. T. & Merlin, D. Dextran sodium sulfate inhibits the activities of both polymerase and reverse transcriptase: lithium chloride purification, a rapid and efficient technique to purify RNA. BMC Res. Notes 6, 360 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sodhi, C. P. et al. Fat composition in infant formula contributes to the severity of necrotising enterocolitis. Br. J. Nutr. 120, 665–680 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Quaroni, A., Isselbacher, K. J. & Ruoslahti, E. Fibronectin synthesis by epithelial crypt cells of rat small intestine. Proc. Natl. Acad. Sci. USA 75, 5548–5552 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Good, M. et al. Amniotic fluid inhibits toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc. Natl. Acad. Sci. USA 109, 11330–11335 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Remon, J. I. et al. Depth of bacterial invasion in resected intestinal tissue predicts mortality in surgical necrotizing enterocolitis. J. Perinatol. 35, 755–762 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lambert, D. K. et al. Necrotizing enterocolitis in term neonates: data from a multihospital health-care system. J. Perinatol. 27, 437–443 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Chassaing, B., Aitken, J. D., Malleshappa, M. & Vijay-Kumar, M. Dextran sulfate sodium (Dss)-induced colitis in mice. Curr. Protoc. Immunol. 104, 15 25 11–15 25 14 (2014).

    Article  Google Scholar 

  57. Ginzel, M. et al. Dextran sodium sulfate (Dss) induces necrotizing enterocolitis-like lesions in neonatal mice. PLoS One 12, e0182732 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Leaphart, C. L. et al. A critical role for Tlr4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. J. Immunol. 179, 4808–4820 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Cao, M. et al. Physical activity and gastric residuals as biomarkers for region-specific nec lesions in preterm neonates. Neonatology 110, 241–247 (2016).

    Article  PubMed  Google Scholar 

  60. Pan, X. et al. Blood transcriptomic markers of necrotizing enterocolitis in preterm pigs. Pediatr. Res. 91, 1113–1120 (2022).

    Article  CAS  PubMed  Google Scholar 

  61. Raouf, Z. et al. Colitis-induced small intestinal hypomotility is dependent on enteroendocrine cell loss in mice. Cell Mol. Gastroenterol. Hepatol. 18, 53–70 (2024).

  62. Henrick, B. M. et al. Bifidobacteria-mediated immune system imprinting early in life. Cell 184, 3884–3898 e3811 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Toumi, R. et al. Beneficial role of the probiotic mixture ultrabiotique on maintaining the integrity of intestinal mucosal barrier in Dss-induced experimental colitis. Immunopharmacol. Immunotoxicol. 35, 403–409 (2013).

    Article  PubMed  Google Scholar 

  64. Zhang, Y. et al. Probiotic mixture protects dextran sulfate sodium-induced colitis by altering tight junction protein expressions and increasing Tregs. Med. Inflamm. 2018, 9416391 (2018).

    Article  Google Scholar 

  65. Khailova, L. et al. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am. J. Physiol. Gastrointest. Liver Physiol. 297, G940–G949 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yan, F. & Polk, D. B. Probiotics and probiotic-derived functional factors-mechanistic insights into applications for intestinal homeostasis. Front Immunol. 11, 1428 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Walsh, C., Lane, J. A., Van Sinderen, D. & Hickey, R. M. Human milk oligosaccharide-sharing by a consortium of infant derived bifidobacterium species. Sci. Rep. 12, 4143 (2022).

  68. Chandrasekharan, B. et al. Interactions between commensal bacteria and enteric neurons, via Fpr1 induction of ros, increase gastrointestinal motility in mice. Gastroenterology 157, 179–192 e172 (2019).

    Article  CAS  PubMed  Google Scholar 

  69. Dimidi, E., Christodoulides, S., Fragkos, K. C., Scott, S. M. & Whelan, K. The effect of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 100, 1075–1084 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Indrio, F. et al. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J. Pediatr. 152, 801–806 (2008).

    Article  PubMed  Google Scholar 

  71. Chen, W. et al. Gut transit time, using radiological contrast imaging, to predict early signs of necrotizing enterocolitis. Pediatr. Res. 89, 127–133 (2021).

    Article  PubMed  Google Scholar 

  72. Mischke, M. & Plosch, T. The gut microbiota and their metabolites: potential implications for the host epigenome. Adv. Exp. Med. Biol. 902, 33–44 (2016).

    Article  PubMed  Google Scholar 

  73. Merid, S. K. et al. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med. 12, 25 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Al-Hadidi, A., Navarro, J., Goodman, S. D., Bailey, M. T. & Besner, G. E. Lactobacillus reuteri in its biofilm state improves protection from experimental necrotizing enterocolitis. Nutrients 13, 918 (2021).

Download references

Acknowledgements

We would like to thank all the undergrad students involved in this research project for their help, in particular Thomas Cancian, Diego Kaune and Dylan Yoon, as well as the supporting staff of the Johns Hopkins Miller Research Building Animal Facility, particularly Nancy Lim. We would also like to thank Roxann Ashworth, Co-Director of the Johns Hopkins Genetic Resources Core Facility (GRCF) for her assistance with the DNA methylation analyses. All schematic model overviews in the figures were created using Biorender.com.

Funding

D.H.K. was supported by a Royal Netherlands Academy of Arts and Sciences (KNAW) Ter Meulen Grant. D.J.H. is supported by R35 GM141956 and C.T., C.L. and D.S. are supported by T32DK007713.

Author information

Authors and Affiliations

  1. Division of Pediatric Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Daphne H. Klerk, Hannah Moore, Daniel J. Scheese, Cody Tragesser, Zachariah Raouf, Johannes W. Duess, Koichi Tsuboi, Maame E. Sampah, Carla M. Lopez, Sierra Williams-McLeod, Mahmoud G. El Baassiri, Hee-Seong Jang, Thomas Prindle Jr., Sanxia Wang, Menghan Wang, William B. Fulton, Chhinder P. Sodhi & David J. Hackam

  2. Division of Neonatology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Daphne H. Klerk

Authors
  1. Daphne H. Klerk
    View author publications

    Search author on:PubMed Google Scholar

  2. Hannah Moore
    View author publications

    Search author on:PubMed Google Scholar

  3. Daniel J. Scheese
    View author publications

    Search author on:PubMed Google Scholar

  4. Cody Tragesser
    View author publications

    Search author on:PubMed Google Scholar

  5. Zachariah Raouf
    View author publications

    Search author on:PubMed Google Scholar

  6. Johannes W. Duess
    View author publications

    Search author on:PubMed Google Scholar

  7. Koichi Tsuboi
    View author publications

    Search author on:PubMed Google Scholar

  8. Maame E. Sampah
    View author publications

    Search author on:PubMed Google Scholar

  9. Carla M. Lopez
    View author publications

    Search author on:PubMed Google Scholar

  10. Sierra Williams-McLeod
    View author publications

    Search author on:PubMed Google Scholar

  11. Mahmoud G. El Baassiri
    View author publications

    Search author on:PubMed Google Scholar

  12. Hee-Seong Jang
    View author publications

    Search author on:PubMed Google Scholar

  13. Thomas Prindle Jr.
    View author publications

    Search author on:PubMed Google Scholar

  14. Sanxia Wang
    View author publications

    Search author on:PubMed Google Scholar

  15. Menghan Wang
    View author publications

    Search author on:PubMed Google Scholar

  16. William B. Fulton
    View author publications

    Search author on:PubMed Google Scholar

  17. Chhinder P. Sodhi
    View author publications

    Search author on:PubMed Google Scholar

  18. David J. Hackam
    View author publications

    Search author on:PubMed Google Scholar

Contributions

D.J.H., C.P.S., D.H.K., H.M., D.J.S., C.T., Z.R., J.W.D., K.T., M.E.S., S.W., M.G.E.B., H.J., T.P., S.W., M.W., and W.B.F. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. D.J.H., C.P.S., D.H.K. and H.M. drafted the article or revised it critically for important intellectual content; and all authors gave their final approval of the version to be published.

Corresponding authors

Correspondence to Chhinder P. Sodhi or David J. Hackam.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

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

Klerk, D.H., Moore, H., Scheese, D.J. et al. Multi-strain probiotic administration decreases necrotizing enterocolitis severity and alters the epigenetic profile in mice. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03716-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-024-03716-0

This article is cited by

Search

Advanced search

Quick links