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Probiotics and Prebiotics in Infants and Children

Article  in  Current Infectious Disease Reports · May 2013

DOI: 10.1007/s11908-013-0334-4 · Source: PubMed

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 1

3 Probiotics & Prebiotics in

4 Pediatric Disorders
5
6
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8 Y. Vandenplas, E. De Greef, B. Hauser, T. Devreker G. Veereman-Wauters
9
10
11 Pediatric Gastroenterology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium
12
13
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15 Address for correspondence:
16 Y. Vandenplas, UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels,
17 Belgium.
18 Tel: + 32.2.477.57.80; Fax: + 32.2.477.57.83; e-mail: yvanvandenplas@uzbrussel.be
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1 Abstract
2 Background. Probiotics and prebiotics have a major influence on gastro-intestinal flora
3 composition. This review analysis if this change in flora composition can be related to
4 healthcare benefits in children.
5 Method. Literature databases were searched for relevant manuscripts.
6 Results. Despite exhaustive research on the subject, clear benefits for the use of
7 prebiotics and probiotics in pediatrics disorders remain scarce. The best evidence has
8 been provided for probiotics in acute gastroenteritis and prevention of antibiotic
9 associated diarrhea (AAD). However, AAD in children is in general mild, and only
10 seldom necessitates additional interventions. Overall, the duration of acute infectious
11 diarrhea is reduced by approximately 24 hours. Evidence for clinically relevant benefit in
12 all other indications (inflammatory bowel disease, irritable bowel syndrome, constipation,
13 allergy,..) is weak to non existing. Selected probiotic strains given during late pregnancy
14 and early infancy decrease atopic dermatitis. Adverse effects have almost not been
15 shown.
16 Conclusions. Since the risk seems minimal to non existing, pre- and probiotics may be
17 helpful in the prevention and treatment of some disorders in children, although the
18 evidence for benefit is limited. The best evidence has been accumulated for some
19 lactobacilli strains and for Saccharomyces boulardii in the reduction of duration of acute
20 diarrhea due to gastroenteritis and prevention of antibiotic associated diarrhea
21
22

2
 1
2 Background
3 The gastrointestinal (GI) tract is harboring a diverse array of commensal microbes that
4 act like a separate eco-system. The GI flora can be considered as an organ within an
5 organ contributing to host nutrition, developmental regulation of intestinal angiogenesis,
6 protection from pathogens and development of the immune response [1].
7
8 Probiotics are non-pathogenic live micro-organisms that, when consumed in adequate
9 amounts, have a positive effect on the health of the host. Although probiotics are today a
10 “hot topic”, they are not new. More than 2000 years ago, the Roman author Plinius The
11 Old recommended already the use of fermented milk in the treatment of acute
12 gastroenteritis.
13
14 There are minimum requirements for a status of "probiotic microorganism" which
15 include [2]: i) the assessment of strain identity (genus, species, strain level); ii) in vitro
16 tests to screen potential probiotic strains’activity; iii) assessment of safety and in vivo
17 studies for substantiation of health effects in the target host. Probiotics are considered to
18 be safe in ambulatory care in non-immunocompromised patients.
19
20 Most probiotics are registered as food supplement, and thus do not have to fulfill the
21 quality requirements for medication. Research on the mechanisms of action of specific
22 strains and clinical trials with commercialized products are mandatory. In vitro effects of
23 a strain may display opposite behavior in vivo [3]. Effects demonstrated for one strain
24 cannot be extrapolated to other strains, even if they belong to the same species. Only
25 these commercialized products for which convincing data are available can be
26 recommended for medical use. Since some commercialized products are combinations of
27 different strains, clinical testing of each combination of each product is mandatory as
28 they may have synergetic or contradictory effects. Moreover, dosage and duration of
29 administration should be taken into account as different doses and different duration may
30 have opposite effects [4].
31

3
 1 Prebiotics are non-digestible food ingredients that stimulate the growth and/or activity of
2 bacteria in the digestive system in ways claimed to be beneficial to health. Full-spectrum
3 prebiotics provide molecular link-lengths from 2-64 links per molecule, and nourish
4 bacteria throughout the colon, e.g. oligofructose-enriched inulin. In infant formula, most
5 of the time galacto-oligosaccharides (GOS) and/or fructo-oligosaccharides (FOS) are
6 used. The majority of research done on prebiotics is based on full-spectrum prebiotics.
7
8 More and more “synbiotics” come on the market. These are combinations of a prebiotic
9 and most of the time several strains of probiotics. Manufacturers market these products
10 by listing all the benefits of each ingredient separately. Whether this marketing strategy is
11 scientifically valid is uncertain. It becomes also more and more difficult to obtain
12 information about the exact strains in different products. The lack of legal protection
13 authorizes competitors to copy successful products without any investments for the
14 company that copies products [5].
15
16 Application of pre- and probiotics in prevention and treatment.
17 Acute infectious gastroenteritis
18 Up to 70 to 80 % of all infectious diarrheas are of viral origin of which Rota-virus is still
19 the most prevalent pathogen. Breastfeeding is known to offer the best infectious
20 prevention in young infants because of the presence of immunogenic factors, among
21 which pre-and probiotics. Therefore, breastfeeding should be maximally endorsed. Based
22 on this knowledge, cow’s based formulas have been developed to mimic the immune
23 capacity of breastfeeding by adding pre-and probiotics.
24
25 Prevention with probiotics and prebiotics
26 Probiotics have been largely studied to the prevention of acute infectious diarrhea. Large,
27 randomized controlled trials provide evidence of a very modest effect (statistically
28 significant, but of questionable clinical importance) of some probiotic strains
29 (Lactobacillus (L.) GG, L. reuteri, Bifidobacteria (B.) lactis) on the prevention of
30 community-acquired diarrhea [6-14]. L. reuteri protects for the development of diarrhea
31 in Indonesian children with undernutrition [10]. For prevention of diarrhea acquired in

4
 1 day-care centers, many randomized and placebo-controlled trials have been published,
2 conducted in different parts of the world. Probiotics tested were L. GG, B. lactis, alone or
3 in combination with Str. Thermophilus; and L. reuteri, L. rhamnosus (not GG), and L.
4 acidophilus, in various trials either alone or in comparison with each other. The evidence
5 of their efficacy in these settings is only modest for the prevention of diarrhea, although
6 somewhat better for prevention of upper respiratory infections [11]. Seven children
7 would need to be treated with a probiotic to prevent one patient from developing
8 nosocomial Rota gastroenteritis [12]. However, the protective effect on prevention of
9 diarrhea becomes far less significant if the incidence of diarrhea (episodes per patient-
10 month) rather than the percentage of patients with diarrhea are taken into account [12]. In
11 hospitalized children, the administration of L reuteri DSM 17938 compared with placebo
12 had no effect on the overall incidence of nosocomial diarrhea, including rotavirus
13 infection [15].
14
15 Data with prebiotics in the prevention of acute gastroenteritis are limited. A formula
16 containing GOS and FOS was reported to prevent intestinal and extra-intestinal infections
17 [16]. However, the effect of the same specific prebiotics, a GOS/FOS mixture, as well as
18 the effect of a synbiotic with GOS and B lactis HN019 on diarrhea was reported in other
19 studies to be not convincing [17,18]. The incidence rate of gastrointestinal infections in
20 infants of the control group was 3 times higher than in the probiotic group [19].
21 Therefore, consumption of a prebiotic infant formula enriched with the human milk
22 probiotic strain L. fermentum CECT5716 from 1 to 6 months of life is well tolerated and
23 safe. Furthermore, the consumption of this formula may improve the health of the infants
24 by reducing the incidence of gastrointestinal infections [19].
25
26 The European Society of Paediatric Gastroenterology, Hepatology and Nutrition
27 (ESPGHAN) concluded that there was insufficient evidence to recommend the use of
28 infant formula enriched with probiotics, mainly because of the efficacy shown was
29 insufficiently convincing [20]. On the other hand, most of the studies did show some
30 benefit, although for different endpoints and not always statistically significant. Serious
31 adverse events were not reported. The conclusions of the American Academy of

5
 1 Pediatrics are quite similar: "Available data do not support routine use of probiotics to
2 prevent nosocomial rotavirus diarrhea in child care centers [21]. But, there may be
3 special circumstances in which probiotic use in children in long-term health care facilities
4 or in child care centers is beneficial [21].
5
6 In summary: the majority of the studies show some positive effect or trend of pre- and
7 probiotics in the prevention of diarrhea, and no adverse events. However, the benefit is
8 seldom significant.
9
10 Treatment with probiotics and prebiotics

11 The cornerstone of the treatment of acute GE is oral rehydration and rapid re-
12 alimentation. More data are needed to optimize the management of diarrhea and
13 highlight the research priorities at a global level; such priorities include the re-evaluation
14 of therapeutic options [22]. Therapeutic strategies need to be assessed in different
15 settings, and pharmacoeconomic analyses based on country-specific data are needed.
16 Transfer to clinical practice should result from the implementation of guidelines tailored
17 at a local level, with an eye on costs [22].

18
19 Probiotics aim to enhance normalization of the gastrointestinal flora and diminish the
20 duration of acute diarrhea. There are only limited studies performed in chronic diarrhea
21 of infectious origin; most of these studies are with S. boulardii. The multicenter trial by
22 Guandalini et al. was one of the very first demonstrating a decrease in duration of
23 infectious diarrhea with probiotic administration [23]. Individual trials and meta-analyses
24 on bacterial probiotics concluded that the majority of the studies had been performed in
25 the developed world, and that there was efficacy for L. rhamnosus GG, L. acidophilus, L.
26 reuteri and L. bulgaricus [24-28]). In particular, the duration of (viral) diarrhea was
27 approximately reduced by 24 hours (17 to 30 hours) with 4 children needed to be treated
28 to protect one subject from diarrhea compared to controls [25]. The more strains are
29 studied, the more strain specificity appears clinically relevant. Lactobacillus paracasei
30 strain ST11 has no effect on rotavirus but ameliorates the outcome of nonrotavirus
31 diarrhea [29]. Bifidobacterium longum subsp. infantis CECT 7210 can be considered a

6
 1 probiotic able to inhibit rotavirus infection [30]. The efficacy of L. GG appeared related
2 to the logarithm of the dose (>1011 as the most efficient dose) [26]. Probiotics may also
3 reduce the relapse rate of diarrhea [27]. There is a need for trials comparing the efficacy
4 of different strains, as has been done recently comparing L. reuteri and L. casei CRL431
5 [10] suggesting efficacy for the first.
6
7 S boulardii, a probiotic yeast, was first studied more than 15 years ago showing a
8 significant reduction in duration of symptoms [31]). Since then, several double-blind,
9 prospective, randomized trials performed with S boulardii in children with acute gastro-
10 enteritis have systematically shown a significant improvement in comparison to placebo
11 [32,33]. Diarrhea reduction with S. boulardii is also about one day. The efficacy of S.
12 boulardii was recently confirmed in an Indian trial [34].
13

14 In 2010, a Cochrane review included 36 studies with a total of 8014 participants; of these,
15 56 trials recruited infants and young children. It was concluded that alongside rehydration
16 therapy, probiotics appear to be safe and have a clear beneficial effects in shortening the
17 duration and reducing stool frequency in acute infectious diarrhoea [35]. The mean
18 difference in duration of diarrhea was 24.76 hours (95% confidence interval 15.9 to 33.6
19 hours; n=4555, trials=35), diarrhea lasting ≥4 days (risk ratio 0.41; 0.32 to 0.53; n=2853,
20 trials=29) and stool frequency on day 2 (mean difference 0.80; 0.45 to 1.14; n=2751,
21 trials=20) [35]. In recommendations for general practitioners in the USA, probiotics are
22 positioned as helpful in the treatment of acute gastroenteritis [36]. However, more
23 research is still needed to guide the use of particular probiotic regimens in specific patient
24 groups [35].

25
26 Probiotics seem more effective when given early in the course of diarrhea, and are more
27 helpful for otherwhise healthy infants and young children with watery diarrhea secondary
28 to viral gastroenteritis but not invasive bacterial infections [20]. A shortening of the
29 duration of diarrhea, as well as a reduced hospital stay suggests a relevant social and
30 economic benefit of biotherapeutic treatment in adjunction to ORS in acute infectious
31 gastroenteritis in children [37]. Because of the decreased need for additional

7
 1 consultations and concommittant medication, probiotics (and synbiotics) are suggested to
2 have cost reducing effect [38].

4 The few studies with prebiotics that were performed in the treatment of acute infectious
5 gastroenteritis are negative [39]. Recently, a study with and zind and prebiotics reported a
6 decrease in duration of diarrhea, a decreased intake of ORS, a decreased number of
7 missed working days by the parents, a decreased need of adjunctive drugs [40]. Recently,
8 studies have been published with synbiotics showing the effect of a combination of FOS,
9 zinc and several probiotics (Str. Thermophilus, B. lactis, L. acidophilus) on the duration
10 of diarrhea [41,42]. In a very recent review paper, Lactobacillus GG and S. boulardii are
11 confirmed as first choice probiotics [43].

12
13 Antibiotic associated diarrhea (AAD)
14 Antibiotic treatment is known to disturb the GI microflora, which results in a range of
15 clinical symptoms, especially diarrhea. The incidence of AAD in children in first line
16 healthcare is about 10 %, independent of the reason for antibiotic administration [44];
17 the risk for AAD is increased in young children (18 % in children younger than 2 years),
18 and with some antibiotics such as amoxicillin-clavulanate (23 % with this antibiotic)
19 [44]. However, the vast majority of AADs are very mild to moderate and hospitalisation
20 is seldom required.
21
22 Prevention with probiotics and prebiotics

23 The pooled relative risk in a meta-analysis of 63 RCTs, which included 11,811

24 participants, indicated a statistically significant association of probiotic administration
25 with reduction in AAD (relative risk, 0.58; 95% CI, 0.50 to 0.68; P < .001; I(2), 54%;
26 [risk difference, -0.07; 95% CI, -0.10 to -0.05], [number needed to treat, 13; 95% CI, 10.3
27 to 19.1]) [45]. Another metaanalysis concluded the number needed to treat was 8 [46].
28 According to a recent meta-analysis, probiotics reduce the risk of AAD in children
29 significantly [47]. Preplanned subgroup analysis showed that reduction of the risk of
30 AAD was associated with the use of L. GG (95% CI 0.15 to 0.6), S. boulardii (95% CI

8
 1 0.07-0.6), or B. lactis and Str. thermophilus (95% CI 0.3 to 0.95) [47]. For every 7
2 patients that would develop diarrhea while being treated with antibiotics, one fewer will
3 develop AAD if also receiving probiotics [47]. Only S. boulardii was reported to be
4 effective in Clostridium Difficile (C. Dif.) disease [48-50]. Recently, a large single-center
5 study showed in elderly that S. boulardii was not effective in preventing the development
6 of AAD or in prevention of C. Dif. infection [51].In many studies, there is no evidence to
7 support the use of any (other) probiotic to prevent the recurrence of C. Dif. infection or to
8 treat existing C. Dif. diarrhea [9]. In most studies, the probiotic is started together with
9 antibiotic treatment [20].

10
11 Despite heterogeneity in probiotic strain, dose, and duration, as well as in study quality,
12 the overall evidence maintains a protective effect of probiotics in preventing AAD
13 [20,50-53], independent of age [3]. If probiotics are also effective in preventing C. Dif
14 infection remains debated [53]. None of the trials that reported on adverse events
15 documented any serious side effect [49]. More research is needed to determine which
16 probiotics are associated with the greatest efficacy and for which patients receiving which
17 specific antibiotics [45].
18
19 The administration of two prebiotics (inulin and fructo-oligosaccharide) was not effective
20 for preventing diarrhea and AAD [54].

21

22 Treatment with probiotics and prebiotics

23 Almost all studies are focusing on the prevention of AAD; there are no data on efficacy
24 of probiotics or prebiotics in the treatment of AAD, except for very limited data on S
25 boulardii in Clostridium difficile diarrhea. S. boulardii was shown to be effective in
26 secondary prevention; it’s role in primary prevention is poorly defined [55]. There have
27 been no RCTs with probiotics in the treatment of AAD in children [20].

28

29

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 1 Traveler’s diarrhea
2 Traveler’s diarrhea is a frequent condition of great socio-economic impact. It is one of
3 these topics on which there are more reviews than original research published. Different
4 randomized trials have been performed evaluating the efficacy of probiotics in the
5 prevention of traveler’s diarrhea. One trial with L. Acidophilus and two with L. GG
6 showed negative results [56-58]. One trial with S. boulardii reported a small but
7 significant preventive effect in a subgroup, suggesting geographical differences in
8 efficacy [59]. In a review, McFarland concluded that there is comparable evidence for
9 efficacy for L. rhamnosus GG, L. casei DN-114001 and S. boulardii, and no efficacy for
10 L. acidophilus [60]. Since the number of studies in traveler’s diarrhea is very limited, a
11 recent meta-analysis concluded that there is no efficacy of probiotics in traveler's diarrhea
12 [3]. There are no data on prebiotics and prevention or treatment of traveler's diarrhea.
13 Overall, the number of studies is to small to allow to formulate recommendations [61].
14
15 Inflammatory bowel disease (IBD)
16 The concept of dysbiosis, a breakdown of balance between “protective” and “harmful”
17 intestinal bacteria, has been generally accepted as one of the pathophysiologic
18 abnormalities in IBD patients.

19 Even though pediatric data are scarce and although there is a lack of evidence of benefit,
20 almost 80 % of the children with an IBD have a regular intake of probiotics [62]. A small
21 study with 4 Crohn’s disease (CD) patients, suggested an effect of L GG on disease
22 activity [63]. A 2 year follow-up study with L. GG in children with CD in remission,
23 resulted in a relapse rate of 31% in the probiotic group versus 17% in the placebo group
24 (non significant difference, but higher relapse rate in the probiotic group) [64]. There was
25 also no difference in the time lapse before the relapse [64]. In ulcerative colitis (UC), L.
26 reuteri enemas would be effective for distal active colitis [65] and VSL#3 would be
27 effective in obtaining remission and decreases the relapse rates [66]. Well designed
28 randomized controlled trials supporting the application of probiotics in the management of
29 IBD are still limited [67]. Meta-analyses could only be performed for a limited number of
30 studies revealing overall risk ratios of 2.70 (95% CI 0.47, 15.33) for inducing remission

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 1 in active UC with Bifido-fermented milk versus placebo or no additive treatment (n = 2);

2 1.88 (95% CI 0.96, 3.67) for inducing remission in active UC with VSL#3 versus placebo

3 (n = 2); 1.08 (95% CI 0.86, 1.37) for preventing relapses in inactive UC with Escherichia

4 (E.) coli Nissle 1917 versus standard treatment (n = 3); 0.17 (95% CI 0.09, 0.33) for

5 preventing relapses in inactive UC/ileo-anal pouch anastomosis patients with VSL#3

6 versus placebo; 1.21 (95% CI 0.57, 2.57) for preventing endoscopic recurrences in

7 inactive CD with L. rhamnosus GG versus placebo (n = 2); and 0.93 (95% CI 0.63, 1.38)

8 for preventing endoscopic recurrences in inactive CD with L. johnsonii versus placebo

9 (n = 2) [67]. Further well designed studies based on intention-to-treat analyses by several

10 independent research groups are still warranted to support the promising results for E.
11 coli Nissle in inactive UC and the multispecies product VSL#3 in active UC and inactive
12 pouch patients. So far, no evidence is available to support the use of probiotics in CD
13 [67]. Well-designed, large randomized controlled trials using probiotics in patients with
14 IBD are required for probiotics to become mainstream therapy [68].Given present data,
15 adjunct VSL#3 use for pediatric UC induction and maintenance of remission is not cost-
16 effective, although several key parameters could make this strategy cost-effective [69].

17
18 Irritable bowel syndrome (IBS)

19 There is a large literature on the effect of probiotics on IBS in adults, but data in children
20 are limited. A Cochrane review from 2009 failed to show an effect of fiber supplements
21 and recorded a limited effect of Lactobacillus on symptoms compared to placebo (OR
22 1.17 (95% CI 0.62, 2.21)) [70].

23 A randomized trial of 6 weeks with L. GG versus placebo showed overall negative results
24 in 50 children and young adults, although there was a lower incidence of perceived
25 abdominal distension in L.GG group [71]. L. GG but not placebo caused a significant
26 reduction of both frequency and severity of abdominal pain compared to baseline and
27 influenced intestinal permeability testing [72]. A meta-analysis showed that, compared
28 with placebo, LGG supplementation is associated with a significantly higher rate of

11
 1 treatment responders in the overall population with abdominal pain-related functional
2 gastrointestinal disorders and in the irritable bowel syndrome (IBS) subgroup [73].
3 However, no difference was found in children with functional abdominal pain or
4 functional dyspepsia who received placebo or LGG. A randomized cross-over trial with
5 VSL#3 and placebo for 6 weeks, with a 2 week washout period in between in 59 patients
6 showed a superior effect of VSL#3 compared to placebo in symptom relief, as well as in
7 abdominal pain/discomfort, abdominal bloating/gassiness, and family assessment of life
8 disruption [73]. No significant difference was found in the stool pattern [74].
9
10 There are no data on prevention of treatment of IBS with prebiotics. Data from one trial
11 suggest that, in infants, a prebiotic-containing whey-based formula provides superior
12 gastrointestinal comfort than a control formula [75]. A peptide-based formula containing
13 fiber was as well-tolerated as a fiber-free formula in a small population of children with
14 gastrointestinal impairments [76]. Extremes of stool consistency were normalized with
15 the fiber formula. No significant differences were observed in vomiting, abdominal pain,
16 feeding intakes, or weight gain between the two formulas [76]. Synbiotics should be
17 further investigated in this indication [77].
18
19 Helicobacter pylori
20 The use of probiotics in H. pylori-colonized subjects with gastric inflammation is
21 supported by many observations. Specific strains of Lactobacillus and Bifidobacterium
22 exert in vitro bactericidal effects against H. pylori through the release of bacteriocins or
23 production of organic acids, and/or inhibit its adhesion to epithelial cells. Such protective
24 effects have been confirmed in animal models. Clinical trials are very important, since in
25 vitro results cannot always be reproduced in patients. Probiotics decrease the bacterial
26 load and improve the immune response [78]. Results of clinical trials indicate that
27 probiotics generally do not eradicate H. pylori but decrease the density of colonization,
28 thereby maintaining lower levels of this pathogen in the stomach; in association with
29 antibiotic treatments, some probiotics increased eradication rates and/or decreased
30 adverse effects due to the antibiotics. Many studies show a moderate higher eradication
31 rate (~10%) of H. pylori when probiotics are added to the antibiotics and proton pump

12
 1 inhibitor [79]. Although L. GG seems not to improve eradication [80], most probiotic
2 bacteria and yeasts reduce adverse effects of standard H. pylori eradication regimens
3 [81,82]. Cranberry juice extract inhibits H. pylori proliferation and it is suggested that
4 polyphenols are responsible for this action [83]. The morphological analysis suggested
5 that cranberry induces H. pylori to develop a coccoid form, thereby inhibiting its growth
6 bacteriostatically [83,84]. There are no data on prebiotics in H. pylori eradication.

7
8 Necrotizing enterocolitis (NEC)

9 NEC is a severe condition occurring especially in preterm babies. Abnormal

10 gastrointestinal flora development has been hypothesized as one of the possible etiologic
11 factors. The first publication reporting that L. acidophilus and B. infantis reduced NEC
12 dates back from 1999 [85]. Short afterwards, oligofructose was shown to not decrease
13 NEC [86], which was followed by a negative study showing that seven days of L. GG
14 supplementation starting with the first feed was not effective in reducing the incidence of
15 urinary tract infection, NEC and sepsis in preterm infants [87]. Then, several randomized
16 trials with different lactobacilli and bifidobacteria showed a significant reduction in
17 development of NEC [88,89]. Although S. boulardii was shown to ameliorate
18 hypoxia/reoxygenation-induced NECs in young mice [90], it did not protect for NEC in
19 infants [91]. A Cochrane review concluded in 2008 that enteral probiotic supplementation
20 reduced the incidence of NEC Stage II or more and mortality [92]. No systemic
21 infections or serious adverse events were directly attributed to the administered probiotic
22 microorganism [92]. According to the published trials, the number needed to treat to
23 prevent one case of NEC is 21 and 27 [92]. However, the centers in which these trails
24 have been performed have a much higher incidence of NEC than most European or North
25 American centers. The recommendation may be different in centers with a high incidence
26 of NEC in which the other measurements to decrease NEC are difficult to apply. The
27 updated Cochrane review from 2011 comes to different conclusions: enteral
28 supplementation of probiotics prevents severe NEC and all cause mortality in preterm
29 infants [93]. The updated review of available evidence supports a change in practice.
30 More studies are needed to assess efficacy in ELBW infants and assess the most effective

13
 1 formulation and dose to be utilized [93]. The debate to give systematically probiotics to
2 preterms or not is still going one. The American Pediatric Surgical Association Outcomes
3 and Clinical Trials Committee systematic review concluded in 2012 acknowledges that
4 recent Cochrane Reviews support the use of prophylactic probiotics in preterm infants
5 less than 2500 grams to reduce the incidence of NEC, as well as the use of human breast
6 milk rather than formula when possible. There is no clear evidence to support delayed
7 initiation or slow advancement of feeds [94]. However, an expert group of nutritionists
8 and neonatologists concluded that there is insufficient evidence to recommend routine
9 use of probiotics to decrease NEC [95]. According to this group, there is encouraging
10 data (2b LoE) which justifies the further investigation regarding the efficacy and safety of
11 specific probiotics in circumstances of high local incidence of severe NEC [95]. Other
12 experts suggest that it may become unethical to not give probiotics to preterm babies to
13 decrease NEC [96].
14
15
16 Constipation
17 Constipation is a frequent problem in childhood in which pre-and probiotics could have a
18 positive influence on the intestinal flora with an effect on stool consistency and
19 frequency. Unfortunately, study results are contradictory. In an open trial, B. breve was
20 effective in increasing stool frequency in children with functional constipation [97].
21 Furthermore it had a positive effect with respect to stool consistency, decreasing the
22 number of faecal incontinence episodes and in diminishing abdominal pain [97]. In
23 another open trial, a probiotic mixture (Ecologic(R)Relief) containing B. bifidum, B.
24 infantis, B. longum, L. casei, L. plantarum and L. rhamnosus showed positive effects on
25 symptoms of constipation [98]. L. casei rhamnosus Lcr35 was effective in treating
26 children with chronic constipation [99]. B. lactis was reported to be non effective in
27 constipation [3,4]. L. reuteri (DSM 17938) had a positive effect in infants with chronic
28 constipation on bowel frequency, even when there was no improvement in stool
29 consistency and episodes of inconsolable crying episodes [100]. A Brazilian study
30 showed a positive influence of yoghurt on stool frequency with an additional effect of
31 yoghurt supplemented with Bifidobacterium Longum [101]. In constipated children, the
32 fermented dairy product containing B lactis strain DN-173 010 did increase stool

14
 1 frequency, but this increase was comparable in the control group [102]. There is currently
2 not sufficient evidence to recommend fermented dairy products containing B lactis strain
3 DN-173 010 in this category of patients [102]. Prebiotics added to infant formula have
4 been shown to soften stools in non-constipated infants. Data of a trial with a partial
5 hydrolysate, beta-palmitate and prebiotics are not significant [103]. There is some
6 evidence that fiber supplements are more effective than placebo [103]. No evidence for
7 any effect was found for fluid supplements, prebiotics, probiotics, or behavioural
8 intervention [104]. There is a lack of well-designed randomized controlled trials of high
9 quality concerning nonpharmacologic treatments for children with functional constipation
10 [104]. Until more data are available, probiotics for the treatment of constipation condition
11 should be considered investigational [105].

12

13 Allergy and atopic dermatitis

14 Prevention with probiotics and prebiotics

15 The use of GOS/FOS in dietary products was shown to possibly provide an opportunity
16 to stimulate the adaptive immune response in a Th1-direction and subsequently inhibit
17 infections and Th2-related immune disorders in humans, for instance allergies [106].
18 Prebiotics were shown to reduce immunoglobulin free light-chain concentrations in
19 infants at risk for allergy [107]. Simultaneous pro- and prebiotic treatment (a mixture of 4
20 strains and GOS) given to pregnant women during 2-4 weeks before delivery and to the
21 infants during 6 months compared with placebo showed no effect on the cumulative
22 incidence of allergic diseases at the age of 2 years but tended to reduce IgE-associated
23 (atopic) diseases since a significant reduction of (atopic) eczema was noticed [108].
24 However, Taylor and coworkers challenge the role of probiotics in allergy prevention
25 since they recorded that early probiotic supplementation with L acidophilus did not
26 reduce the risk of AD in high-risk infants and was even associated with increased
27 allergen sensitization in infants receiving supplements [109]. A Cochrane review from
28 2007 concluded that there was insufficient evidence to recommend the addition of
29 probiotics to infant feeds for prevention of allergic disease or food hypersensitivity [110].
30 Although there was a reduction in clinical eczema in infants, this effect was not

15
 1 consistent between studies and caution was advised in view of methodological concerns
2 regarding included studies [110]. However, the efficacy of probiotic intervention to
3 reduce atopic dermatitis and/or allergic disease may depend on the moment of
4 intervention. Preventive administration of probiotics may be only effective if given
5 during pregnancy. Probiotics given to nonselected mothers reduced the cumulative
6 incidence of AD, but had no effect on atopic sensitization [111].A recent the meta-
7 analysis showed that the administration of lactobacilli during pregnancy prevented atopic
8 eczema in children aged from 2 to 7 years [112]. However, a mixture of various bacterial
9 strains does not affect the development of atopic eczema, independent of whether they
10 contain lactobacilli or not [112]. Lactobacillus rhamnosus HN001 was reported effective
11 against eczema in the first 2 years of life persists to age 4 years, while Bifidobacterium
12 animalis subsp lactis HN019 had no effect [113]. Therefore, not only timing of
13 administration seems important, but also strain specificity. However, timing of
14 administration and strain specificity was then again contradicted by the meta-analysis by
15 Pelucchi and coworkers, being in support of a moderate role of probiotics in the
16 prevention of atopic dermatitis and IgE-associated atopic dermatitis in infants, but
17 regardless of the time of probiotic use (pregnancy or early life) or the subject(s) receiving
18 probiotics (mother, child, or both) [114]. The data on probiotics and allergy need further
19 clarification, because data are somehow contradictory. It might be that geographical or
20 genetic differences play a detrimental role, especially for atopic dermatitis.
21
22 A large study in 259 high risk infants, prebiotic supplements to formula feeding reduced
23 the development of atopic dermatitis at the age of 6 months [115]. However, systematic
24 reviews failed to proof the efficiency of prebiotics in atopic dermatitis prevention [116].
25
26 Recently, in a double-blind, placebo-controlled multi-centre trial, 90 infants with atopic
27 dermatitis, age <7 months, were randomized to receive an infant formula with B. breve
28 M-16V and a mixture of short chain GOS and long chain FOS, or the same formula
29 without synbiotics during 12 weeks [117]. There were no significant differences between
30 the synbiotic and the placebo group [117]. The same group showed that synbiotics
31 prevent asthma-like symptoms in infants with atopic dermatitis [118]. At the same time,

16
 1 another group reported that a synbiotic combination of L. salivarius plus FOS is superior
2 to the prebiotic alone for treating moderate to severe childhood AD [119].

4 Treatment with prebiotics and probiotics

5 While some studies with probiotics as a treatment for atopic dermatitis show a benefit
6 [120], most studies are negative. No benefit was reported from supplementation with B.
7 lactis or L. paracasei in the treatment of eczema, when given as an adjunct to basic
8 topical treatment, and no effect on the progression of allergic disease from age 1 to 3
9 years [121]. Most reviews conclude that probiotics are not effective in reducing atopic
10 dermatitis. These contradictory results suggest strain specificity or a genetic influence on
11 the efficacy of probiotics in children with atopic dermatitis. A Cochrane Review dealt
12 with dietary exclusions for people with eczema and found little evidence to support any
13 dietary exclusion, apart from avoidance of eggs in infants with suspected egg allergy
14 supported by evidence of sensitization [116]. A review of 13 studies of probiotics for
15 treating established eczema did not show convincing evidence of a clinically worthwhile
16 benefit, an observation that has been substantiated in a subsequent Cochrane Review
17 [116,122]. No treatment data are available for prebiotics in AD.

18

19 Colic

20 Colic is a frequent problem in infants and often parents desperate for a solution. In this
21 indication, the effect of L. reuteri has been exhaustively studied in breastfed infants [123-
22 125]. However, there are no data with L. reuteri in formula fed babies. Dupont et al.
23 reported efficacy of another probiotic strain in formula fed infants [126]. There are very
24 limited data with prebiotics in the prevention or treatment of colic. One study suggests
25 oligosaccharides may contribute to an improved intestinal comfort [75].

26
27
28
29

17
 1 Extra-intestinal infections and other effects
2 A formula containing galacto- and fructo-oligosaccharides prevents extra-intestinal
3 infections [16]. No pediatric studies have demonstrated definite beneficial effects of
4 administering probiotics to treat extra-intestinal infections like respiratory tract infections
5 or otitis media [20,21]. There is no evidence that probiotics decrease extra-intestinal
6 infections. There is some evidence that some lactobacilli might prevent recurrent urinary
7 tract infection in women. However, data in children are lacking. The same is true for
8 recurrent vulvovaginitis. Sazawal and coworkers showed that prebiotic and probiotic
9 fortified milk prevented morbidities among children in a community-based, randomized,
10 double-blind, controlled trial [127]. Supplementation of infant formula with prebiotics
11 showed some contradictory results: a decrease of respiratory tract infections and
12 antibiotic use in some studies and no benefit in others [20,21].
13
14 Prebiotics have a long lasting bifidogenic effect [128,129]. No effect of prebiotics
15 supplementation on vaccination specific antibody levels was found in children up to the
16 age of 12 months; the vaccine specific antibody levels in infants fed the study prebiotics
17 or a control diet were similar during the first year of life [130].
18
19 Purified phytases from Bifidobacterium longum spp. infantis and Bifidobacterium
20 pseudocatenulatum reduced the contents of phytate as compared to control samples
21 (untreated or treated with fungal phytase) and led to increased levels of myo-inositol
22 triphosphate [131]. This is the first example of the application of purified bifidobacterial
23 phytases in food processing and shows the potential of these enzymes to be used in
24 products for human consumption [131]. Lactic acid bacteria improve the synthesis of
25 vitamins B2, B11 and B12 and have the potential strategies to increase B-group vitamin
26 content in cereals-based products [132]. Vitamins-producing LAB have been leading to
27 the elaboration of novel fermented functional foods [132].

28

29

30

18
 1 Safety and side effects
2 Probiotics have a long record of safety, which relates primarily to lactobacilli and
3 bifidobacteria [133]. Experience with other forms of probiotic is more limited. There is
4 no such thing as zero risk, particularly in the context of certain forms of host
5 susceptibility [133]. Probiotics are “Generally Regarded As Safe” and side-effects in
6 ambulatory care have almost not been reported. Large scale epidemiological studies in
7 countries where probiotic use is endemic demonstrate (in adults) low rates of systemic
8 infection, between 0.05 and 0.40 % [134]. Administration during pregnancy and early
9 infancy is considered safe [135]. Probiotic compounds may contain hidden allergens of
10 food and may not be safe for subjects with allergy to cow's milk or hen's egg [136].
11 Documented invasive infections have been primarily noted to occur in immuno-
12 compromised adults [137]. Invasive infections in infants and children are exceedingly
13 rare [137-139]. Two cases of bacteriemia attribuable to Lactobacillus supplementation,
14 with identical molecular clinical and supplement isolates, were recently reported in an
15 infant and a child without underlying gastrointestinal disease or immuno-compromised
16 status [140]. Sepsis with probiotic lactobacilli has been reported in children with short
17 gut. Fungemia with S. boulardii. has been reported in about 50 patients, all with a central
18 venous catheter [141]. Recently, plasmid transfer of antibiotic resistance has been shown
19 to be clinically possible to occur. Long-term use of probiotics under antibiotic selection
20 pressure could cause antibiotic resistance, and the resistance gene could be transferred to
21 other bacteria [142]. Translocation from the gastro-intestinal tract in the systemic
22 circulation has not been reported. The case reports on sepsis emphasize that probiotic
23 supplementation should be used with caution in children with indwelling central venous
24 catheters, prolonged hospitalizations, and a recognized or potential compromise of gut
25 mucosal integrity [141]. There is poor public understanding of the concept of risk, in
26 general, and risk/benefit analysis, in particular [133]. Uncertainty persists regarding the
27 potential for transfer of antibiotic resistance with probiotics, but the risk seems to be low
28 with currently available probiotic products [133]. As with other forms of therapeutics, the
29 safety of probiotics should be considered on a strain-by-strain basis [133]. The potential
30 benefits of supplementation should be weighed against the risk of development of an
31 invasive infection resulting from probiotic therapy.

19
 1
2
3
4
5
6 Conclusion
7 Probiotics and prebiotics have an influence on GI flora composition. However, despite
8 large research on the subject, clear indications for their use in treatment and prevention
9 remain scarce even though their administration seems safe and negative effects are
10 scarce. It is difficult to translate heterogeneous-based study results, which are mainly due
11 to varying genera, strains, doses, study settings and measured outcomes, into evidence-
12 based recommendations [143].
13
14 A recent review analyzed the data from 3 synbiotic studies (N = 475), 10 probiotics
15 studies (N = 933) and 12 prebiotics studies (N = 1563) added to infant formula [144].
16 Probiotics did not lower the incidence of diarrhea, colic, spitting up / regurgitation,
17 crying, restlessness or vomiting. Prebiotics in formula did increase weight gain.
18 Prebiotics increased stool frequency but had no impact on stool consistency, the
19 incidence of colic, spitting up / regurgitation, crying, restlessness or vomiting. There was
20 no impact of prebiotics on infections and gastrointestinal microflora. There is not enough
21 evidence to state that supplementation of term infant formula with synbiotics, probiotics
22 or prebiotics does result in improved growth or clinical outcomes in term infants [144].
23 There are no data available to establish if synbiotics are superior to probiotics or
24 prebiotics [144]
25
26 During the last decade, evidence from multiple good quality clinical research studies
27 resulted in the fact that pre-, pro- and synbiotics can no longer be neglected. However,
28 future research has to focus on specificity, safety, dosage, and combinations.
29
30
31
32

20
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