Skip to main content
Download PDF

Effects of Lactobacillus reuteri DSM 17938 in preterm infants: a double-blinded randomized controlled study

Italian Journal of Pediatrics volume 45, Article number: 140 (2019) Cite this article

Abstract

Background

Preterm infants have immature gastrointestinal tracts and poor immunity. In this study, the effects of Lactobacillus reuteri DSM 17938 first on early feeding tolerance, growth, and second on infection prevention in preterm infants were evaluated.

Methods

One hundred fourteen formula-fed preterm infants with a gestational age between 30 weeks and 37 weeks, and a birth weight between 1500 and 2000 g were enrolled; 57 in the intervention and 57 in the control group:the intervention group was given a dose of 1 × 108 colony-forming units (5 drops) of L. reuteri DSM 17938 once daily, beginning with the first feeding until discharge. The control group did not receive probiotics. Early feeding tolerance (as time to full enterla feeding and number of reflux), growth, incidences of sepsis, localized infection, NEC, and adverse effects were recorded for both groups.

Results

The number of Daily reflux episodes (times/d) was lower (2.18 ± 0.83 vs. 3.77 ± 0.66, P < 0.01) and time to full enteral feedings (120 mL/kg/d) (9.95 ± 2.46 d vs. 13.80 ± 3.47 d, P < 0.05) was shorter in the intervention group. Average daily weight gain (14.55 ± 3.07 g/d vs. 10.12 ± 2.80 g/d), head circumference increas e(0.0760 ± 0.0157 cm/d vs. 0.0681 ± 0.0108 cm/d), and body length increase (0.1878 ± 0.0151 cm/d vs. 0.1756 ± 0.0166 cm/d) of the intervention group were higher (P < 0.01). There were no significant differences in the incidences of sepsis (4.44% vs. 8.33%), localized infection (6.67% vs. 8.33%), or NEC (2.22% vs. 10.42%) between the 2 groups (P > 0.05). The number of daily defecations (times/d) in the intervention group was higher (3.08 ± 0.33 vs. 2.29 ± 0.20, P < 0.01) and the length of hospital stay was shorter than that in the control group (20.60 ± 5.36 d vs. 23.75 ± 8.57 d, P < 0.05). No adverse effects were noted among the infants receiving L. reuteri.

Conclusion

L. reuteri may be an useful tool in improving early feeding tolerance in preterm infants, promoting growth, increasing the frequency of defecation, and shortening the length of hospital stay.

Trial registration

ChiCTR, ChiCTR1900025590. Registered 1 February 2019- Retrospectively registered, http://www.chictr.org.cn/listbycreater.aspx.

Background

The survival rate of preterm infants has increased substantially in recent years. Preterm infants, due to their immature development, are characterized by underdeveloped gastrointestinal tracts, delayed colonization of intestinal flora, and low immune function. Therefore, preterm infants are prone to feeding intolerance, infection, and even neonatal necrotizing enterocolitis (NEC), all of which affect growth and quality of life [1].

Probiotics are living microorganisms, which, when administered in adequate amounts, can confer a health benefit to the host [2]. As a microecological preparation, probiotics seem to be useful in nourishing the intestines, adjusting the microbiota, ameliorating immunity and reducing inflammation. In 2017, the World Gastroenterology Organization updated global guidelines about the use of probiotics and prebiotics. A large amount of clinical trials confirmed that probiotics have a beneficial effect on the prevention and treatment of digestive diseases [3]. The clinical application of probiotics in neonates is increasingly widespread for many indications, including the prevention and treatment of feeding intolerance, diarrhea, NEC, neonatal jaundice, and allergic diseases [4].

Lactobacillus reuteri (L. reuteri) DSM 17938 is a progeny strain of L. reuteri ATCC 55730, which was originally extracted from the breast milk of Peruvian women living in the Andes. In 2007, 2 plasmids with antibiotic resistance (tetracycline and lincomycin) were removed in order to enhance safety, and the modified strain was stored at The German Center for the Conservation of Microbial Species, also called the DSMZ, and named L. reuteri DSM 17938. This strain can live throughout the gastrointestinal tract and colonize in normal human gastric bodies, including the gastric antrum, duodenum, and ileum [5]. In one study, its colonization required continuous supplementation for 7 days, and the highest colonization rate was reached at 21 days; after discontinuing supplementation, the colonization rate decreased significantly at 1 week and was undetectable at 2 months [6]. The role of L. reuteri in the effective treatment of infantile colic is clearly illustrated [7, 8], and it has been widely used in the prevention and treatment of infantile reflux, functional constipation, and acute gastroenteritis. However, research of the effects of L. reuteri on the clinical course in preterm infants is limited.

The aim of the study was to investigate the efficacy of L. reuteri in early feeding tolerance, growth, infection prevention, and other aspects of preterm infant development.

Materials and methods

Patients

Preterm infants admitted to the First Neonatal Ward of Shengjing Hospital of China Medical University from January 2017 to June 2018 were enrolled for this double-blinded randomized controlled study. Inclusion criteria: formula-fed preterm infants admitted within 12 h of birth whose gestational age ≥ 30 and < 37 weeks; birthweight≥1500 g and ≤ 2000 g with vital sign and hemodynamic parameters stable. Exclusion criteria: congenital diseases, expected hospitalization less than 2 weeks and maternal or neonatal antibiotics or other probiotics before admission.

The study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University. Informed consent was obtained from the infants’ parents. Randomization was conducted according to a random computer-determined allocation order considering gestational age.

Study design

After admission, routine treatment and nursing support were provided for all infants enrolled according to their conditions. Formula milk feeding (provided by the hospital, 335 kJ/100 mL, Abbott Laboratories, USA) was given to the preterm infants after stabilization, started with 20 mL/kg/d and was defined as full enteral feeding when 120 mL/kg/d were reached. Increment were 10–20 mL/kg/d depending on the gestational age of the infant. The amount of feeding was advanced if tolerated with 10–20 mL/kg/d. This feeding policy was not altered during the study period. Parenteral nutrition was supplemented for undernutrition, as defined by the “Guidelines for Clinical Application of Neonatal Nutrition Support in China” [9]. L. reuteri DSM 17938 (Biogaia AB, Stockholm, Sweden) was administered to the preterm infants in the intervention group at a dose of 1 × 108 colony-forming units (5 drops) once daily, beginning with the first feeding until discharge from the hospital. For infants who were fed orally, 5 drops were instilled to the posterior oropharynx of the infants after suctioning oral secretions. For infants without oral feeds, 5 drops were administered through a gastric tube followed by a flush of 0.5 mL of sterile water. The minimum duration of the intervention was 7 days. No probiotics were administered to the control group. If enteral feeding was stopped due to feeding intolerance such as increased abdominal girth, emesis, gastric residual of 25% of the previous feed volume or NEC during hospitalization, L. reuteri was stopped and resumed after feeding resumed. Blinding was possible because the nurses who administered L. reuteri to the infants were not involved in the daily care and the attending neonatal team was unaware of the randomization assignments.

Primary and secondary outcomes

Primary outcomes of this study were feeding tolerance and growth in preterm infants. Secondary outcome was infection prevention. To assess feeding tolerance, the time to full enteral feedings (TFF) and number of reflux episodes were recorded. To assess growth indicators, we measured the growth of body weight, body length, and head circumference, calculating the difference of these parameters at the end toward the beginning of study period, then we divided them as daily increase. To assess infection prevention, incidences of nosocomial infection and NEC were recorded. Adverse effects, including culture-proven sepsis, flatulence and diarrhoea were also recorded.

Definitions and diagnostic criteria

Reflux was defined as the passage of refluxed gastric contents into the oral pharynx [10]. Nosocomial infection was defined as an infection occurring after 48 h of hospitalization, including infections that occurred during hospitalization and infections that occurred after discharge from pathogens to which infants were exposed in the hospital [11]. NEC was defined as acute necrotizing intestinal disease with abdominal distension, vomiting, and hematochezia as the main symptoms. NEC may be caused by various factors in the perinatal period; it should be diagnosed according to clinical manifestations and abdominal X-rays and should be categorized by modified Bell’s classification [12].

Statistical analysis

SPSS Statistics version 24 statistical software was used for statistical analysis. The measurement data are presented as means ± standard deviations. The t-test was used for comparisons between groups. Categorical data were compared by the χ2 test. A p-value of less than 0.05 was considered statistically significant. This study was registered at the website http://www.chictr.org.cn/listbycreater.aspx under the number ChiCTR1900025590.

Results

Patient description

A total of 114 cases were eventually enrolled and randomly allocated in the study. 57 patients received L. reuteri and 57 neonates were included in the control group. In all, 21 (18%) patients were excluded because of major congenital malformations and the using of other probiotics (12 [21.1%] in the intervention group and 9 [15.8%] in the control group). Finally, 45 cases could be analyzed in the intervention group and 48 cases in the control group (Fig. 1).

Fig. 1
figure 1

Study flow chart

Full size image

The characteristics of the preterm infants at study inclusion are shown in Table 1. There were no significant differences in gender, gestational age, birth weight, or Apgar score between the 2 groups.

Table 1 Comparison of the Characteristics Between the 2 Groups of Preterm Infants
Full size table

Primary and secondary outcomes

The study outcomes observed in the two study groups are shown and compared in Table 2.

Table 2 Comparison of Feeding Tolerance, Growth, and Infection incidence Between the 2 Groups
Full size table

Feeding tolerance

The number of daily reflux episodes (times/d) in the intervention group was significantly lower than that in the control group (2.18 ± 0.83 vs. 3.77 ± 0.66, P < 0.01). TFF in the intervention group was significantly shorter than that in the control group (9.95 ± 2.46 d vs.13.80 ± 3.47 d, P < 0.05).

Growth

The average daily weight gain (14.55 ± 3.07 g/d vs. 10.12 ± 2.80 g/d), daily head circumference growth (0.0760 ± 0.0157 cm/d vs. 0.0681 ± 0.0108 cm/d), and body length increase (0.1878 ± 0.0151 cm/d vs. 0.1756 ± 0.0166 cm/d) of the preterm infants in the intervention group were significantly higher than those of the control group (P < 0.01).

Infection

Nosocomial infection could be divided into sepsis and localized infection. In this study, there were 2 cases of sepsis and 3 cases of localized infection (2 cases of neonatal pneumonia, 1 case of urinary tract infection) in the intervention group while 4 cases of sepsis and 4 cases of localized infection (3 cases of neonatal pneumonia, 1 case of urinary tract infection) in the control group. There was no significant difference in the incidences of sepsis (4.44% vs. 8.33%), localized infection (6.67% vs. 8.33%) or NEC (2.22% vs. 10.42%) between the 2 groups (P > 0.05).

Other indicators

The number of daily defecations in the intervention group was 3.08 ± 0.33, which was 2.29 ± 0.20 in the control group. The length of hospital stay in the intervention group was shorter than that in the control group (20.60 ± 5.36 d vs. 23.75 ± 8.57 d, P < 0.05). The preterm infants in the intervention group had no adverse effects while receiving L. reuteri.

Discussion

Preterm infants have poor sucking and swallowing abilities, immature digestive systems, insufficient gastrointestinal motility, and low gastrointestinal mucosal barrier function, and they are prone to feeding intolerance such as regurgitation, vomiting, abdominal distension, and gastric retention during feeding [13]. Studies have shown that probiotics could stimulate the secretion of gastrin and motilin, promote gastrointestinal motility, reduce the incidence of feeding intolerance, and shorten the time to achieve total enteral nutrition [14]. Reflux refers to the reverse movement of gastric contents, usually referred to gastroesophageal reflux (GOR). GOR is a prominent condition among preterm infants. Symptoms such as apnoea, bradycardia, vomiting, poor weight gain and irritability have been attributable to GOR, which is called gastroesophageal reflux disease (GORD), when symptoms are severe [15]. Experimental data showed that L. reuteri can promote gastric motility, accelerate gastric emptying, promote colonic peristalsis, and reduce the incidence of dyspepsia and reflux [16, 17]. Indrio et al. [18] conducted a randomized, double-blind, controlled study of 30 preterm infants: 10 preterm infants were exclusively breastfed and the remaining 20 were fed formula; the formula-fed infants were randomly assigned to receive L. reuteri or a placebo for 30 days. The results showed that the number of reflux episodes in the L. reuteri group was significantly lower than that in the placebo group (P < 0.01). Moreover, the incidence of reflux episodes in the supplemented group resulted similar to that of the breastfed group. It demonstrated that oral supplementation with L. reuteri improved feeding tolerance in preterm infants. This is consistent with our findings. Our study demonstrated that L. reuteri was able to reduce severity and number of reflux episodes (GORD incidence was 8.88% in the intervention vs. 12.5% in the control group). We may speculate that this lead to a shorter TFF, thus improving the rapidity of the growth of formula-fed preterm infants. Our study also found that oral administration of L. reuteri may increase the daily defecation frequency of formula-fed preterm infants and shorten their hospital stays. Our study showed that no adverse effects occurred while formula-fed preterm infants were receiving L. reuteri, which was consistent with the results of Oncel et al. [19].

In the neonatal period, infections are common and are a major risk factor for neonatal death, especially septicemia, which has an insidious onset and rapid progression [20]. The digestive tract of preterm infants is hypoplasic, bacterial flora is less diverse, and colonization is delayed compared to full-term infants. Most digestive bacteria, including Klebsiella, Enterobacter, and Clostridium, are potentially pathogenic and can trigger digestive tract injury. Digestive tract injury combined with the deficiency of the innate immune system increases the probability that pathogens will spread throughout the entire body and cause a systemic infection [21]. Probiotics influence the functions of various immune cells, such as lymphocytes and dendritic cells, by direct or indirect regulation and they play a role in immune regulation and control of inflammation progression. L. reuteri DSM 17938 can ferment in vivo to produce acetic acid and reuterin. Acetic acid can lower the pH in vivo and it has a strong antibacterial effect on many pathogens; reuterin can cause oxidative stress in pathogens and effectively resist bacteria [22, 23]. Valeur [5] reported that L. reuteri activated CD4+ Th-cells and coordinated other immune cells to regulate the immune response. Preidis et al. [24] showed that L. reuteri could significantly induce the production of immunoglobulin A, inhibit the adhesion of bacteria and viruses to epithelial cells, and neutralize toxins. A randomized controlled trial showed that L. reuteri significantly reduced the incidence of diarrhea and respiratory infections in preschoolers, as well as shortened the course of disease [25]. Oncel et al. [26] reported that L. reuteri could significantly reduce the incidence of septicemia in extremely low birthweight (ELBW) infants with a gestational age of less than 32 weeks (6.5% vs. 12.5%, P = 0.041). On the contrary, in our study, there were no statistical differences in the incidence of sepsis (4.44% vs. 8.33%, P > 0.05) or localized infection (6.67% vs. 8.33%, P > 0.05) between the two groups. These two different results may be related to different sub-population, gestational age, birth weight or feeding patterns. Whether L. reuteri can prevent infection should be verified with larger sample sizes in future research.

The main pathogenesis of NEC include immature intestinal development, imperfect intestinal flora, formula feeding, and circulation disorders. The establishment of the microecological environment in the gastrointestinal tract is significant for maintaining the stability of the body environment and inhibiting intestinal inflammation. Breastfeeding is currently the only recognized protective factor against NEC. Research has confirmed that probiotics could effectively prevent and reduce the incidence of NEC in preterm infants [27, 28]. L. reuteri can improve the intestinal microecological environment, maintain the integrity of the gastrointestinal mucosal barrier, directly or indirectly regulate a variety of immune cell functions, and control the progression of intestinal inflammation [29]. Liu et al. [30, 31] found that L. reuteri could significantly down-regulate the level of tumor necrosis factor alpha by regulating TLR2, TLR4, and NF-кB signaling pathways in the intestine and reduce the incidence and severity of experimental NEC in rats. Hunter et al. [32] retrospectively analyzed 311 ELBW infants (79 cases with oral L. reuteri administration) and found that the incidence of NEC was significantly reduced in neonates receiving L. reuteri (15.1% vs. 2.5%, P = 0.0475). Our study showed that the incidence of NEC in the intervention group was 2.22% (1 case, stage IIA), while the incidence of NEC in the control group was 10.42% (5 cases in total: 3 cases in stage IIB, 2 cases in stage IIIA), which showed no statistically significant difference between the 2 groups (P > 0.05). More research is needed to confirm if oral administration of L. reuteri can reduce the incidence and severity of NEC in formula-fed preterm infants.

Conclusion

In summary, L. reuteri DSM17938, as a safe microecological preparation, can reduce daily reflux, shorten the TFF; improve early feeding tolerance; accelerate increases in body weight, body length, and head circumference; promote growth; increase the frequency of defecation; and shorten the length of hospital stay in formula-fed preterm infants. Large sample sizes and multicenter studies are needed to confirm if oral administration of L. reuteri can reduce the incidences of nosocomial infection and NEC.

Availability of data and materials

The datasets generated and analysed during the current study are available in the Harvard Dataverse repository, https://doi.org/10.7910/DVN/XAEK0F

Abbreviations

HC:

Head circumference

L. reuteri :

Lactobacillus reuteri

NEC:

Necrotizing enterocolitis

TFF:

Time to full enteral feedings

References

  1. Tudehope D, Fewtrell M, Kashyap S, Udaeta E. Nutritional needs of the micropreterm infant. J Pediatr. 2013;162(3):S72–80. https://doi.org/10.1016/j.jpeds.2012.11.056.

    Article  CAS  PubMed  Google Scholar 

  2. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, 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. 2014;11(8):506–14. https://doi.org/10.1038/nrgastro.2014.66.

    Article  Google Scholar 

  3. Guarner F, Khan AG, Garisch J, Eliakim R, Gangl A, Thomson A, et al. World gastroenterology organisation global guidelines: probiotics and prebiotics october 2011. J Clin Gastroenterol. 2012;46(6):468–81. https://doi.org/10.1097/MCG.0b013e3182549092.

    Article  PubMed  Google Scholar 

  4. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. J Physiol Pharmacol. 2009;60(Suppl 6):27–31.

    PubMed  Google Scholar 

  5. Valeur N, Engel P, Carbajal N, Connolly E, Ladefoged K. Colonization and immunomodulation by lactobacillus reuteri ATCC 55730 in the human gastrointestinal tract. Appl Environ Microbiol. 2004;70(2):1176–81. https://doi.org/10.1128/AEM.70.2.1176-1181.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wolf B, Garleb K, Ataya D, Casas I. Safety and tolerance of lactobacillus reuteri in healthy adult male subjects. Microb Ecol Health Dis. 1995;8(2):41–50. https://doi.org/10.3109/08910609509141381.

    Article  Google Scholar 

  7. Cameron D, Hock QS, Kadim M, Mohan N, Ryoo E, Sandhu B, et al. Probiotics for gastrointestinal disorders: proposed recommendations for children of the Asia-Pacific region. World J Gastroenterol. 2017;23(45):7952–64. https://doi.org/10.3748/wjg.v23.i45.7952.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hojsak I, Fabiano V, Pop TL, Goulet O, Zuccotti GV, Çokuğraş FC, et al. Guidance on the use of probiotics in clinical practice in children with selected clinical conditions and in specific vulnerable groups. Acta Paediatr. 2018;107(6):927–37. https://doi.org/10.1111/apa.14270.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Cai W, Tang Q, Wang Y, Fen Y, Wu J, Qian L. Guidelines for clinical application of neonatal nutrition support in China. J Clin Pediatr. 2013;31(12):1177–82.

    Google Scholar 

  10. Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the north American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2001;32:S1–S31. https://doi.org/10.1097/00005176-200100002-00001.

    Article  PubMed  Google Scholar 

  11. Stoll BJ. Infections of the neonatal infant. In: Behrman R, Kliegman R, HB J, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia: WB Saunders; 2004.

  12. Walsh MC, Kliegman RM, Fanaroff AA. Necrotizing enterocolitis: a practitioner's perspective. Pediatr Rev. 1988;9(7):219–26. https://doi.org/10.1542/pir.9-7-219.

    Article  CAS  PubMed  Google Scholar 

  13. Vandenplas Y, Gutierrez-Castrellon P, Velasco-Benitez C, Palacios J, Jaen D, Ribeiro H, et al. Practical algorithms for managing common gastrointestinal symptoms in infants. Nutrition. 2013;29(1):184–94. https://doi.org/10.1016/j.nut.2012.08.008.

    Article  PubMed  Google Scholar 

  14. Olsen R, Greisen G, Schrøder M, Brok J. Prophylactic probiotics for preterm infants: a systematic review and meta-analysis of observational studies. Neonatology. 2016;109(2):105–12. https://doi.org/10.1159/000441274.

    Article  PubMed  Google Scholar 

  15. Dermyshi E, Mackie C, Kigozi P, Schoonakker B, Dorling J. Antacid therapy for gastroesophageal reflux in preterm infants: a systematic review. BMJ Paediatr Open. 2018;2(1):e000287. https://doi.org/10.1136/bmjpo-2018-000287.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Garofoli F, Civardi E, Indrio F, Mazzucchelli I, Angelini M, Tinelli C, et al. The early administration of lactobacillus reuteri DSM 17938 controls regurgitation episodes in full-term breastfed infants. Int J Food Sci Nutr. 2014;65(5):646–8. https://doi.org/10.3109/09637486.2014.898251.

    Article  PubMed  Google Scholar 

  17. Wu R, Pasyk M, Wang B, Forsythe P, Bienenstock J, Mao YK, et al. Spatiotemporal maps reveal regional differences in the effects on gut motility for lactobacillus reuteri and rhamnosus strains. Neurogastroenterol Motil. 2013;25(3):e205–e14. https://doi.org/10.1111/nmo.12072.

    Article  CAS  PubMed  Google Scholar 

  18. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr. 2008;152(6):801–6. https://doi.org/10.1016/j.jpeds.2007.11.005.

    Article  PubMed  Google Scholar 

  19. Oncel MY, Arayici S, Sari FN, Simsek GK, Yurttutan S, Erdeve O, et al. Comparison of lactobacillus reuteri and nystatin prophylaxis on Candida colonization and infection in very low birth weight infants. J Matern-Fetal Neonat Med. 2015;28(15):1790–4. https://doi.org/10.3109/14767058.2014.968842.

    Article  CAS  Google Scholar 

  20. Khair K, Rahman M, Sultana T, Roy C, Rahman M, Ahmed A. Early diagnosis of neonatal septicemia by hematologic scoring system, C-reactive protein and serum haptoglobin. Mymensingh Med J. 2012;21(1):85–92.

    CAS  PubMed  Google Scholar 

  21. Ouwehand AC. What role for probiotics in Necrotising enterocolitis. Arch Pediatr. 2014;2(3):e14912. https://doi.org/10.5812/pedinfect.14912.

    Article  Google Scholar 

  22. De Weirdt R, Crabbé A, Roos S, Vollenweider S, Lacroix C, van Pijkeren JP, et al. Glycerol supplementation enhances L. reuteri’s protective effect against S. typhimurium colonization in a 3-D model of colonic epithelium. PLoS One. 2012;7(5):e37116. https://doi.org/10.1371/journal.pone.0037116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schaefer L, Auchtung TA, Hermans KE, Whitehead D, Borhan B, Britton RA. The antimicrobial compound reuterin (3-hydroxypropionaldehyde) induces oxidative stress via interaction with thiol groups. Microbiology. 2010;156(6):1589–99. https://doi.org/10.1099/mic.0.035642-0.

    Article  CAS  PubMed  Google Scholar 

  24. Preidis GA, Saulnier DM, Blutt SE, Mistretta T-A, Riehle KP, Major AM, et al. Probiotics stimulate enterocyte migration and microbial diversity in the neonatal mouse intestine. FASEB J. 2012;26(5):1960–9. https://doi.org/10.1096/fj.10-177980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gutierrez-Castrellon P, Lopez-Velazquez G, Diaz-Garcia L, Jimenez-Gutierrez C, Mancilla-Ramirez J, Estevez-Jimenez J, et al. Diarrhea in preschool children and lactobacillus reuteri: a randomized controlled trial. Pediatrics. 2014;133(4):904–9. https://doi.org/10.1542/peds.2013-0652.

    Article  Google Scholar 

  26. Oncel MY, Sari FN, Arayici S, Guzoglu N, Erdeve O, Uras N, et al. Lactobacillus reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: a randomised controlled trial. Arch Dis Child-Fetal Matern Ed. 2014;99(2):F110–F5. https://doi.org/10.1136/archdischild-2013-304745.

    Article  Google Scholar 

  27. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010;125(5):2009–1301. https://doi.org/10.1542/peds.2009-1301.

    Article  Google Scholar 

  28. Dylag K, Hubalewska-Mazgaj M, Surmiak M, Szmyd J, Brzozowski T. Probiotics in the mechanism of protection against gut inflammation and therapy of gastrointestinal disorders. Curr Pharm Des. 2014;20(7):1149–55. https://doi.org/10.2174/13816128113199990422.

    Article  CAS  PubMed  Google Scholar 

  29. Lau CS, Chamberlain RS. Probiotic administration can prevent necrotizing enterocolitis in preterm infants: a meta-analysis. J Pediatr Surg. 2015;50(8):1405–12. https://doi.org/10.1016/j.jpedsurg.2015.05.008.

    Article  PubMed  Google Scholar 

  30. Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-κB signaling in the intestine. Am J Physiol Gastrointest Liver Physiol. 2012;302(6):G608–G17. https://doi.org/10.1152/ajpgi.00266.2011.

    Article  CAS  PubMed  Google Scholar 

  31. Hoang TK, He B, Wang T, Tran DQ, Rhoads JM, Liu Y. Protective effect of lactobacillus reuteri DSM 17938 against experimental necrotizing enterocolitis is mediated by toll-like receptor 2. Am J Physiol Gastrointest Liver Physiol. 2018;315(2):231–40. https://doi.org/10.1152/ajpgi.00084.2017.

    Article  CAS  Google Scholar 

  32. Hunter C, Dimaguila MAV, Gal P, Wimmer JE, Ransom JL, Carlos RQ, et al. Effect of routine probiotic, lactobacillus reuteri DSM 17938, use on rates of necrotizing enterocolitis in neonates with birthweight< 1000 grams: a sequential analysis. BMC Pediatr. 2012;12(1):142. https://doi.org/10.1186/1471-2431-12-142.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Li Yunyang, M.S.M, Shenyang Yike biotechnology co. LTD, and Chen Jing, Sc.D., Shenyang Agriculture University, for their help with the statistical analysis.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Neonatology, Shengjing Hospital, China Medical University, Shenyang, China

    Xuewei Cui, Yongyan Shi, Siyang Gao, Xindong Xue & Jianhua Fu

Authors
  1. Xuewei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yongyan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Siyang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xindong Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianhua Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CX and FJ: designed research; CX, GS and SY: conducted research and collected data; CX: wrote the manuscript; XX and SY: directed the writing of the manuscript; FJ: had primary responsibility for final content. All authors designed, supervised, and analyzed the study and assisted with the preparation of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jianhua Fu.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee of Shengjing Hospital of China Medical University.

Consent for publication

Informed consent was obtained from the infants’ parents.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

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

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, X., Shi, Y., Gao, S. et al. Effects of Lactobacillus reuteri DSM 17938 in preterm infants: a double-blinded randomized controlled study. Ital J Pediatr 45, 140 (2019). https://doi.org/10.1186/s13052-019-0716-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13052-019-0716-9

Keywords

Italian Journal of Pediatrics

ISSN: 1824-7288

Contact us