Abstract
Probiotics for the prevention of necrotizing enterocolitis have attracted a huge interest. Combined data from heterogeneous randomised controlled trials suggest that probiotics may decrease the incidence of NEC. However, the individual studies use a variety of probiotic products, and the group at greatest risk of NEC, i.e., those with a birth weight of less than 1000 g, is relatively under-represented in these trials so we do not have adequate evidence of either efficacy or safety to recommend universal prophylactic administration of probiotics to premature infants. These problems have polarized neonatologists, with some taking the view that it is unethical not to universally administer probiotics to premature infants, whereas others regard the meta-analyses as flawed and that there is insufficient evidence to recommend routine probiotic administration. Another problem is that the mechanism by which probiotics might act is not clear, although some experimental evidence is starting to accumulate. This may allow development of surrogate endpoints of effectiveness, refinement of probiotic regimes, or even development of pharmacological agents that may act through the same mechanism. Hence, although routine probiotic administration is controversial, studies of probiotic effects may ultimately lead us to effective means to prevent this devastating disease.
Similar content being viewed by others
References
Hall NJ, Eaton S, Pierro A (2013) Necrotizing enterocolitis: prevention, treatment, and outcome. J Pediatr Surg 48(12):2359–2367
Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, Lillehei C, Valim C, Horbar JD, Jaksic T (2009) Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 44(6):1072–1075
Thyoka M, De Coppi P, Eaton S, Khoo K, Hall NJ, Curry J, Kiely E, Drake D, Cross K, Pierro A (2012) Advanced necrotizing enterocolitis part 1: mortality. EurJ Pediatr Surg 22(1):8–12
Zani A, Cananzi M, Fascetti-Leon F, Lauriti G, Smith VV, Bollini S, Ghionzoli M, D’Arrigo A, Pozzobon M, Piccoli M, Hicks A, Wells J, Siow B, Sebire NJ, Bishop C, Leon A, Atala A, Lythgoe MF, Pierro A, Eaton S, De Coppi P (2014) Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut 63(2):300–309
Caplan M, Frost B (2011) Myth: necrotizing enterocolitis: Probiotics will end the disease, and surgical intervention improves the outcome. Semin Fetal Neonatal Med 16(5):264–268
Kelleher J, Mallick H, Soltau TD, Harmon CM, Dimmitt RA (2013) Mortality and intestinal failure in surgical necrotizing enterocolitis. J Pediatr Surg 48(3):568–572
Rees CM, Pierro A, Eaton S (2007) Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 92(3):F193–F198
Downard CD, Renaud E, St Peter SD, Abdullah F, Islam S, Saito JM, Blakely ML, Huang EY, Arca MJ, Cassidy L, Aspelund G (2012) Treatment of necrotizing enterocolitis: an American pediatric Surgical association outcomes and clinical trials committee systematic review. J Pediatr Surg 47(11):2111–2122
van Acker J, de Smet F, Muyldermans G, Bougatef A, Naessens A, Lauwers S (2001) Outbreak of necrotizing enterocolitis associated with Enterobacter sakazakii in powdered milk formula. J Clin Microbiol 39(1):293–297
Rotbart HA, Levin MJ (1983) How contagious is necrotizing enterocolitis? Pediatr Infect Dis 2(5):406–413
Scheifele DW (1990) Role of bacterial toxins in neonatal necrotizing enterocolitis. J Pediatr 117(1 Pt 2):S44–S46
Scheifele DW, Olsen EM, Pendray MR (1985) Endotoxinemia and thrombocytopenia during neonatal necrotizing enterocolitis. Am J Clin Pathol 83(2):227–229
Cheu HW, Brown DR, Rowe MI (1989) Breath hydrogen excretion as a screening test for the early diagnosis of necrotizing enterocolitis. Am J Dis Child 143(2):156–159
de Meij TGJ, van der Schee MPC, Berkhout DJC, van de Velde ME, Jansen AE, Kramer BW, van Weissenbruch MM, van Kaam AH, Andriessen P, van Goudoever JB, Niemarkt HJ, de Boer NKH. Early detection of necrotizing enterocolitis by fecal volatile organic compounds analysis. J Pediatr. doi:10.1016/j.jpeds.2015.05.044
Garner CE, Ewer AK, Elasouad K, Power F, Greenwood R, Ratcliffe NM, Costello BD, Probert CS (2009) Analysis of Faecal volatile organic compounds in preterm infants who develop necrotising enterocolitis: a pilot study. J Pediatr Gastroenterol Nutr 49(5):559–565
Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124(4):837–848. doi:10.1016/j.cell.2006.02.017
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J, Meta HITC, Bork P, Ehrlich SD, Wang J (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464(7285):59–65. doi:10.1038/nature08821
Cerutti A, Rescigno M (2008) The biology of intestinal immunoglobulin A responses. Immunity 28(6):740–750. doi:10.1016/j.immuni.2008.05.001
Macpherson AJ, Harris NL (2004) Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4(6):478–485. doi:10.1038/nri1373
Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118(2):229–241. doi:10.1016/j.cell.2004.07.002
Guinane CM, Cotter PD (2013) Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther adv Gastroenterol 6(4):295–308. doi:10.1177/1756283X13482996
Zhang H, DiBaise JK, Zuccolo A, Kudrna D, Braidotti M, Yu Y, Parameswaran P, Crowell MD, Wing R, Rittmann BE, Krajmalnik-Brown R (2009) Human gut microbiota in obesity and after gastric bypass. Proc Natl Acad Sci 106(7):2365–2370. doi:10.1073/pnas.0812600106
Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci 104(34):13780–13785. doi:10.1073/pnas.0706625104
Tissier H (1900) Recherches sur la flore Intestinale des Nourrissons. Thesis no 529, Paris, Paris
Funkhouser LJ, Bordenstein SR (2013) Mom knows best: the universality of maternal microbial transmission. PLoS Biol 11(8):e1001631. doi:10.1371/journal.pbio.1001631
Jimenez E, Marin ML, Martin R, Odriozola JM, Olivares M, Xaus J, Fernandez L, Rodriguez JM (2008) Is meconium from healthy newborns actually sterile? Res Microbiol 159(3):187–193. doi:10.1016/j.resmic.2007.12.007
Dominguez-Bello MG, Blaser MJ, Ley RE, Knight R (2011) Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterology 140(6):1713–1719. doi:10.1053/j.gastro.2011.02.011
Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, van den Brandt PA, Stobberingh EE (2006) Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118(2):511–521. doi:10.1542/peds.2005-2824
Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R (2010) Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci 107(26):11971–11975. doi:10.1073/pnas.1002601107
Gronlund MM, Gueimonde M, Laitinen K, Kociubinski G, Gronroos T, Salminen S, Isolauri E (2007) Maternal breast-milk and intestinal bifidobacteria guide the compositional development of the Bifidobacterium microbiota in infants at risk of allergic disease. Clin Exp Allerg J Br Soc Allerg Clin Immunol 37(12):1764–1772. doi:10.1111/j.1365-2222.2007.02849.x
Gronlund MM, Lehtonen OP, Eerola E, Kero P (1999) Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr 28(1):19–25
Morelli L (2008) Postnatal development of intestinal microflora as influenced by infant nutrition. J Nutr 138(9):1791S–1795S
Martin R, Langa S, Reviriego C, Jiminez E, Marin ML, Xaus J, Fernandez L, Rodriguez JM (2003) Human milk is a source of lactic acid bacteria for the infant gut. J Pediatr 143(6):754–758. doi:10.1016/j.jpeds.2003.09.028
Barrett E, Deshpandey AK, Ryan CA, Dempsey EM, Murphy B, O’Sullivan L, Watkins C, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C (2015) The neonatal gut harbours distinct bifidobacterial strains. Arch Dis Child Fetal Neonatal Ed. doi:10.1136/archdischild-2014-306110
Hopkins MJ, Sharp R, Macfarlane GT (2001) Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut 48(2):198–205
Schwiertz A, Gruhl B, Lobnitz M, Michel P, Radke M, Blaut M (2003) Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants. Pediatr Res 54(3):393–399. doi:10.1203/01.PDR.0000078274.74607.7A
Adlerberth I, Wold AE (2009) Establishment of the gut microbiota in Western infants. Acta Paediatr 98(2):229–238. doi:10.1111/j.1651-2227.2008.01060.x
Westerbeek EA, van den Berg A, Lafeber HN, Knol J, Fetter WP, van Elburg RM (2006) The intestinal bacterial colonisation in preterm infants: a review of the literature. Clin Nutr 25(3):361–368. doi:10.1016/j.clnu.2006.03.002
Rouge C, Goldenberg O, Ferraris L, Berger B, Rochat F, Legrand A, Gobel UB, Vodovar M, Voyer M, Roze JC, Darmaun D, Piloquet H, Butel MJ, de La Cochetiere MF (2010) Investigation of the intestinal microbiota in preterm infants using different methods. Anaerobe 16(4):362–370. doi:10.1016/j.anaerobe.2010.06.002
Sears CL (2005) A dynamic partnership: celebrating our gut flora. Anaerobe 11(5):247–251. doi:10.1016/j.anaerobe.2005.05.001
Neu J, Walker WA (2011) Necrotizing enterocolitis. New Eng J Med 364(3):255–264. doi:10.1056/NEJMra1005408
de la Cochetiere MF, Piloquet H, des Robert C, Darmaun D, Galmiche JP, Roze JC (2004) Early intestinal bacterial colonization and necrotizing enterocolitis in premature infants: the putative role of Clostridium. Pediatr Res 56(3):366–370. doi:10.1203/01.PDR.0000134251.45878.D5
Claud EC (2009) Neonatal necrotizing enterocolitis—inflammation and intestinal immaturity. Anti-Inflamm Antiallerg Agents Med Chem 8(3):248–259. doi:10.2174/187152309789152020
Wang Y, Hoenig JD, Malin KJ, Qamar S, Petrof EO, Sun J, Antonopoulos DA, Chang EB, Claud EC (2009) 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 3(8):944–954. doi:10.1038/ismej.2009.37
Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, Theriaque D, Li N, Sharma R, Hudak M, Neu J (2011) Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 6(6):e20647. doi:10.1371/journal.pone.0020647
Stewart CJ, Marrs EC, Nelson A, Lanyon C, Perry JD, Embleton ND, Cummings SP, Berrington JE (2013) Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis. PLoS One 8(8):e73465. doi:10.1371/journal.pone.0073465
Brower-Sinning R, Zhong D, Good M, Firek B, Baker R, Sodhi CP, Hackam DJ, Morowitz MJ (2014) Mucosa-associated bacterial diversity in necrotizing enterocolitis. PLoS One 9(9):e105046. doi:10.1371/journal.pone.0105046
Metchnikoff E, Mitchell PC (1907) The prolongation of life; optimistic studies. W. Heinemann (ed); G.P. Putnam’s Sons, London, New York
Food and Agriculture Organization of the United Nations., World Health Organization. (2006) Probiotics in food : health and nutritional properties and guidelines for evaluation. FAO food and nutrition paper, vol 85. Food and Agriculture Organization of the United Nations: World Health Organization, Rome
Sanders ME, Guarner F, Guerrant R, Holt PR, Quigley EM, Sartor RB, Sherman PM, Mayer EA (2013) An update on the use and investigation of probiotics in health and disease. Gut 62(5):787–796. doi:10.1136/gutjnl-2012-302504
Millar, Bacon C, Smith SL, Walker V, Hall MA (1993) Enteral feeding of premature infants with Lactobacillus GG. Arch Dis Child 69(5 Spec No):483–487
Kitajima H, Sumida Y, Tanaka R, Yuki N, Takayama H, Fujimura M (1997) Early administration of Bifidobacterium breve to preterm infants: randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 76(2):F101–F107
Hoyos AB (1999) Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit. Int J Infect Dis IJID Off Publ Int Soc Infect Dis 3(4):197–202
Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli FF (2002) Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biol Neonate 82(2):103–108. doi:10.1159/000063096
Costalos C, Skouteri V, Gounaris A, Sevastiadou S, Triandafilidou A, Ekonomidou C, Kontaxaki F, Petrochilou V (2003) Enteral feeding of premature infants with Saccharomyces boulardii. Early Hum Dev 74(2):89–96
Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, Hammerman C (2005) Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 147(2):192–196. doi:10.1016/j.jpeds.2005.03.054
Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, Oh W (2005) Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 115(1):1–4. doi:10.1542/peds.2004-1463
Manzoni P, Mostert M, Leonessa ML, Priolo C, Farina D, Monetti C, Latino MA, Gomirato G (2006) Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin Infect Dis Off Publ Infect Dis Soc Am 42(12):1735–1742. doi:10.1086/504324
Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, Radke M, Blaut M (2006) Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J Clin Microbiol 44(11):4025–4031. doi:10.1128/JCM.00767-06
Deshpande G, Rao S, Patole S (2007) Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: a systematic review of randomised controlled trials. Lancet 369(9573):1614–1620
AlFaleh K, Anabrees J, Bassler D (2010) Probiotics Reduce the risk of necrotizing enterocolitis in preterm infants: a meta-analysis. Neonatology 97(2):93–99
Beattie LM, Hansen R, Barclay AR (2010) Probiotics for preterm infants: confounding features warrant caution. Pediatrics 126(3):e742–e743. doi:10.1542/peds.2010-1949C (author reply e743–e745)
Neu J, Shuster J (2010) Nonadministration of routine probiotics unethical–really? Pediatrics 126(3):e740–e741. doi:10.1542/peds.2010-1949A (author reply e743–e745)
Garland SM, Jacobs SE, Tobin JM, Opie GF, Donath S, ProPrems study G (2010) A cautionary note on instituting probiotics into routine clinical care for premature infants. Pediatrics 126(3):e741–e742. doi:10.1542/peds.2010-1949B (author reply e743–e745)
Mihatsch WA, Braegger CP, Decsi T, Kolacek S, Lanzinger H, Mayer B, Moreno LA, Pohlandt F, Puntis J, Shamir R, Stadtmuller U, Szajewska H, Turck D, van Goudoever JB (2012) Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants. Clinical nutrition 31(1):6–15. doi:10.1016/j.clnu.2011.09.004
Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, Morley CJ, Garland SM, ProPrems Study G (2013) Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 132(6):1055–1062. doi:10.1542/peds.2013-1339
PIPs Study. https://www.npeu.ox.ac.uk/pips
AlFaleh K, Anabrees J (2014) Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev 4:CD005496. doi:10.1002/14651858.CD005496.pub4
Janvier A, Lantos J, Barrington K (2013) The politics of probiotics: probiotics, necrotizing enterocolitis and the ethics of neonatal research. Acta Paediatr 102(2):116–118. doi:10.1111/apa.12083
Millar M, Wilks M, Fleming P, Costeloe K (2012) Should the use of probiotics in the preterm be routine? Arch Dis Child Fetal Neonatal Ed 97(1):F70–F74. doi:10.1136/adc.2009.178939
Shinefield HR, Ribble JC, Eichenwald HF, Boris M, Sutherland JM (1963) Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. V. An analysis and interpretation. Am J Dis Child 105:683–688
Blair EB, Tull AH (1969) Multiple infections among newborns resulting from colonization with Staphylococcus aureus 502A. Am J Clin Pathol 52(1):42–49
Lu P, Sodhi CP, Jia H, Shaffiey S, Good M, Branca MF, Hackam DJ (2014) Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 306(11):G917–G928
Siggers RH, Siggers J, Boye M, Thymann T, Molbak L, Leser T, Jensen BB, Sangild T (2008) Early administration of probiotics alters bacterial colonization and limits diet-induced gut dysfunction and severity of necrotizing enterocolitis in preterm pigs. J Nutr 138(8):1437–1444
Cilieborg MS, Thymann T, Siggers R, Boye M, Bering SB, Jensen BB, Sangild PT (2011) The Incidence of necrotizing enterocolitis is increased following probiotic administration to preterm pigs. J Nutr 141(2):223–230
Liu YY, Fatheree NY, Mangalat N, Rhoads JM (2012) Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-kappa B signaling in the intestine. Am Physiol Gastrointest Liver Physiol 302(6):G608–G617
Ganguli K, Collado MC, Rautava J, Lu L, Satokari R, von Ossowski I, Reunanen J, de Vos WM, Palva A, Isolauri E, Salminen S, Walker WA, Rautava S (2015) Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut. Pediatr Res 77(4):528–535. doi:10.1038/pr.2015.5
Patel RM, Myers LS, Kurundkar AR, Maheshwari A, Nusrat A, Lin PW (2012) Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am J Pathol 180(2):626–635
Khailova L, Patrick SKM, Arganbright KM, Halpern MD, Kinouchi T, Dvorak B (2010) Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 299(5):G1118–G1127
Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N (2013) Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol 304(2):G132–G141
Shiou S-R, Yu Y, Guo Y, He S-M, Mziray-Andrew CH, Hoenig J, Sun J, Petrof EO, Claud EC (2013) Synergistic protection of combined probiotic conditioned media against neonatal necrotizing enterocolitis-like intestinal injury. PLoS One 8(5):e65108. doi:10.1371/journal.pone.0065108
Guo S, Guo Y, Ergun A, Lu L, Walker WA, Ganguli K (2015) Secreted metabolites of Bifidobacterium infantis and Lactobacillus acidophilus protect immature human enterocytes from IL-1β-induced inflammation: a transcription profiling analysis. PLoS One 10(4):e0124549. doi:10.1371/journal.pone.0124549
Good M, Sodhi CP, Ozolek JA, Buck RH, Goehring KC, Thomas DL, Vikram A, Bibby K, Morowitz MJ, Firek B, Lu P, Hackam DJ (2014) Lactobacillus rhamnosus HN001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of TLR9, vol 306. vol 11. doi:10.1152/ajpgi.00452.2013
Dilli D, Aydin B, Fettah ND, Ozyazici E, Beken S, Zenciroglu A, Okumus N, Ozyurt BM, Ipek MS, Akdag A, Turan O, Bozdag S (2015) The ProPre-Save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J Pediatr 166(3):545–551. doi:10.1016/j.jpeds.2014.12.004 (e541)
Acknowledgments
SE gratefully acknowledges support from Great Ormond Street Hospital Children’s Charity, PF gratefully acknowledges the support Barts and the London Charity, and NJH is supported by the NIHR Southampton Biomedical Research Centre in Nutrition.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fleming, P., Hall, N.J. & Eaton, S. Probiotics and necrotizing enterocolitis. Pediatr Surg Int 31, 1111–1118 (2015). https://doi.org/10.1007/s00383-015-3790-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00383-015-3790-0