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Microbiome dysbiosis: a modifiable state and target to prevent Staphylococcus aureus infections and other diseases in neonates

Journal of Perinatology volume 44, pages 125–130 (2024)Cite this article

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Abstract

Bacterial infections present a significant threat to neonates. Increasingly, studies demonstrate associations between human diseases and the microbiota, the communities of microorganisms on or in the body. A “healthy” microbiota with a great diversity and balance of microorganisms can resist harmful pathogens and protect against infections, whereas a microbiota suffering from dysbiosis, can predispose to pathogen colonization and subsequent infection. For decades, strategies such as bacterial interference, decolonization, prebiotics, and probiotics have been tested to reduce Staphylococcus aureus disease and other infections in neonates. More recently, microbiota transplant has emerged as a strategy to broadly correct dysbiosis, promote colonization resistance, and prevent infections. This paper discusses the benefits of a healthy neonate’s microbiota, exposures that alter the microbiota, associations of dysbiosis and neonatal disease, strategies to prevent dysbiosis, such as microbiota transplantation, and presents a framework of microbiome manipulation to reduce Staphylococcus aureus (S. aureus) and other infections in neonates.

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Fig. 1: Factors influencing the dynamic neonatal microbiome and strategies to prevent or correct an unhealthy microbiome.

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References

  1. Pammi M, Cope J, Tarr PI, Warner BB, Morrow AL, Mai V, et al. Intestinal dysbiosis in preterm infants preceding necrotizing enterocolitis: a systematic review and meta-analysis. Microbiome. 2017;5:31.

    PubMed  PubMed Central  Google Scholar 

  2. Zhao N, Khamash DF, Koh H, Voskertchian A, Egbert E, Mongodin EF, et al. Low diversity in nasal microbiome associated with Staphylococcus aureus colonization and bloodstream infections in hospitalized neonates. Open Forum Infect Dis. 2021;8:ofab475.

    PubMed  PubMed Central  Google Scholar 

  3. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. 2015;21:109–17.

    PubMed  Google Scholar 

  4. Pannaraj PS, Li F, Cerini C, Bender JM, Yang S, Rollie A, et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr. 2017;171:647–54.

    PubMed  PubMed Central  Google Scholar 

  5. Weyrich LS, Dixit S, Farrer AG, Cooper AJ, Cooper AJ. The skin microbiome: associations between altered microbial communities and disease. Aust J Dermatol. 2015;56:268–74.

    Google Scholar 

  6. Duar RM, Kyle D, Casaburi G. Colonization resistance in the infant gut: the role of B. infantis in reducing pH and preventing pathogen growth. High Throughput. 2020;9:7.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hoang DM, Levy EI, Vandenplas Y. The impact of caesarean section on the infant gut microbiome. Acta Paediatr. 2021;110:60–7.

    PubMed  Google Scholar 

  8. Parnanen KMM, Hultman J, Markkanen M, Satokari R, Rautava S, Lamendella R, et al. Early-life formula feeding is associated with infant gut microbiota alterations and an increased antibiotic resistance load. Am J Clin Nutr. 2022;115:407–21.

    PubMed  Google Scholar 

  9. Reyman M, van Houten MA, Watson RL, Chu M, Arp K, de Waal WJ, et al. Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial. Nat Commun. 2022;13:893.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Madan JC, Koestler DC, Stanton BA, Davidson L, Moulton LA, Housman ML, et al. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. mBio. 2012;3:e00251–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Stressmann FA, Rogers GB, van der Gast CJ, Marsh P, Vermeer LS, Carroll MP, et al. Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience. Thorax. 2012;67:867–73.

    PubMed  Google Scholar 

  12. Lee CC, Feng Y, Yeh YM, Lien R, Chen CL, Zhou YL, et al. Gut dysbiosis, bacterial colonization and translocation, and neonatal sepsis in very-low-birth-weight preterm infants. Front Microbiol. 2021;12:746111.

    PubMed  PubMed Central  Google Scholar 

  13. Graspeuntner S, Waschina S, Kunzel S, Twisselmann N, Rausch TK, Cloppenborg-Schmidt K, et al. Gut dysbiosis with Bacilli dominance and accumulation of fermentation products precedes late-onset sepsis in preterm infants. Clin Infect Dis. 2019;69:268–77.

    CAS  PubMed  Google Scholar 

  14. Mukhopadhyay S, Lee JJ, Hartman E, Woodford E, Dhudasia MB, Mattei LM, et al. Preterm infants at low risk for early-onset sepsis differ in early fecal microbiome assembly. Gut Microbes. 2022;14:2154091.

    PubMed  PubMed Central  Google Scholar 

  15. Nurjadi D, Eichel VM, Tabatabai P, Klein S, Last K, Mutters NT, et al. Surveillance for colonization, transmission, and infection with methicillin-susceptible Staphylococcus aureus in a neonatal intensive care unit. JAMA Netw Open. 2021;4:e2124938.

    PubMed  PubMed Central  Google Scholar 

  16. Schwartz DJ, Shalon N, Wardenburg K, DeVeaux A, Wallace MA, Hall-Moore C, et al. Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit. Sci Transl Med. 2023;15:eadg5562.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Fujimura KE, Sitarik AR, Havstad S, Lin DL, Levan S, Fadrosh D, et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat Med. 2016;22:1187–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Stewart CJ, Ajami NJ, O’Brien JL, Hutchinson DS, Smith DP, Wong MC, et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature. 2018;562:583–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chi C, Buys N, Li C, Sun J, Yin C. Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis. Eur J Clin Nutr. 2019;73:657–70.

    CAS  PubMed  Google Scholar 

  20. Sharif S, Oddie SJ, Heath PT, McGuire W. Prebiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants. Cochrane Database Syst Rev. 2023;6:CD015133.

    PubMed  Google Scholar 

  21. Patel RM, Underwood MA. Probiotics and necrotizing enterocolitis. Semin Pediatr Surg. 2018;27:39–46.

    PubMed  Google Scholar 

  22. Chi C, Li C, Buys N, Wang W, Yin C, Sun J. Effects of probiotics in preterm infants: a network meta-analysis. Pediatrics. 2021;147:e20200706.

    PubMed  Google Scholar 

  23. Zhang GQ, Hu HJ, Liu CY, Shakya S, Li ZY. Probiotics for preventing late-onset sepsis in preterm neonates: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Medicine. 2016;95:e2581.

    PubMed  PubMed Central  Google Scholar 

  24. Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B, McMaster Probiotic P, et al. Probiotics reduce mortality and morbidity in preterm, low-birth-weight infants: a systematic review and network meta-analysis of randomized trials. Gastroenterology. 2020;159:467–80.

    CAS  PubMed  Google Scholar 

  25. Bertelli C, Pillonel T, Torregrossa A, Prod’hom G, Fischer CJ, Greub G, et al. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin Infect Dis. 2015;60:924–7.

    CAS  PubMed  Google Scholar 

  26. Cavicchiolo ME, Magnani M, Calgaro S, Bonadies L, Castagliulo I, Morelli L, et al. Neonatal sepsis associated with Lactobacillus supplementation. J Perinat Med. 2019;48:87–88.

    PubMed  Google Scholar 

  27. Chiang MC, Chen CL, Feng Y, Chen CC, Lien R, Chiu CH. Lactobacillus rhamnosus sepsis associated with probiotic therapy in an extremely preterm infant: pathogenesis and a review for clinicians. J Microbiol Immunol Infect. 2021;54:575–80.

    CAS  PubMed  Google Scholar 

  28. Poindexter B, Committee on Fetus and Newborn. Use of probiotics in preterm infants. Pediatrics. 2021;147:e2021051485.

    PubMed  Google Scholar 

  29. Govindarajan V, Devadas S, Shah PA, Diggikar S. Impact of kangaroo mother care on skin microbiome of very preterm infants - a pilot study. Indian J Pediatr. 2023. https://doi.org/10.1007/s12098-023-04562-4. Epub ahead of print.

  30. Hendricks-Munoz KD, Xu J, Parikh HI, Xu P, Fettweis JM, Kim Y, et al. Skin-to-skin care and the development of the preterm infant oral microbiome. Am J Perinatol. 2015;32:1205–16.

    PubMed  PubMed Central  Google Scholar 

  31. Chan GJ, Valsangkar B, Kajeepeta S, Boundy EO, Wall S. What is kangaroo mother care? Systematic review of the literature. J Glob Health. 2016;6:010701.

    PubMed  PubMed Central  Google Scholar 

  32. Arya S, Chhabra S, Singhal R, Kumari A, Wadhwa N, Anand P, et al. Effect on neonatal sepsis following immediate kangaroo mother care in a newborn intensive care unit: a post-hoc analysis of a multicentre, open-label, randomised controlled trial. EClinicalMedicine. 2023;60:102006.

    PubMed  PubMed Central  Google Scholar 

  33. Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis. 2015;15:191.

    PubMed  PubMed Central  Google Scholar 

  34. Khan MY, Dirweesh A, Khurshid T, Siddiqui WJ. Comparing fecal microbiota transplantation to standard-of-care treatment for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2018;30:1309–17.

    PubMed  Google Scholar 

  35. Yoon YK, Suh JW, Kang EJ, Kim JY. Efficacy and safety of fecal microbiota transplantation for decolonization of intestinal multidrug-resistant microorganism carriage: beyond Clostridioides difficile infection. Ann Med. 2019;51:379–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nicholson MR, Mitchell PD, Alexander E, Ballal S, Bartlett M, Becker P, et al. Efficacy of fecal microbiota transplantation for clostridium difficile infection in children. Clin Gastroenterol Hepatol. 2020;18:612–9.e11.

    PubMed  Google Scholar 

  37. Korpela K, Helve O, Kolho KL, Saisto T, Skogberg K, Dikareva E, et al. Maternal fecal microbiota transplantation in cesarean-born infants rapidly restores normal gut microbial development: a proof-of-concept study. Cell. 2020;183:324–34.e5.

    CAS  PubMed  Google Scholar 

  38. Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22:250–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Committee Opinion No. 725: Vaginal Seeding. Obstet Gynecol. 2017;130:e274-e278.

  40. Weiner-Lastinger LM, Abner S, Edwards JR, Kallen AJ, Karlsson M, Magill SS, et al. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: summary of data reported to the National Healthcare Safety Network, 2015-7. Infect Control Hosp Epidemiol. 2020;41:1–18.

    PubMed  Google Scholar 

  41. Ericson JE, Popoola VO, Smith PB, Benjamin DK, Fowler VG, Benjamin DK Jr, et al. Burden of invasive Staphylococcus aureus infections in hospitalized infants. JAMA Pediatr. 2015;169:1105–11.

    PubMed  PubMed Central  Google Scholar 

  42. Huang YC, Chou YH, Su LH, Lien RI, Lin TY. Methicillin-resistant Staphylococcus aureus colonization and its association with infection among infants hospitalized in neonatal intensive care units. Pediatrics. 2006;118:469–74.

    PubMed  Google Scholar 

  43. Song X, Cheung S, Klontz K, Short B, Campos J, Singh N. A stepwise approach to control an outbreak and ongoing transmission of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit. Am J Infect Control. 2010;38:607–11.

    PubMed  Google Scholar 

  44. Gregory ML, Eichenwald EC, Puopolo KM. Seven-year experience with a surveillance program to reduce methicillin-resistant Staphylococcus aureus colonization in a neonatal intensive care unit. Pediatrics. 2009;123:e790–6.

    PubMed  Google Scholar 

  45. Maraqa NF, Aigbivbalu L, Masnita-Iusan C, Wludyka P, Shareef Z, Bailey C, et al. Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus colonization and infection among infants at a level III neonatal intensive care unit. Am J Infect Control. 2011;39:35–41.

    PubMed  Google Scholar 

  46. Shane AL, Hansen NI, Stoll BJ, Bell EF, Sanchez PJ, Shankaran S, et al. Methicillin-resistant and susceptible Staphylococcus aureus bacteremia and meningitis in preterm infants. Pediatrics. 2012;129:e914–22.

    PubMed  PubMed Central  Google Scholar 

  47. Milstone AM, Voskertchian A, Koontz DW, Khamash DF, Ross T, Aucott SW, et al. Effect of treating parents colonized with Staphylococcus aureus on transmission to neonates in the intensive care unit: a randomized clinical trial. JAMA. 2020;323:319–28.

    PubMed  Google Scholar 

  48. Khamash DF, Voskertchian A, Milstone AM. Manipulating the microbiome: evolution of a strategy to prevent S. aureus disease in children. J Perinatol. 2018;38:105–9.

    CAS  PubMed  Google Scholar 

  49. Houck PW, Nelson JD, Kay JL. Fatal septicemia due to Staphylococcus aureus 502A. Report of a case and review of the infectious complications of bacterial interference programs. Am J Dis Child. 1972;123:45–8.

    CAS  PubMed  Google Scholar 

  50. Uehara Y, Nakama H, Agematsu K, Uchida M, Kawakami Y, Abdul Fattah AS, et al. Bacterial interference among nasal inhabitants: eradication of Staphylococcus aureus from nasal cavities by artificial implantation of Corynebacterium sp. J Hosp Infect. 2000;44:127–33.

    CAS  PubMed  Google Scholar 

  51. Piewngam P, Khongthong S, Roekngam N, Theapparat Y, Sunpaweravong S, Faroongsarng D, et al. Probiotic for pathogen-specific Staphylococcus aureus decolonisation in Thailand: a phase 2, double-blind, randomised, placebo-controlled trial. Lancet Microbe. 2023;4:e75–83.

    PubMed  Google Scholar 

  52. Heinrich N, Mueller A, Bartmann P, Simon A, Bierbaum G, Engelhart S. Successful management of an MRSA outbreak in a neonatal intensive care unit. Eur J Clin Microbiol Infect Dis. 2011;30:909–13.

    CAS  PubMed  Google Scholar 

  53. Hitomi S, Kubota M, Mori N, Baba S, Yano H, Okuzumi K, et al. Control of a methicillin-resistant Staphylococcus aureus outbreak in a neonatal intensive care unit by unselective use of nasal mupirocin ointment. J Hosp Infect. 2000;46:123–9.

    CAS  PubMed  Google Scholar 

  54. Jernigan JA, Titus MG, Groschel DH, Getchell-White S, Farr BM. Effectiveness of contact isolation during a hospital outbreak of methicillin-resistant Staphylococcus aureus. Am J Epidemiol. 1996;143:496–504.

    CAS  PubMed  Google Scholar 

  55. Milstone AM, Budd A, Shepard JW, Ross T, Aucott S, Carroll KC, et al. Role of decolonization in a comprehensive strategy to reduce methicillin-resistant Staphylococcus aureus infections in the neonatal intensive care unit: an observational cohort study. Infect Control Hosp Epidemiol. 2010;31:558–60.

    PubMed  PubMed Central  Google Scholar 

  56. Milstone AM, Song X, Coffin S, Elward A. Identification and eradication of methicillin-resistant Staphylococcus aureus colonization in the neonatal intensive care unit: results of a national survey. Infect Control Hosp Epidemiol. 2010;31:766–8.

    PubMed  PubMed Central  Google Scholar 

  57. Delaney HM, Wang E, Melish M. Comprehensive strategy including prophylactic mupirocin to reduce Staphylococcus aureus colonization and infection in high-risk neonates. J Perinatol. 2013;33:313–8.

    CAS  PubMed  Google Scholar 

  58. You JH, Chan CY, Wong MY, Ip M. Active surveillance and decolonization of methicillin-resistant Staphylococcus aureus on admission to neonatal intensive care units in Hong Kong: a cost-effectiveness analysis. Infect Control Hosp Epidemiol. 2012;33:1024–30.

    PubMed  Google Scholar 

  59. Popoola VO, Colantuoni E, Suwantarat N, Pierce R, Carroll KC, Aucott SW, et al. Active surveillance cultures and decolonization to reduce Staphylococcus aureus infections in the neonatal intensive care unit. Infect Control Hosp Epidemiol. 2016;37:381–7.

    PubMed  PubMed Central  Google Scholar 

  60. Popoola VO, Milstone AM. Decolonization to prevent Staphylococcus aureus transmission and infections in the neonatal intensive care unit. J Perinatol. 2014;34:805–10.

    CAS  PubMed  Google Scholar 

  61. Voskertchian A, Akinboyo IC, Colantuoni E, Johnson J, Milstone AM. Association of an active surveillance and decolonization program on incidence of clinical cultures growing Staphylococcus aureus in the neonatal intensive care unit. Infect Control Hosp Epidemiol. 2018;39:882–4.

    PubMed  PubMed Central  Google Scholar 

  62. Ristagno EH, Bryant KA, Boland LF, Stout GG, Junkins AD, Woods CR, et al. Effect of intranasal mupirocin prophylaxis on methicillin-resistant Staphylococcus aureus transmission and invasive staphylococcal infections in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 2018;39:741–5.

    PubMed  Google Scholar 

  63. Akinboyo IC, Voskertchian A, Gorfu G, Betz JF, Ross TL, Carroll KC, et al. Epidemiology and risk factors for recurrent Staphylococcus aureus colonization following active surveillance and decolonization in the NICU. Infect Control Hosp Epidemiol. 2018;39:1334–9.

    PubMed  PubMed Central  Google Scholar 

  64. Chapman AK, Aucott SW, Gilmore MM, Advani S, Clarke W, Milstone AM. Absorption and tolerability of aqueous chlorhexidine gluconate used for skin antisepsis prior to catheter insertion in preterm neonates. J Perinatol. 2013;33:768–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Chapman AK, Aucott SW, Milstone AM. Safety of chlorhexidine gluconate used for skin antisepsis in the preterm infant. J Perinatol. 2012;32:4–9.

    CAS  PubMed  Google Scholar 

  66. Tamma PD, Aucott SW, Milstone AM. Chlorhexidine use in the neonatal intensive care unit: results from a national survey. Infect Control Hosp Epidemiol. 2010;31:846–9.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institutes of Health under Award Numbers K24AI141580 (AMM), K23HD100594 (JJ), T32 AI052071 (ECP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anushree Aneja, Erica C. Prochaska & Aaron M. Milstone

  2. Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Julia Johnson

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Aneja, A., Johnson, J., Prochaska, E.C. et al. Microbiome dysbiosis: a modifiable state and target to prevent Staphylococcus aureus infections and other diseases in neonates. J Perinatol 44, 125–130 (2024). https://doi.org/10.1038/s41372-023-01810-5

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