Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2024, vol. 33, nr 9, September, p. 999–1005

doi: 10.17219/acem/174307

Publication type: review

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Qin Y, Linhui Pan L. Prebiotics and sepsis in infants: An updated systematic review and meta-analysis. Adv Clin Exp Med. 2024;33(9):999–1005. doi:10.17219/acem/174307

Prebiotics and sepsis in infants: An updated systematic review and meta-analysis

Yuejia Qin1,2,3,4,A,B,C,D, Linhui Pan1,3,4,E,F

1 Anesthesiology Department, Tumor Hospital Affiliated to Guangxi Medical University, Nanning, China

2 Intensive Care Unit, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, China

3 Guangxi Clinical Research Center for Anesthesiology (GK AD22035214), Nanning, China

4 Guangxi Health Commission Key Laboratory of Basic Science and Prevention of Perioperative Organ Disfunction, Nanning, China

Graphical abstract


Graphical abstracts

Abstract

Background. Sepsis is a critical situation, and its treatment and reduction are important clinical issues. Antibiotics are a routine treatment option, but their adverse effects are a concern in pediatric patients, especially infants. Prebiotics might be an alternative option.

Objectives. The aim of this study was to provide an updated systemic review and meta-analysis of randomized controlled trials (RCTs) on the use of prebiotics for sepsis in infants, which could assist clinicians in deciding whether to use this treatment.

Methods. The study included RCTs related to prebiotics and sepsis in infants. A random effects model and the odds ratio (OR) were applied to estimate the effect of prebiotic use and the incidence of sepsis in infants. The analysis included 16 studies with a total of 6,438 infants. The primary outcome was the OR of sepsis for infants who received prebiotics.

Results. The results of the meta-analysis demonstrated that the pooled OR of sepsis was significantly lower for infants who used prebiotics. However, the results indicated a medium level of heterogeneity.

Conclusions. The results showed that the use of prebiotics might be associated with a reduction of sepsis in infants. The standardized application of this treatment might be an intriguing topic for future clinical research.

Key words: sepsis, meta-analysis, odds ratio, infant, prebiotic

Introduction

Infants are prone to sepsis, especially those with lower birth weight, lower gestational age, asphyxia, and those administered antibiotics.1, 2, 3 In addition, infants can easily contract infections, such as necrotizing enterocolitis, which can lead to sepsis and alterations in laboratory parameters.4 Changes in non-cytotoxic T lymphocytes could also occur after the onset of sepsis due to the suppression of immune function in infants.5 Furthermore, sepsis in infants may result in warm shock physiology accompanied by vasodilation, which could contribute to septic shock and increase the mortality rate.6 Therefore, understanding the relationship between infants and sepsis is critical.

The therapeutic options for treating sepsis in infants are limited. Mechanical ventilation and empirical antibiotics have been reported to be associated with higher sepsis frequency in infants.1, 2, 3 Thus, clinicians may need to establish other therapeutic options for such patients, and one possible alternative is prebiotics. The current evidence on the mechanisms of prebiotics in immune function mostly comes from animal studies, which provide clues about how to relieve sepsis in infants through immunomodulatory actions.

Prebiotics could promote the growth of beneficial bacteria, enhance immune-stimulatory processes, and increase the expression of immunomodulatory functions with antioxidant characteristics.7, 8, 9 Furthermore, they may enhance intestinal trophic effects and immune system maturation.10

Oligosaccharides from human breast milk are prebiotics that have been shown to modulate immune responses,11 which is consistent with the latest studies on the mechanisms of prebiotic effects on immunomodulatory function. In addition, prebiotics seem to have no significant side effects,12 and may help to avoid mechanical ventilation use in infants. Therefore, they have the potential to decrease sepsis risk in such patients.13

Objectives

Sepsis is a critical situation in clinical practice for which antibiotic therapy is a routine option. However, adverse effects of antibiotics have to be considered in pediatric patients. This meta-analysis aimed to provide an update on the effects of prebiotic use in sepsis events in infants. Based on the literature, we hypothesized that prebiotics would decrease the risk of sepsis. We included randomized controlled trials (RCTs) with placebo controls (no administration of prebiotics) due to the lower risk of bias in such studies. The results could provide valuable information on how to manage infants.

Methods

Literature database
and enrollment criteria

We searched the literature using the following keywords: “prebiotic,” “versus,” “placebo,” “comparison,” “short-chain galacto-oligosaccharides,” “long-chain fructo-oligosaccharides,” “pectin-derived acidic oligosaccharides,” “acidic oligosaccharides,” “sepsis,” “neonate,” “infant,” “septic,” “oligosaccharides,” “fructans,” “oligofructose,” “inulin,” “randomized,” “clinical,” “controlled,” “trials,” “treatment,” “therapy,” “efficacy,” and “outcome.” We searched the ScienceDirect, PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases for relevant prospective RCT studies published before October 2022. The inclusion criteria were: 1. Studies comparing prebiotics with placebo in infants; 2. Those with information on the sepsis characteristics, including the occurrence and rates; 3. Reports published in journals in the Science Citation Index Database written in English; and 4. RCTs with a placebo-controlled design.

Assessment of study quality
and data collection

We conducted the meta-analysis in accordance with the Cochrane Handbook for Systematic Reviews and Interventions14 and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.15 Data collected from the studies included sepsis events, the number of infants who experienced such events after receiving prebiotics or a placebo, the odds ratio (OR), and the standard error (SE).

Data collection and assessment

Two reviewers screened abstracts and collections of articles and extracted data on sepsis outcomes from the texts, tables and figures. The risk of bias was then assessed according to the following criteria: 1. Bias arising from the randomization process; 2. Bias due to deviations from intended interventions; 3. Bias due to missing outcome data; 4. Bias in the measurement of the outcomes, and 5. Bias in the selection of the reported results. The reviewers showed strong agreement in their assessments (kappa = 0.9). Ultimately, the final results were reviewed by all authors.

Meta-analysis and statistical analysis

We generated pooled estimates of the relative risks (RRs) and ORs for sepsis events and prebiotic treatments and used the Cochrane Collaboration Review Manager Software Package RevMan v. 5.4 (Cochrane Collaboration, Copenhagen, Denmark) to perform the meta-analyses. The Mantel–Haenszel method was used to calculate RR, with DerSimonian and Laird’s random effects models and summary statistics also produced. The risk estimates of individual studies were combined using the variance-weighted averages in the random effects model.

The group that received prebiotic treatments and the control group were compared to determine whether prebiotics decreased the rate of sepsis events. The χ2 tests were performed, and the I2 statistic was used to examine the heterogeneity between studies.15 According to the Cochrane Handbook for Systematic Reviews and Interventions,14 the choice between a fixed-effect and a random-effects meta-analysis should not solely be made according to the statistical test for heterogeneity. Methodological or conceptual heterogeneity is unavoidable in a meta-analysis, so a random effects model may be more reasonable. Therefore, a random effects model was applied in this study. Two-sided p-values were obtained from the statistical analyses, and a funnel plot was used to assess publication bias.

Results

Study screening and enrollment

After the initial search, 112 articles were selected, with no additional records found from other sources. These articles included 59 duplicates, which were removed. After evaluating the relevance of the abstracts and titles of the remaining 53 articles, 19 were excluded. The full texts of the remaining 34 articles were screened, and 18 more were discarded.

Ultimately, 16 articles were included in the meta-analysis.16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 The PRISMA flow diagram of this study is shown in Figure 1. The prebiotics group included 3,211 infants, with 3,227 infants in the control group (the total population size was 6,438). Table 1 summarizes the demographic data and characteristics of the 16 studies. Figure 2 shows the assessment of risk bias of the included 16 studies.

Risk ratio and odds ratio
of sepsis events between groups

The prebiotics group had a significantly lower RR of sepsis events according to the random effects model (Z = 3.70 and p = 0.001 for overall effect). Low heterogeneity was obtained, with an I2 value of 32% (Figure 3). The prebiotics group also had a significantly lower OR of sepsis events according to the model (Z = 3.31 and p = 0.001 for overall effect), and the heterogeneity was low, with an I2 value of 38% (Figure 4).

Discussion

The results suggest that prebiotic treatment could be beneficial for reducing the rate of sepsis events in this large sample of infants, which was supported by the RR, OR and 95% confidence intervals (95% CIs). One strength of this meta-analysis is that the studies were RCTs, and most only used prebiotics for the treatment groups. The results indicate that this treatment could be an option for infant patients.

Prebiotics may decrease the colonization and growth of pathogenic bacteria and other pathogens, which could help decrease the risk of sepsis and mortality.32 In the intestines, they may also reduce pathogen cytotoxicity and adhesion,33 improve motility and permeability, and improve the integrity of the epithelial surface.34 Furthermore, strengthening of the intestinal barrier by prebiotics may prevent sepsis and infection by inhibiting the migration of pathogens and toxins across the intestinal mucosa and promoting their removal. In addition, prebiotics could enhance immune responses and modulate the responses to pathogens or toxins.35, 36, 37, 38

Oligosaccharides are prebiotics reported to significantly enhance the growth of probiotic bacteria, such as Bifidobacteria and Lactobacilli. In addition, oligosaccharides may reduce pathogen adhesion.39 A study on the long-term safety and effects of prebiotics in pediatric patients found that they can decrease the amount of antibiotics required, which suggests that this treatment is associated with a lower rate of infection.40 Another study also supports the protective role of prebiotics in suppressing the germination of spores, inhibiting growth into toxin-producing cells, and reducing the colonization of pathogens in the gut.41 These mechanisms could explain the decreased rate of sepsis events among infants that received prebiotics.

The effects of prebiotics are comparable to those of breast milk in several ways, such as increased body weight, lower fever rates, modulatory effects on diarrhea, decreased constipation, and inhibitory effects on respiratory tract infections in infancy.42 Prebiotic supplementation has also been recommended if breast milk is unavailable. Therefore, treatment with prebiotics could be an economical choice for infants.

Limitations

This study had several limitations. First, some RCTs had small sample sizes, while others had appropriate sample sizes, and this imbalance could be a concern. Even though a weighting method was applied to decrease the bias, the impact of this issue should not be ignored.

There was also an imbalance in the sexes of the infants examined, which could influence the interpretation of the results. Similarly, there were variations in age, prebiotic content, doses, placebo used, and treatment duration, which are also potential sources of bias. The lack of patient-level data may be another concern and prevented us from fully evaluating patient-level covariates. Thus, possible subgroup effects could not be investigated.

Another limitation is that the definition and severity of sepsis in the included RCTs differed. Also, some RCTs were double-blinded, while some were single-blinded, and the timing of sepsis was variable between studies, which could affect the results. This issue required consideration when we reported such a significant result of lower sepsis (OR or RR) in this group of pediatric patients.

Conclusions

The results of this meta-analysis showed that prebiotic use could be associated with a reduction in sepsis rates in infants, and prebiotics significantly lowered the sepsis risk in preterm infants. Therefore, they should be considered as an option in clinical practice. Fewer sepsis events under the use of prebiotics might potentially suggest that prebiotics might decrease the mortality and the damage to vulnerable organs. In addition, prebiotics might decrease the sequelae of infection, and the need for antibi­otic use among preterm infants. Future clinical research should examine the standardized application of prebiotics in infant patients.

Tables


Table 1. Summary of enrolled studies

Studies

Subjects (prebiotic compared to control)

Prebiotic content compared to control

Blinded and treatment duration

Outcome of interest

Armanian et al., 2016 (Iran)16

25 (30.48 ±2.31 weeks old) compared to 50 (29.80 ±2.16 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides 1.5 g/kg/day compared to distilled water

double-blinded 21 days

growth of beneficial Lactobacillus colonies, sepsis, fecal microbiota pattern, duration of dependency to oxygen, hospitalization, and death

Campeotto et al., 2011 (France)17

24 (15 M, 9 F, 33.5 ±1.3 weeks old) compared to 34 (16 M, 18 F, 33.4 ±1.4 weeks old)

fermentation-induced non-digestible oligosaccharides compared to formula

double-blinded 30 days

benefits on inflammatory and immune markers, sepsis, inflammatory and immune markers

Dasopoulou et al., 2015 (Greece)18

85 (34 ±0.33 weeks old) compared to 82 (34 ±0.33 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides
1.2 g/kg/day compared to formula

double-blinded 16 days

increase motilin, reduce gastric residue, motilin, necrotizing enterocolitis, mortality, sepsis, and feeding intolerance

Dilli et al., 2015 (Turkey)19

100 (52 M, 48 F, 29 ±1.7 weeks old) compared to 100 (58 M, 42 F, 28.2 ±2.2 weeks old)

inulin 1.35 g/kg/day compared to maltodextrin

double-blinded 56 days

inulin could not decrease necrotizing enterocolitis sepsis, mortality, duration of hospital stay

Guney-Varal et al., 2017 (Turkey)20

70 (29.7 ± 1.9 weeks old compared to 40 (29.3 ± 1.7 weeks old

383 mg of fructooligosaccharides and 100 mg of galactooligosaccharides compared to formula

double-blinded 36.5 ±12.6 days

≥stage 2 necrotizing enterocolitis and mortality, culture-proven sepsis and days to reach full enteral feeding

LeCouffe et al., 2014 (the Netherlands)21

48 (26 M, 22 F, 30.2 ±1.6 weeks old) compared to 45 (26 M, 19 F, 29.5 ±2.0 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides, pectin-derived acidic oligosaccharides 1.5 g/kg/day compared to maltodextrin

single-blinded 28 days

neurodevelopmental outcome, sepsis

Luoto et al., 2014 (Finland)22

23 (11 M, 12 F) compared to 24 (19 M, 5 F ) 32–35 weeks old

short chain galactooligosaccharides/polydextrose 1.2 g/kg/day compared to microcrystalline cellulose and dextrose anhydrate

double-blinded 57 days

respiratory tract infections and its duration, sepsis

Modi et al., 2010 (UK)23

73 (48 M, 25 F, 30 ±0.5 weeks old) compared to 81 (50 M, 31 F, 31 ±0.5 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides 1.2 g/kg/day compared to formula

double-blinded 28 days

necrotizing enterocolitis, mortality, sepsis, feeding intolerance

Nandhini et al., 2016 (India)24

108 compared to 110

100 mg of  fructooligosaccharide compared to no intervention

open-label 7 days

necrotizing enterocolitis, mortality, sepsis, hospitalization duration, number of days to reach full enteral feeding and colony counts in stool culture

Niele et al., 2013 (the Netherlands)25

48 (30.1 ±1.6 weeks old) compared to 46 (29.5. ±2 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides, pectin-derived acidic oligosaccharides 1.5 g/kg/day compared to maltodextrin

double-blinded 28 days

allergic and infectious diseases, sepsis

Panigrahi et al., 2017 (India)26

2278 compared to 2278

(2314 M, 2242 F)

150 mg of  fructooligosaccharide with 100 mg maltodextrin as excipient compared to 250 mg of  maltodextrin

double-blinded

a composite of sepsis or death, the former composed of septicemia, meningitis, culture-negative sepsis other infections (including diarrhea, omphalitis, local infections, abscess, and otitis media) and weight gain

Riskin et al., 2010 (Israel)27

15 (10 M, 5 F, 30.3 ±2.8 weeks old) compared to 13 (5 M, 8 F, 128.7 ±2.9 weeks old)

digestible oligosaccharides lactulose 1.5 g/kg/day compared to dextrose

double-blinded 35 days

necrotizing enterocolitis, mortality, sepsis, feeding intolerance, and days to reach full enteral feeding

Serce et al., 2020 (Turkey)28

104 (61 M, 43 F 29 ±1.9 weeks old) compared to 104 (52 M, 52 F 28 ±2.2 weeks old)

383 mg of fructooligosaccharide, 100 mg of galactooligosaccharide, 2 mg of bovine lactoferrin compared to distilled water

double-blinded 21 days

necrotizing enterocolitis severity, mortality, sepsis, hospitalization duration, time to reach 100 mL/kg/day of oral feeding

Torres et al., 2020 (Peru)29

99 compared to 100

oligosaccharides compared to mature breast milk

single-blinded

late-onset sepsis, neonatal sepsis

van den Berg et al., 2013 (the Netherlands)30

38 (21 M, 17 F, 29.9 ±1.7 weeks old) compared to 39 (24 M, 15 F, 29.6 ±2.1 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides, pectin-derived acidic oligosaccharides 1.5 g/kg/day compared to maltodextrin

single-blinded 28 days

neurodevelopment, cytokines, infections, sepsis

Westerbeek et al., 2011 (the Netherlands)31

73 (29.9 ±1.9 weeks old) compared to 81 (29.3 ±2.1 weeks old)

short chain galactooligosaccharides/long chain fructooligosaccharides, pectin-derived acidic oligosaccharides 1.5 g/kg/day compared to maltodextrin

double-blinded 28 days

stool viscosity, stool frequency, stool pH, sepsis

Figures


Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. The identification and selection of potentially relevant literature, through abstract and title screening, adhered to the PRISMA guidelines. The full texts of eligible studies were screened, and suitable articles were enrolled into the final meta-analysis
Fig. 2. Risk of bias assessment visualization. The risk of bias assessment updated version (ROB v2) was used to assess the risk of bias for the randomized controlled trials (RCTs)
Fig. 3. Forest plot of risk ratio (RR) for sepsis events in infants (prebiotic compared to control). The prebiotic group of preterm infants had a significantly lower RR of sepsis events than the control group
Fig. 4. Forest plot of odds ratio (OR) for sepsis events in infants (prebiotic compared to control). The prebiotic group of preterm infants had a significantly lower OR of sepsis events than the control group

References (42)

  1. Shuai X, Li X, Wu Y. Prediction for late-onset sepsis in preterm infants based on data from East China. Front Pediatr. 2022;10:924014. doi:10.3389/fped.2022.924014
  2. Dierikx TH, Deianova N, Groen J, et al. Association between duration of early empiric antibiotics and necrotizing enterocolitis and late-onset sepsis in preterm infants: A multicenter cohort study. Eur J Pediatr. 2022;181(10):3715–3724. doi:10.1007/s00431-022-04579-5
  3. Goh GL, Lim CSE, Sultana R, De La Puerta R, Rajadurai VS, Yeo KT. Risk factors for mortality from late-onset sepsis among preterm very-low-birthweight infants: A single-center cohort study from Singapore. Front Pediatr. 2022;9:801955. doi:10.3389/fped.2021.801955
  4. Garg PM, Paschal JL, Ansari MAY, Block D, Inagaki K, Weitkamp JH. Clinical impact of NEC-associated sepsis on outcomes in preterm infants. Pediatr Res. 2022;92(6):1705–1715. doi:10.1038/s41390-022-02034-7
  5. Hibbert J, Strunk T, Nathan E, et al. Composition of early life leukocyte populations in preterm infants with and without late-onset sepsis. PLoS One. 2022;17(3):e0264768. doi:10.1371/journal.pone.0264768
  6. Johnston N, De Waal K. Clinical and haemodynamic characteristics of preterm infants with early onset sepsis. J Paediatr Child Health. 2022;58(12):2267–2272. doi:10.1111/jpc.16218
  7. Wang Z, Zhao Y, Jiang Y, Chu W. Prebiotic, antioxidant, and immunomodulatory properties of acidic exopolysaccharide from marine Rhodotorula RY1801. Front Nutr. 2021;8:710668. doi:10.3389/fnut.2021.710668
  8. Thambiraj SR, Phillips M, Koyyalamudi SR, Reddy N. Yellow lupin (Lupinus luteus L.) polysaccharides: Antioxidant, immunomodulatory and prebiotic activities and their structural characterisation. Food Chem. 2018;267:319–328. doi:10.1016/j.foodchem.2018.02.111
  9. Breton J, Plé C, Guerin-Deremaux L, et al. Intrinsic immunomodulatory effects of low-digestible carbohydrates selectively extend their anti-inflammatory prebiotic potentials. BioMed Res Int. 2015;2015:162398. doi:10.1155/2015/162398
  10. Azagra-Boronat I, Massot-Cladera M, Mayneris-Perxachs J, et al. Immunomodulatory and prebiotic effects of 2’-fucosyllactose in suckling rats. Front Immunol. 2019;10:1773. doi:10.3389/fimmu.2019.01773
  11. Eiwegger T, Stahl B, Haidl P, et al. Prebiotic oligosaccharides: In vitro evidence for gastrointestinal epithelial transfer and immunomodulatory properties. Pediatr Allergy Immunol. 2010;21(8):1179–1188. doi:10.1111/j.1399-3038.2010.01062.x
  12. Pol K, De Graaf C, Meyer D, Mars M. The efficacy of daily snack replacement with oligofructose-enriched granola bars in overweight and obese adults: A 12-week randomised controlled trial. Br J Nutr. 2018;119(9):1076–1086. doi:10.1017/S0007114518000211
  13. 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(5):657–670. doi:10.1038/s41430-018-0377-6
  14. Cumpston MS, McKenzie JE, Welch VA, Brennan SE. Strengthening systematic reviews in public health: Guidance in the Cochrane Handbook for Systematic Reviews of Interventions, 2nd edition. J Public Health (Oxf). 2022;44(4):e588–e592. doi:10.1093/pubmed/fdac036
  15. Knobloch K, Yoon U, Vogt PM. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and publication bias. J Craniomaxillofac Surg. 2011;39(2):91–92. doi:10.1016/j.jcms.2010.11.001
  16. Armanian AM, Barekatain B, Hoseinzadeh M, Salehimehr N. Prebiotics for the management of hyperbilirubinemia in preterm neonates. J Matern Fetal Neonatal Med. 2016;29(18):3009–3013. doi:10.3109/14767058.2015.1113520
  17. Campeotto F, Suau A, Kapel N, et al. A fermented formula in pre-term infants: Clinical tolerance, gut microbiota, down-regulation of faecal calprotectin and up-regulation of faecal secretory IgA. Br J Nutr. 2011;105(12):1843–1851. doi:10.1017/S0007114510005702
  18. Dasopoulou M, Briana DD, Boutsikou T, et al. Motilin and gastrin secretion and lipid profile in preterm neonates following prebiotics supplementation. J Parenter Enteral Nutr. 2013;39(3):359–368. doi:10.1177/0148607113510182
  19. Dilli D, Aydin B, Fettah ND, et al. The propre-save study: Effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J Pediatr. 2015;166(3):545–551.e1. doi:10.1016/j.jpeds.2014.12.004
  20. 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. Turk J Pediatr. 2017;59(1):13–19. doi:10.24953/turkjped.2017.01.003
  21. LeCouffe N, Westerbeek E, Van Schie P, Schaaf V, Lafeber H, Van Elburg R. Neurodevelopmental outcome during the first year of life in preterm infants after supplementation of a prebiotic mixture in the neonatal period: A follow-up study. Neuropediatrics. 2014;45(1):22–29. doi:10.1055/s-0033-1349227
  22. 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(2):405–413. doi:10.1016/j.jaci.2013.08.020
  23. Modi N, Uthaya S, Fell J, Kulinskaya E. A randomised, double-blind, controlled trial of the effect of prebiotic oligosaccharides on enteral tolerance in preterm infants (ISRCTN77444690). Pediatr Res. 2010;68(5):440–445. doi:10.1203/PDR.0b013e3181f1cd59
  24. Nandhini LP, Biswal N, Adhisivam B, Mandal J, Bhat BV, Mathai B. Synbiotics for decreasing incidence of necrotizing enterocolitis among preterm neonates: A randomized controlled trial. J Matern Fetal Neonatal Med. 2016;29(5):821–825. doi:10.3109/14767058.2015.1019854
  25. Niele N, Van Zwol A, Westerbeek EA, Lafeber HN, Van Elburg RM. Effect of non-human neutral and acidic oligosaccharides on allergic and infectious diseases in preterm infants. Eur J Pediatr. 2013;172(3):317–323. doi:10.1007/s00431-012-1886-2
  26. Panigrahi P, Parida S, Nanda NC, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017;548(7668):407–412. doi:10.1038/nature23480
  27. Riskin A, Hochwald O, Bader D, et al. The effects of lactulose supplementation to enteral feedings in premature infants: A pilot study. J Pediatr. 2010;156(2):209–214. doi:10.1016/j.jpeds.2009.09.006
  28. Serce Pehlevan O, Benzer D, Gursoy T, Karatekin G, Ovali F. Synbiotics use for preventing sepsis and necrotizing enterocolitis in very low birth weight neonates: A randomized controlled trial. Clin Exp Pediatr. 2020;63(6):226–231. doi:10.3345/cep.2019.00381
  29. Torres Roldan VD, Urtecho SM, Gupta J, et al. Human milk oligosaccharides and their association with late-onset neonatal sepsis in Peruvian very-low-birth-weight infants. Am J Clin Nutr. 2020;112(1):106–112. doi:10.1093/ajcn/nqaa102
  30. Van Den Berg JP, Westerbeek EAM, Van Der Klis FRM, Berbers GAM, Lafeber HN, Van Elburg RM. Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial. PLoS One. 2013;8(8):e70904. doi:10.1371/journal.pone.0070904
  31. Westerbeek EAM, Hensgens RI, Mihatsch W, Boehm G, Lafeber HN, Van Elburg RM. The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants. Acta Paediatr. 2011;100(11):1426–1431. doi:10.1111/j.1651-2227.2011.02295.x
  32. Tulumoğlu Ş, Erdem B, Şimşek Ö. The effects of inulin and fructo-oligosaccharide on the probiotic properties of Lactobacillus spp. isolated from human milk. Z Naturforsch C J Biosci. 2018;73(9–10):367–373. doi:10.1515/znc-2018-0001
  33. Di R, Vakkalanka MS, Onumpai C, et al. Pectic oligosaccharide structure-function relationships: Prebiotics, inhibitors of Escherichia coli O157:H7 adhesion and reduction of Shiga toxin cytotoxicity in HT29 cells. Food Chem. 2017;227:245–254. doi:10.1016/j.foodchem.2017.01.100
  34. Vieira ADS, Bedani R, Albuquerque MAC, Biscola V, Saad SMI. The impact of fruit and soybean by-products and amaranth on the growth of probiotic and starter microorganisms. Food Res Int. 2017;97:356–363. doi:10.1016/j.foodres.2017.04.026
  35. Abasubong KP, Li X, Adjoumani JY, Jiang G, Desouky HE, Liu W. Effects of dietary xylooligosaccharide prebiotic supplementation on growth, antioxidant and intestinal immune‐related genes expression in common carp Cyprinus carpio fed a high-fat diet. J Anim Physiol Anim Nutr (Berl). 2022;106(2):403–418. doi:10.1111/jpn.13669
  36. Mio K, Otake N, Nakashima S, Matsuoka T, Aoe S. Ingestion of high beta-glucan barley flour enhances the intestinal immune system of diet-induced obese mice by prebiotic effects. Nutrients. 2021;13(3):907. doi:10.3390/nu13030907
  37. Lee HB, Son SU, Lee JE, et al. Characterization, prebiotic and immune-enhancing activities of rhamnogalacturonan-I-rich polysaccharide fraction from molokhia leaves. Int J Biol Macromol. 2021;175:443–450. doi:10.1016/j.ijbiomac.2021.02.019
  38. Ferret-Bernard S, Le Normand L, Romé V, et al. Maternal supplementation of food ingredient (prebiotic) or food contaminant (mycotoxin) influences mucosal immune system in piglets. Nutrients. 2020;12(7):2115. doi:10.3390/nu12072115
  39. Leong A, Liu Z, Almshawit H, et al. Oligosaccharides in goats’ milk-based infant formula and their prebiotic and anti-infection properties. Br J Nutr. 2019;122(4):441–449. doi:10.1017/S000711451900134X
  40. Kukkonen K, Savilahti E, Haahtela T, et al. Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: Randomized, double-blind, placebo-controlled trial. Pediatrics. 2008;122(1):8–12. doi:10.1542/peds.2007-1192
  41. Rätsep M, Kõljalg S, Sepp E, et al. A combination of the probiotic and prebiotic product can prevent the germination of Clostridium difficile spores and infection. Anaerobe. 2017;47:94–103. doi:10.1016/j.anaerobe.2017.03.019
  42. Shahramian I, Kalvandi G, Javaherizadeh H, et al. The effects of prebiotic supplementation on weight gain, diarrhoea, constipation, fever and respiratory tract infections in the first year of life. J Paediatr Child Health. 2018;54(8):875–880. doi:10.1111/jpc.13906
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