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.

  • Review Article
  • Published:

Lactobacillus rhamnosus GG as a probiotic for preterm infants: a strain specific systematic review and meta-analysis

European Journal of Clinical Nutrition (2024)Cite this article

Subjects

Abstract

Lactobacillus rhamnosus GG (LGG) is a widely used and extensively researched probiotic. Probiotic effects are considered to be strain specific. We aimed to comprehensively assess the strain-specific effects of LGG in preterm infants. A systematic review of RCTs and non-RCTs to evaluate the effect of LGG in preterm infants. We followed the Cochrane methodology, and preferred reporting items for systematic reviews (PRISMA) statement for conducting and reporting this review. We searched the Cochrane central register of controlled trials, PubMed, EMBASE and CINAHL databases till December 2023. The review was registered in PROSPERO 2022 CRD42022324933. Meta-analysis of data from RCTs that used LGG as the sole probiotic showed significantly lower risk of NEC ≥Stage II [5 RCTs, n = 851, RR:0.50 (95% CI: 0.26, 0.93), P = 0.03] in the LGG group. There was no significant difference in the risk of LOS [7 RCTs, n = 1037, RR:1.08 (95% CI 0.84, 1.39), P = 0.55], mortality [3 RCTs, n = 207, RR: 0.99 (95% CI: 0.42, 2.33), P = 0.99], time to reach full feeds [2 RCTs, n = 19, SMD = 0.11 days (95% CI: −0.22, 0.45), P = 0.51] and duration of hospital stay [3 RCTs, n = 293, SMD: −0.14 days (95% CI: −0.37 to 0.09), P = 0.23]. Meta-analysis of data from non-RCTs showed no significant effect of LGG on NEC, LOS, and mortality. RCTs showed beneficial effects of LGG when used as the sole probiotic in reducing the risk of NEC, whereas observational studies did not. Strain-specific systematic review of LGG provides important data for guiding research and clinical practice.

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
Fig. 2: Forest plots of definite NEC, late-onset sepsis, mortality: single strain LGG vs control of RCTs.
Fig. 3: Forest plots of time to reach full feeds and duration of hospital stay: single strain LGG vs control of RCTs.
Fig. 4: Baujat plot investigating the source of heterogeneity for late-onset sepsis.
Fig. 5

Similar content being viewed by others

Data availability

Data reviewed and analysed during this meta-analysis is available from the corresponding author upon reasonable request.

References

  1. Araya M, Morelli L, Reid G, Sanders ME, Stanton C, Pineiro M, et al. Guidelines for the evaluation of probiotics in food. Joint FAO/WHO Working Group Report on drafting guidelines for the evaluation of probiotics in food. 2002:1-11.

  2. Morgan RL, Preidis GA, Kashyap PC, Weizman AV, Sadeghirad B. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Deshmukh M, Patole S. Prophylactic Probiotic Supplementation for Preterm Neonates-A Systematic Review and Meta-Analysis of Nonrandomized Studies. Adv Nutr. 2021;12:1411–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fuller R. Probiotics in man and animals. J Appl Bacteriol. 1989;66:365–78.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. Saturio S, Nogacka AM, Alvarado-Jasso GM, Salazar N, de Los Reyes-Gavilán CG, Gueimonde M, et al. Role of Bifidobacteria on Infant Health. Microorganisms. 2021;9:2415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Makino H. Bifidobacterial strains in the intestines of newborns originate from their mothers. Biosci Microbiota Food Health. 2018;37:79–85.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Un-Nisa A, Khan A, Zakria M, Siraj S, Ullah S, Tipu MK, et al. Updates on the Role of Probiotics against Different Health Issues: Focus on Lactobacillus. Int J Mol Sci. 2022;24:142.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boggio Marzet C, Burgos F, Del Compare M, Gerold I, Tabacco O, Vinderola G. Approach to probiotics in pediatrics: the role of Lactobacillus rhamnosus GG. Arch Argent Pediatr. 2022;120:e1–e7.

    PubMed  Google Scholar 

  10. Martinelli M, Banderali G, Bobbio M, Civardi E, Chiara A, D’Elios S, et al. Probiotics’ efficacy in paediatric diseases: which is the evidence? A critical review on behalf of the Italian Society of Pediatrics. Ital J Pediatr. 2020;46:104.

    Article  PubMed  PubMed Central  Google Scholar 

  11. van den Akker CHP, van Goudoever JB, Shamir R, Domellöf M, Embleton ND, Hojsak I, 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. 2020;70:664–80.

    Article  PubMed  Google Scholar 

  12. Mathipa-Mdakane MG, Thantsha MS. Lacticaseibacillus rhamnosus: A Suitable Candidate for the Construction of Novel Bioengineered Probiotic Strains for Targeted Pathogen Control. Foods. 2022;11:785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Papizadeh M, Rohani M, Hosseini SN, Abbas SA. Lactobacillus rhamnosus Gorbach-Goldin (GG): A top well-researched probiotic strain. J Med Bacteriology. 2016;5:46.

    CAS  Google Scholar 

  14. Forestier C, De Champs C, Vatoux C, Joly B. Probiotic activities of Lactobacillus casei rhamnosus: in vitro adherence to intestinal cells and antimicrobial properties. Res Microbiol. 2001;152:167–73.

    Article  CAS  PubMed  Google Scholar 

  15. Doron S, Snydman DR, Gorbach SL. Lactobacillus GG: bacteriology and clinical applications. Gastroenterol Clin North Am. 2005;34:483–98.

    Article  PubMed  Google Scholar 

  16. Tuomola EM, Ouwehand AC, Salminen SJ. The effect of probiotic bacteria on the adhesion of pathogens to human intestinal mucus. FEMS Immunol Med Microbiol. 1999;26:137–42.

    Article  CAS  PubMed  Google Scholar 

  17. Depoorter L, Vandenplas Y. Probiotics in Pediatrics. A Review and Practical Guide. Nutrients. 2021;13:2176.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Baujat B, Mahé C, Pignon JP, Hill C. A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials. Stat Med. 2002;21:2641–52.

    Article  PubMed  Google Scholar 

  20. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive–Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009;38:287–98.

    Article  PubMed  Google Scholar 

  21. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17:39.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Al-Hosni M, Duenas M, Hawk M, Stewart LA, Borghese RA, Cahoon M, et al. Probiotics-supplemented feeding in extremely low-birth-weight infants. J Perinatol. 2012;32:253–9.

    Article  CAS  PubMed  Google Scholar 

  23. Arora MK, Saini R. To study the role of probiotics in the prevention of necrotizing enterocolitis in preterm neonates. Int J Contemp Pediatr. 2017;4:1792–97.

    Article  Google Scholar 

  24. Chrzanowska-Liszewska D, Seliga-Siwecka J, Kornacka MK. The effect of Lactobacillus rhamnosus GG supplemented enteral feeding on the microbiotic flora of preterm infants-double blinded randomized control trial. Early Hum Dev. 2012;88:57–60.

    Article  PubMed  Google Scholar 

  25. Chowdhury T, Ali MM, Hossain MM, Singh J, Yousuf AN, Yasmin F, et al. Efficacy of Probiotics Versus Placebo in the Prevention of Necrotizing Enterocolitis in Preterm Very Low Birth Weight Infants: A Double-Blind Randomized Controlled Trial. J Coll Physicians Surg Pak. 2016;26:770–4.

    PubMed  Google Scholar 

  26. Dongol Singh SS, Klobassa DS, Resch B, Urlesberger B, Shrestha RP. Placebo Controlled Introduction of Prophylactic Supplementation of Probiotics to Decrease the Incidence of Necrotizing Enterocolitis at Dhulikhel Hospital in Nepal. Kathmandu Univ Med J (KUMJ). 2017;15:319–23.

    Google Scholar 

  27. Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A Prospective Double-blind Study Biol Neonate 2002;82:103–8.

    CAS  PubMed  Google Scholar 

  28. Dashti AS, Afjeh SA, Basiry A, Shirvani F, Seifi K, Taheri ZM. Prophylactic probiotics for prevention of necrotizing enterocolitis (NEC) in low birth weight neonates. Arch Pediatr Infect Dis. 2014;2:174–9.

    Article  Google Scholar 

  29. Dutta S, Ray P, Narang A. Comparison of stool colonization in premature infants by three dose regimes of a probiotic combination: a randomized controlled trial. Am J Perinatol. 2015;32:733–40.

    PubMed  Google Scholar 

  30. Fernández-Carrocera LA, Solis-Herrera A, Cabanillas-Ayón M, Gallardo-Sarmiento RB, García-Pérez CS, Montaño-Rodríguez R, et al. Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2012;98:F5–9.

    Article  PubMed  Google Scholar 

  31. Güney-Varal İ, Köksal N, Özkan H, Bağcı O, Doğan P. The effect of early administration of combined multi-strain and multi-species probiotics on gastrointestinal morbidities and mortality in preterm infants: A randomized controlled trial in a tertiary care unit. Turkish J Pediatr. 2017;59:13–9.

    Article  Google Scholar 

  32. Manzoni P, Mostert M, Leonessa ML, Priolo C, Farina D, Monetti C, et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis. 2006;42:1735–42.

    Article  CAS  PubMed  Google Scholar 

  33. Meha T, Jaiswal A, Raja A, Sinha A. Role of oral probiotics in prevention of necrotising enterocolitis in preterm neonates in a tertiary care centre in Northern India. Int J Contemp Pediatr. 2016;3:1293–6.

    Article  Google Scholar 

  34. Millar MR, Bacon C, Smith SL, Walker V, Hall MA. Enteral feeding of premature infants with Lactobacillus GG. Arch Dis Child. 1993;69:483–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Romeo M, Romeo D, Trovato L, Oliveri S, Palermo F, Cota F, et al. Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome. J Perinatol. 2011;31:63–9.

    Article  CAS  PubMed  Google Scholar 

  36. Rougé C, Piloquet H, Butel M-J, Berger B, Rochat F, Ferraris L, et al. Oral supplementation with probiotics in very-low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2009;89:1828–35.

    Article  PubMed  Google Scholar 

  37. Shashidhar A, Suman Rao P, Nesargi S, Bhat S, Chandrakala B. Probiotics for promoting feed tolerance in very low birth weight neonates—A randomized controlled trial. Indian Pediatr. 2017;54:363–7.

    Article  CAS  PubMed  Google Scholar 

  38. Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, et al. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. J Pediatr Gastroenterol Nutr. 2009;48:216–25.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Van Niekerk E, Nel DG, Blaauw R, Kirsten GF. Probiotics reduce necrotizing enterocolitis severity in HIV-exposed premature infants. J Tropical Pediatr. 2015;61:155–64.

    Article  Google Scholar 

  40. Agarwal R, Sharma N, Chaudhry R, Deorari A, Paul VK, Gewolb IH, et al. Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight neonates. J Pediatr Gastroenterol Nutr. 2003;36:397–402.

    PubMed  Google Scholar 

  41. K R. Role of Probiotics in Prevention of Necrotising Enterocolitis in Preterm Babies (Doctoral dissertation, Thanjavur Medical College, Thanjavur). 2016.

  42. Luoto R, Ruuskanen O, Waris M, Kalliomäki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2014;133:405–13.

    Article  PubMed  Google Scholar 

  43. Sadowska-Krawczenko I, Korbal P, Polak A, Wietlicka-Piszcz M, Szajewska H. Ocena skuteczności Lactobacillus rhamnosus ATC A07FA w zapobieganiu martwiczego zapalenia jelit wcześniaków z bardzo małą urodzeniową masą ciała: badanie z randomizacją (wstępne wyniki). Pediatr Pol. 2012;87:139–45.

    Article  Google Scholar 

  44. Pärtty A, Luoto R, Kalliomäki M, Salminen S, Isolauri E. Effects of early prebiotic and probiotic supplementation on development of gut microbiota and fussing and crying in preterm infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;163:1272–7.e1-2.

    Article  PubMed  Google Scholar 

  45. Havranek T, Al-Hosni M, Armbrecht E. Probiotics supplementation increases intestinal blood flow velocity in extremely low birth weight preterm infants. J Perinatol. 2013;33:40–4.

    Article  CAS  PubMed  Google Scholar 

  46. Dang S, Shook L, Garlitz K, Hanna M, Desai N. Nutritional outcomes with implementation of probiotics in preterm infants. J Perinatol. 2015;35:447–50.

    Article  CAS  PubMed  Google Scholar 

  47. Kane AF, Bhatia AD, Denning PW, Shane AL, Patel RM. Routine Supplementation of Lactobacillus rhamnosus GG and Risk of Necrotizing Enterocolitis in Very Low Birth Weight Infants. J Pediatr. 2018;195:73–9.e2.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kim SYWH, Kim EK, Jung YH, Koh JW, Song IG, Shin SH, et al. Influence of routine probiotic supplementation on the incidence of necrotizing enterocolitis and late onset sepsis. Neonatal Med. 2016;23:88–94.

    Article  Google Scholar 

  49. Lambæk IDFG, Gormsen M, Brok J, Greisen G. Probiotics to prevent necrotising enterocolitis in very preterm infants. Dan Med J. 2016;63:A5203.

    PubMed  Google Scholar 

  50. Luoto RMJ, Isolauri E, Lehtonen L. Incidence of necrotizing enterocolitis in very‐low‐birth‐weight infants related to the use of Lactobacillus GG. Acta Paediatr. 2010;99:1135–8.

    Article  CAS  PubMed  Google Scholar 

  51. Que J, Van Oerle R, Albersheim S, Panczuk J, Piper H. The effect of daily probiotics on the incidence and severity of necrotizing enterocolitis in infants with very low birth weight. Can J Surg. 2021;64:E644–e9.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sato R, Malai S, Razmjouy B. Necrotizing Enterocolitis Reduction Using an Exclusive Human-Milk Diet and Probiotic Supplementation in Infants With 1000-1499 Gram Birth Weight. Nutr Clin Pr. 2020;35:331–4.

    Article  Google Scholar 

  53. Uberos J, Aguilera-Rodríguez E, Jerez-Calero A, Molina-Oya M, Molina-Carballo A, Narbona-López E. Probiotics to prevent necrotising enterocolitis and nosocomial infection in very low birth weight preterm infants. Br J Nutr. 2017;117:994–1000.

    Article  CAS  PubMed  Google Scholar 

  54. Sato R, Malai S, Razmjouy B. Necrotizing Enterocolitis Reduction Using an Exclusive Human‐Milk Diet and Probiotic Supplementation in Infants With 1000–1499 Gram Birth Weight. Nutr Clin Pract. 2020;35:331–4.

    Article  PubMed  Google Scholar 

  55. Chang HY, Chen JH, Chang JH, Lin HC, Lin CY, Peng CC. Multiple strains probiotics appear to be the most effective probiotics in the prevention of necrotizing enterocolitis and mortality: An updated meta-analysis. PLoS One. 2017;12:e0171579.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chapman CM, Gibson GR, Rowland I. Health benefits of probiotics: are mixtures more effective than single strains? Eur J Nutr. 2011;50:1–17.

    Article  CAS  PubMed  Google Scholar 

  57. McFarland LV. Efficacy of Single-Strain Probiotics Versus Multi-Strain Mixtures: Systematic Review of Strain and Disease Specificity. Dig Dis Sci. 2021;66:694–704.

    Article  CAS  PubMed  Google Scholar 

  58. Ouwehand AC, Invernici MM, Furlaneto FAC, Messora MR. Effectiveness of Multistrain Versus Single-strain Probiotics: Current Status and Recommendations for the Future. J Clin Gastroenterol. 2017;S35–s40. 2018;52. Suppl 1, Proceedings from the 9th Probiotics, Prebiotics and New Foods, Nutraceuticals and Botanicals for Nutrition & Human and Microbiota Health Meeting, held in Rome, Italy from September 10 to 12.

  59. van den Akker CHP, van Goudoever JB, Szajewska H, Embleton ND, Hojsak I, Reid D, et al. Probiotics for Preterm Infants: A Strain-Specific Systematic Review and Network Meta-analysis. J Pediatr Gastroenterol Nutr. 2018;67:103–22.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neonatology, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India

    Anitha Ananthan

  2. Department of Neonatology, Surya Mother and Child Care Hospital, Mumbai, India

    Haribalakrishna Balasubramanian

  3. Department of Neonatology, Joondalup Health Campus, Perth, WA, Australia

    Chandra Rath, Saravanan Muthusamy & Shripada Rao

  4. School of Medicine, University of Western Australia, Perth, WA, Australia

    Shripada Rao & Sanjay Patole

  5. Neonatal Directorate, King Edward Memorial Hospital for Women, Perth, WA, Australia

    Sanjay Patole

Authors
  1. Anitha Ananthan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haribalakrishna Balasubramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chandra Rath
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Saravanan Muthusamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shripada Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sanjay Patole
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AA: drafted the manuscript with input from HB, SR, SP and other co-authors and is responsible for the final content; AA, HB, CR, and SM: wrote the statistical analysis plan; AA, HB, CR, SM, SR and SP: reviewed, contributed to, and approved the statistical analysis plan; AA and HB compiled the data; AA: conducted the data analysis; and all authors: read, contributed to, and approved the final manuscript.

Corresponding author

Correspondence to Anitha Ananthan.

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

Ananthan, A., Balasubramanian, H., Rath, C. et al. Lactobacillus rhamnosus GG as a probiotic for preterm infants: a strain specific systematic review and meta-analysis. Eur J Clin Nutr (2024). https://doi.org/10.1038/s41430-024-01474-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41430-024-01474-0

Search

Advanced search

Quick links