Probiotics and Prebiotics in Infants and Children
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- Vandenplas, Y., De Greef, E., Devreker, T. et al. Curr Infect Dis Rep (2013) 15: 251. doi:10.1007/s11908-013-0334-4
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Probiotics and prebiotics have a major influence on gastrointestinal flora composition. This review analyses the relationship between this change in flora composition and health benefits in children. Literature databases were searched for relevant articles. Despite exhaustive research on the subject in different indications, such as prevention and treatment of acute gastroenteritis, antibiotic associated diarrhea (AAD), traveler's diarrhea, inflammatory bowel disease, irritable bowel syndrome, Helicobacter pylori, necrotizing enterocolitis, constipation, allergy and atopic dermatitis, colic and extraintestinal infections, reports of clear benefits for the use of prebiotics and probiotics in pediatric disorders remain scarce. The best evidence has been provided for the use of probiotics in acute gastroenteritis and in prevention of AAD. However, AAD in children is in general mild, and only seldom necessitates additional interventions. Overall, the duration of acute infectious diarrhea is reduced by approximately 24 hours. Evidence for clinically relevant benefit in all other indications (inflammatory bowel disease, irritable bowel syndrome, constipation, allergy) is weak to nonexistent. Selected probiotic strains given during late pregnancy and early infancy decrease atopic dermatitis. Adverse effects have very seldom been reported. Since the risk seems minimal to nonexistent, prebiotics and probiotics may be helpful in the prevention and treatment of some disorders in children, although the evidence for benefit is limited. The best evidence has been accumulated for some lactobacilli strains and for Saccharomyces boulardii in the reduction of the duration of acute diarrhea due to gastroenteritis and prevention of AAD.
The gastrointestinal (GI) tract harbors a diverse array of commensal microbes that act as a separate ecosystem. The GI flora can be considered as an organ within an organ contributing to host nutrition, developmental regulation of intestinal angiogenesis, protection from pathogens and development of the immune response .
Probiotics are nonpathogenic live microorganisms that, when consumed in adequate amounts, have a positive effect on the health of the host. Although probiotics are today a “hot topic”, they are not new. More than 2,000 years ago, the Roman author Plinius The Old recommended the use of fermented milk in the treatment of acute gastroenteritis.
There are minimum requirements for the status of "probiotic microorganism" which include [2••]: (1) the assessment of strain identity (genus, species, strain level), (2) in vitro tests to screen potential probiotic strains for activity, and (3) assessment of safety and in vivo studies for substantiation of health effects in the target host. Probiotics are considered safe as part of ambulatory care in nonimmunocompromised patients.
Most probiotics are registered as food supplements, and thus do not have to fulfill the quality requirements for medicinal agents. Research on the mechanisms of action of specific strains and clinical trials with commercial products are mandatory. The in vivo effects of a strain may be opposite to those shown in vitro. The effects demonstrated by one strain cannot be extrapolated to other strains, even if they belong to the same species. Only those commercial products for which convincing data are available can be recommended for medical use. Since some commercial products are combinations of different strains, clinical testing of each combination product is mandatory as the different strains may have synergistic or contradictory effects. Moreover, dosage and duration of administration should be taken into account as different doses and different durations may have opposite effects .
Prebiotics are nondigestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system in ways claimed to be beneficial to health. Full-spectrum prebiotics provide molecular links with lengths from 2 to 64 links per molecule, and nourish bacteria throughout the colon, e.g. oligofructose-enriched inulin. In infant formula, generally galactooligosaccharides (GOS) and/or FOS are used. Many studies of prebiotics are based on full-spectrum prebiotics, e.g. a mixture of short-chain and long-chain prebiotics.
An increasing number of “synbiotics” are coming on the market. These are combinations of a prebiotic and generally several strains of probiotics. Manufacturers market these products by listing all the benefits of each ingredient separately. Whether this marketing strategy is scientifically valid is uncertain. It is also becoming more and more difficult to obtain information about the exact strains in different products. The lack of legal protection allows competitors to copy a successful product without any investment .
Use of Prebiotics and Probiotics in Prevention and Treatment
Acute Infectious Gastroenteritis
Up to 70 % to 80 % of all infectious diarrheas are of viral origin, and rotavirus is still the most prevalent pathogen [5, 6]. Breastfeeding is known to offer the best protection against infection in young infants because of the presence of immunogenic factors, among which are prebiotics and probiotics [7–9]. Therefore, breastfeeding should be maximally endorsed. Based on this knowledge, formulas based on cows’ milk have been developed to mimic the immune capacity of breastfeeding by adding prebiotics and probiotics.
Prevention with Probiotics and Prebiotics
Probiotics have been studied mainly in relation to the prevention of acute infectious diarrhea. Large, randomized controlled trials have provided evidence of a very modest effect, statistically significant but of questionable clinical relevance. In a study in Indonesian children with undernutrition, Lactobacillus reuteri protected against the development of diarrhea . Many randomized placebo-controlled trials investigating the effectiveness of the probiotics L. rhamnosus GG and Bifidobacteria lactis, alone or in combination with Streptococcus thermophilus and L. reuteri, L. rhamnosus (not GG), and L. acidophilus, either alone or in comparison with each other, in preventing diarrhea in day-care centers in different parts of the world have been published. The evidence for their efficacy in preventing diarrhea in this setting is only modest, although the evidence for their efficacy in preventing upper respiratory infections is somewhat better . In hospitalized children, the administration of L. reuteri DSM 17938 had no effect on the overall incidence of nosocomial diarrhea, including rotavirus infection . The incidence of GI infections in infants of the placebo group was three times higher than in the probiotic group . Therefore, consumption of a prebiotic infant formula enriched with the human milk probiotic strain L. fermentum CECT5716 from 1 to 6 months of life is well tolerated and safe. Furthermore, consumption of this formula may improve the health of the infants by reducing the incidence of GI infections .
The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) concluded that there is insufficient evidence to recommend the use of infant formula enriched with probiotics, mainly because of the efficacy shown was insufficiently convincing [14•]. On the other hand, most of studies have shown some benefit, although for different endpoints, and not always statistically significant. Serious adverse events have not been reported. The conclusions of the American Academy of Pediatrics are quite similar: “Available data do not support routine use of probiotics to prevent nosocomial rotavirus diarrhea in child care centers” . But, there may be special circumstances in which probiotic use in children in long-term health-care facilities or in child-care centers is beneficial .
Data on the use of prebiotics in the prevention of acute gastroenteritis are limited, and there are no new data. A formula containing GOS and FOS has been found to prevent intestinal and extraintestinal infections in some studies but this has not been confirmed in others .
The majority of studies show some positive effect of pre- and probiotics in the prevention of diarrhea, and no adverse events. However, the benefit has seldom been significant.
Treatment with Probiotics and Prebiotics
All studies discussed were performed in infants and children. The cornerstone of the treatment of acute gastroenteritis is oral rehydration and rapid realimentation. More data are needed to optimize the management of diarrhea and highlight the research priorities at a global level. Such priorities include the reevaluation of therapeutic options [17•]. Therapeutic strategies need to be assessed in different settings, and pharmacoeconomic analyses based on country-specific data are needed. Transfer to clinical practice should result from the implementation of guidelines tailored at a local level, with an eye on costs [17•].
The aim of treatment with probiotics is to enhance normalization of the GI flora and diminish the duration of acute diarrhea. There are only limited number of studies on chronic diarrhea of infectious origin; most of these studies have investigated Saccharomyces boulardii. The majority of studies on bacterial probiotics have been performed in the developed world, and meta-analyses have concluded that L. rhamnosus GG, L. acidophilus, L. reuteri and L. bulgaricus show efficacy. L. reuteri DSM 17938 has been reported to be of similar efficacy: it reduced the duration of diarrhea by about 24 hours . The more strains that are studied, the more strain specificity appears clinically relevant. Lactobacillus paracasei strain ST11 has no effect on rotavirus, but ameliorates the outcome of nonrotavirus diarrhea . Bifidobacteria longum subsp. infantis CECT 7210 can be considered a probiotic able to inhibit rotavirus infection . Probiotics may also reduce the relapse rate of diarrhea . There is a need for trials comparing the efficacy of different strains. Such a trial has recently been reported in which L. reuteri and L. casei CRL431 were compared , suggesting efficacy for the former.
Saccharomyces boulardii, a probiotic yeast, was first studied more than 15 years ago and was shown to result in a significant reduction in the duration of symptoms. Since then, several double-blind, prospective, randomized trials in children with acute gastroenteritis have systematically shown a significant improvement following treatment with S. boulardii in comparison to placebo. The reduction in the duration of diarrhea with S. boulardii is also about 1 day. The efficacy of S. boulardii was recently confirmed in a trial in India .
In 2010, a Cochrane review included 63 studies, 56 in infants and young children, with a total of 8,014 participants. It was concluded that alongside rehydration therapy, probiotics appear to be safe and have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhea . The mean difference in duration of diarrhea was 24.76 h (95 % confidence interval 15.9 to 33.6 h; n = 4,555, 35 trials), the risk ratio for diarrhea lasting ≥4 days was 0.41 (95 % CI 0.32 to 0.53; n = 2,853, 29 trials) and the mean difference in stool frequency on day 2 was 0.80 (95 % CI 0.45 to 1.14; n = 2751, 30 trials) . In recommendations for general practitioners in the USA, probiotics are positioned as helpful in the treatment of acute gastroenteritis . However, more research is still needed to guide the use of particular probiotic regimens in specific patient groups .
Probiotics seem more effective when given early in the course of diarrhea, and are more helpful in otherwise healthy infants and young children with watery diarrhea secondary to viral gastroenteritis but not invasive bacterial infections [14•]. A shortening of the duration of diarrhea, as well as a reduced hospital stay indicate a relevant social and economic benefit of probiotics as an adjunct to oral rehydration solution. Because of the decreased need for additional consultations and concomitant medication, probiotics (and synbiotics) are considered to have cost-reducing effect .
The few studies investigating the treatment of acute infectious gastroenteritis with prebiotics were negative . A recent study investigating zinc and prebiotics showed decreases in the duration of diarrhea, intake of oral rehydration solution, number of missed working days by parents, and the need for adjunctive drugs . Recent studies investigating synbiotics have shown the effects of a combination of FOS, zinc and several probiotics (Str. thermophilus, B. lactis, L. acidophilus) on the duration of diarrhea [27, 28]. In a very recent review paper, L. rhamnosus GG and S. boulardii were confirmed as first-choice probiotics .
Prebiotics provide no benefit in the treatment of acute diarrhea and only limited benefit in the prevention of acute gastroenteritis. For probiotics, there is stronger evidence that selected strains prevent nosocomial diarrhea and shorten the duration of gastroenteritis. However, efficacy can only be considered if well-designed trials were performed with commercial products.
Antibiotic treatment is known to disturb the GI microflora, which results in a range of clinical symptoms, especially diarrhea. The incidence of antibiotic-associated diarrhea (AAD) in children in primary health-care is about 10 %, independent of the reason for antibiotic administration, However, in the vast majority of patients the AAD is very mild to moderate and hospitalization is seldom required.
Prevention with Probiotics and Prebiotics
The pooled relative risk in a meta-analysis of 63 randomized controlled trials, which included 11,811 subjects, indicated a statistically significant association between probiotic administration and reduction in AAD (relative risk 0.58, 95 % CI 0.50 to 0.68, P < 0.001; I(2), 54 %; risk difference −0.07, 95 % CI −0.10 to −0.05; number needed to treat 13, 95 % CI 10.3 to 19.1) . Another meta-analysis concluded that eight patients needed to be treated . A preplanned subgroup analysis showed that the reduction in the risk of AAD was associated with the use of L. rhamnosus GG (95 % CI 0.15 to 0.6), S. boulardii (95 % CI 0.07 to 0.6), and B. lactis and Str. thermophilus (95 % CI 0.3 to 0.95) . For every seven patients who would have developed diarrhea while being treated with antibiotics, one fewer will develop AAD if also receiving probiotics . Only S. boulardii was found to be effective in Clostridium difficile infection [33••]. Recently, a large single-center study has shown that S. boulardii is not effective in the elderly in preventing the development of AAD or in preventing C. difficile infection .
Despite heterogeneity in probiotic strain, dose and treatment duration, as well as in the quality of studies, the overall evidence indicates a protective effect of probiotics in preventing AAD [14•, 34–36]. Whether probiotics are also effective in preventing C. difficile infection remains a matter of debate . No serious side effects were documented in any of the trials in which adverse events occurred [33••]. More research is needed to determine which probiotics, patients and specific antibiotics are associated with the greatest efficacy .
The administration of two prebiotics (inulin and FOS) was not effective in preventing diarrhea and AAD .
Treatment with Probiotics and Prebiotics
Almost all studies have focused on the prevention of AAD; there are no data on the efficacy of probiotics or prebiotics in the treatment of AAD, except for very limited data on the use of S. boulardii in the treatment of C. difficile diarrhea. Saccharomyces boulardii was shown to be effective in secondary prevention; its role in primary prevention is poorly defined [38••]. There have been no randomized controlled trials with probiotics in the treatment of AAD in children [14•].
Prebiotics are not effective in the prevention or treatment of AAD. There is evidence for the efficacy of selected probiotic products in the prevention of AAD. Saccharomyces boulardii may also be effective in the treatment of C. difficile colitis.
Traveler’s diarrhea is a frequent condition of great socioeconomic impact, but has only poorly been studied. There are no data in children. It is one of those topics on which there are more reviews published than original research. Reviewing the literature, McFarland concluded that there is comparable evidence for the efficacy of L. rhamnosus GG, L. casei DN-114001 and S. boulardii, and no evidence for the efficacy of L. acidophilus . There are no data on use of prebiotics in the prevention or treatment of traveler's diarrhea. Overall, the number of studies is too small to allow recommendations to be formulated . Recently, Kollaritisch et al., in one of the few studies investigating probiotics in the prevention of traveler’s diarrhea, concluded that “most cases of traveler’s diarrhea are caused by bacteria; treatment for traveler’s diarrhea are loperamide and antibiotics. Preventive strategies such as hygiene measures have limited impact. Prophylactic intake of antibiotics or vaccines to prevent from traveler’s diarrhea can be considered in special situations” . It seems that neither probiotics nor prebiotics can be recommended in this indication.
There are no studies on the prevention of traveler’s diarrhea focusing on children.
Inflammatory Bowel Disease
The concept of dysbiosis, a breakdown of the balance between “protective” and “harmful” intestinal bacteria, has been generally accepted as one of the pathophysiological abnormalities in patients with inflammatory bowel disease (IBD).
Even though pediatric data are scarce and although there is a lack of evidence of benefit, almost 80 % of children with IBD have regular intake of probiotics. In ulcerative colitis (UC), L. reuteri enemas may be effective for distal active colitis  and the VSL#3 probiotic mixture may be effective in obtaining remission and a decrease in the relapse rate . In adults, a recent “current opinion paper” stated that in IBD, a number of trials have shown benefits of a range of probiotics in pouchitis and in UC, although current evidence in Crohn's disease (CD) is less promising . Well-designed randomized controlled trials supporting the use of probiotics in the management of IBD are still limited . It has only been possible to perform meta-analyses for a limited number of studies, and these have shown overall risk ratios of 2.70 (95 % CI 0.47 to 15.33) for inducing remission in active UC treated with bifidobacteria-fermented milk versus placebo or no additional treatment (n = 2), 1.88 (95 % CI 0.96 to 3.67) for inducing remission in active UC with treated with VSL#3 probiotic versus placebo (n = 2), 1.08 (95 % CI 0.86 to 1.37) for preventing relapse in inactive UC with Escherichia coli Nissle 1917 versus standard treatment (n = 3), 0.17 (95 % CI 0.09 to 0.33) for preventing relapse in patients with inactive UC and an ileoanal pouch anastomosis with VSL#3 probiotic versus placebo, 1.21 (95 % CI 0.57 to 2.57) for preventing endoscopic recurrence in inactive CD with L. rhamnosus GG versus placebo (n = 2), and 0.93 (95 % CI 0.63 to 1.38) for preventing endoscopic recurrence in inactive CD with L. johnsonii versus placebo (n = 2) .
Further independent well-designed studies based on intention-to-treat analyses are still warranted to support the promising results for E. coli Nissle in patients with inactive UC and the multispecies product VSL#3 in patients with active UC and an inactive pouch. So far, no evidence is available to support the use of probiotics in CD . Well-designed, large randomized controlled trials using probiotics in patients with IBD are required to support the use of probiotics as mainstream therapy [46•]. Given the present data, the adjunctive use of VSL#3 probiotic for the induction and maintenance of remission of UC in children is not cost-effective, although several key parameters could make this strategy cost-effective .
There are no data on the use of prebiotics for the prevention or treatment of IBD. There are limited data on the selective use of probiotic strains in UC. Data in CD are disappointing.
Irritable Bowel Syndrome
There is a large literature on the effect of probiotics on irritable bowel syndrome (IBS) in adults, but data in children are limited. A Cochrane review from 2009 on IBS in childhood failed to show an effect of fiber supplements, and found a limited effect of Lactobacillus on symptoms compared to placebo (odds ratio 1.17, 95 % CI 0.62 to 2.21) .
Lactobacillus rhamnosus GG but not placebo has been shown to significantly reduce both the frequency and severity of abdominal pain compared to baseline and to influence intestinal permeability . A meta-analysis showed that, compared with placebo, L. rhamnosus GG supplementation is associated with a significantly higher rate of treatment responders in the overall population with abdominal pain-related functional GI disorders and in the IBS subgroup . However, no difference was found in children with functional abdominal pain or functional dyspepsia who received placebo or L. rhamnosus GG. A randomized crossover trial with VSL#3 and placebo for 6 weeks, with a 2-week washout period between in 59 patients showed a superior effect of VSL#3 compared to placebo in relieving symptoms, as well as in abdominal pain/discomfort, abdominal bloating/gassiness, and family assessment of life disruption .
There are no data on the avoidance of treatment of IBS in children following the use of prebiotics. Data from one trial suggest that, in infants, a prebiotic-containing whey-based formula provided superior GI comfort than a control formula . A peptide-based formula containing fiber was as well tolerated as a fiber-free formula in a small population of children with GI impairment . Extremes of stool consistency were normalized with the fiber formula. No significant differences were observed in vomiting, abdominal pain, feed intake, or weight gain between the two formulas .
Some probiotics have considerable potential in the management of IBS and IBD; however, the benefits are strain-specific. High-quality trials of probiotics in GI disorders as well as laboratory investigations of their mechanism of action are required in order to be able to predict who will respond and why . There are no data on prebiotics.
The benefit of probiotics in children with H. pylori colonization and gastric inflammation is supported by many observations , but has also been contradicted [54, 55]. Specific strains of Lactobacillus and Bifidobacterium exert in vitro bactericidal effects against H. pylori through the release of bacteriocins or the production of organic acids, and/or inhibit its adhesion to epithelial cells. Such protective effects have been confirmed in animal models . Clinical trials are very important, since in vitro results cannot always be reproduced in patients. Probiotics decrease the bacterial load and improve the immune response . Results of clinical trials indicate that probiotics generally do not eradicate H. pylori but decrease the density of colonization, thereby maintaining lower levels of this pathogen in the stomach. In association with antibiotic treatments, some probiotics have been shown to increase eradication rates and/or decrease adverse effects due to the antibiotic. Many studies have shown a moderately higher eradication rate (about 10 %) of H. pylori when probiotics are added to antibiotics and proton pump inhibitor . Although L. rhamnosus GG seems not to improve eradication [59•], most probiotic bacteria and yeasts reduce adverse effects of standard H. pylori eradication regimens [59•, 60].
The literature suggests that in adults the addition of probiotics results in an increased eradication rate by about 10 %; the results of randomized control trials in children are inconclusive.
Necrotizing enterocolitis (NEC) is a severe condition occurring especially in preterm babies. Abnormal GI flora development has been hypothesized as one of the possible etiological factors. The effect of supplementation with L. acidophilus and B. infantis in reducing NEC was first reported in 1999 . An updated Cochrane review from 2011 analyzed data from 16 trials including 2,842 infants and concluded that enteral supplementation with probiotics prevents severe NEC and all-cause mortality in preterm infants . The updated review of available evidence supports a change in practice. More studies are needed to assess the efficacy in extremely-low-birth-weight infants and to assess the most effective formulation and dose to be utilized .
The debate as to whether or not to give probiotics systematically to preterm infants is still ongoing. The American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review concluded in 2012 and supported the recent Cochrane reviews that the use of prophylactic probiotics in preterm infants of less than 2,500 g in weight to reduce the incidence of NEC, as well as the use of human breast milk rather than formula when possible. There is no clear evidence to support delayed initiation or a slow advance in feeding . However, an expert group of nutritionists and neonatologists concluded that there is insufficient evidence to recommend the routine use of probiotics to decrease NEC [64••]. According to this group, there is encouraging data (level of evidence 2b) that justifies further investigation of the efficacy and safety of specific probiotics in circumstances of high local incidence of severe NEC [64••]. Other experts suggest that it may become unethical to not give probiotics to preterm babies to decrease NEC [65••].
There are no data on the use of prebiotics in the prevention of NEC . The debate on the pros and cons of the role of probiotics in NEC prevention illustrates the difficulties in translating heterogeneous study results into evidence-based recommendations. So, while some authors conclude that there is as yet no hard evidence of benefit, others believe that it is unethical to withhold a life-saving therapy before more evidence is gathered.
Constipation is a frequent problem in childhood in which prebiotics and probiotics could have a positive influence on the intestinal flora with an effect on stool consistency and frequency. Unfortunately, the results of trials are contradictory. In an open trial, B. breve was effective in increasing stool frequency in children with functional constipation . It also had a positive effect on stool consistency, decreasing the number of fecal incontinence episodes and diminishing abdominal pain . In infants with chronic constipation, L. reuteri (DSM 17938) had a positive effect on bowel frequency, although there was no improvement in stool consistency or episodes of inconsolable crying . A Brazilian study showed a positive influence of yogurt on stool frequency with an additional effect of yogurt supplemented with B. longum . In constipated children, a fermented dairy product containing B. lactis strain DN-173 010 did increase stool frequency, but this increase was comparable to that in the control group .
There is currently insufficient evidence to recommend fermented dairy products containing B. lactis strain DN-173 010 in this category of patients . Prebiotics added to infant formula have been shown to soften stools in nonconstipated infants. No evidence for any effect of fluid supplements, prebiotics, probiotics or behavioral intervention was found . There is a lack of well-designed randomized controlled trials of high-quality concerning nonpharmacological treatment of children with functional constipation .
There is evidence that prebiotics soften stools in nonconstipated infants, but evidence of efficacy in treatment is limited. Some probiotic strains may be helpful, but the design of trials has been too heterogeneous to allow evidence-based recommendations.
Allergy and Atopic Dermatitis
Prevention with Probiotics and Prebiotics
In infants, prebiotics have been shown to reduce immunoglobulin free light-chain concentrations in infants at risk of allergy . A Cochrane review from 2007 concluded, based on data from six studies investigating outcomes in 1,549 infants, that there is insufficient evidence to recommend the addition of probiotics to infant feeds for prevention of allergic disease or food hypersensitivity . Although there was a reduction in clinical eczema in infants, this effect was not consistent between studies and caution was advised in view of methodological concerns regarding the studies included . However, the efficacy of probiotic intervention to reduce atopic dermatitis and/or allergic disease may depend on the timing of the intervention. Preventive administration of probiotics may only be effective if given during pregnancy. Probiotics given to nonselected mothers reduced the cumulative incidence of AD, but had no effect on atopic sensitization .
A recent the meta-analysis showed that the administration of lactobacilli during pregnancy prevented atopic eczema in children aged from 2 to 7 years [75••]. However, a mixture of various bacterial strains did not affect the development of atopic eczema, independent of whether they contained lactobacilli or not [75••]. Lactobacillus rhamnosus HN001 has been reported to be effective against eczema in the first 2 years of life with the effect persisting to age 4 years, while B. animalis subsp lactis HN019 had no effect . Therefore, not only the timing of administration, but also the strain specificity seems important. However, the impact of timing of administration and strain specificity has been contradicted by the results of a meta-analysis by Pelucchi et al. . These authors concluded that there is moderate role for probiotics in the prevention of atopic dermatitis and IgE-associated atopic dermatitis in infants, but regardless of the timing of probiotic use (pregnancy or early life) or whether it is the mother, child or both who receive the probiotic . The data on probiotics and allergy need further clarification, because they are contradictory. It might be that geographical or genetic differences play a detrimental role, especially in atopic dermatitis.
A systematic review of two studies evaluating the efficacy of prebiotics in the prevention of atopic dermatitis failed to show efficacy, as one study suggested benefit and the other failed to do so .
In a recent double-blind, placebo-controlled multicenter trial, 90 infants with atopic dermatitis aged <7 months were randomized to receive an infant formula containing B. breve M-16V and a mixture of short-chain GOS and long-chain FOS, or the same formula without synbiotics for 12 weeks . There were no significant differences between the synbiotic and the placebo groups . The same group showed that synbiotics prevent asthma-like symptoms in infants with atopic dermatitis . Another group reported that a synbiotic combination of L. salivarius and FOS is superior to the prebiotic alone for treating moderate to severe childhood AD .
Treatment with Prebiotics and Probiotics
While some studies investigating the use of probiotics in the treatment of atopic dermatitis have shown a benefit , most studies are negative. No benefit was found from the use of B. lactis or L. paracasei in the treatment of eczema when given as an adjunct to basic topical treatment, and no effect on the progression of allergic disease from age 1 to 3 years . Most reviews have concluded that probiotics are not effective in reducing atopic dermatitis. These contradictory results suggest strain specificity or a genetic influence on the efficacy of probiotics in children with atopic dermatitis. A Cochrane review dealt with dietary exclusions in patients with eczema, and found little evidence to support any dietary exclusion, apart from avoidance of eggs in infants with suspected egg allergy supported by evidence of sensitization . A review of 13 studies investigating probiotics in the treatment of established eczema did not show convincing evidence of a clinically worthwhile benefit, an observation that has been substantiated in a subsequent Cochrane review [78, 84••]. No treatment data are available for the use of prebiotics in the treatment of atopic dermatitis.
There are no data on the use of prebiotics in the treatment of atopic dermatitis, and the few studies on prevention have shown contradictory results. There is limited evidence for the benefit of selected strains of probiotics in the prevention of atopic dermatitis, especially if administration is started during the last trimester of pregnancy and continued during the first months of life. No convincing evidence of a clinically worthwhile benefit of the use of probiotics in the treatment of established eczema has been found.
Colic is a frequent problem in infants and parents are often desperate for a solution. In this indication, the effects of L. reuteri have been exhaustively studied in breastfed infants [85, 86]. However, there are no data on the use of L. reuteri in formula-fed babies. Dupont et al. investigated the efficacy of another probiotic strain in formula-fed infants . There are very limited data on the use of prebiotics in the prevention or treatment of colic. One study has suggested the oligosaccharides may contribute to improved intestinal comfort .
Several randomized controlled trials of the use of probiotics in the treatment of colic support the such use. However, these beneficial results seem not be confirmed by daily routine practice. There are no data for formula-fed infants. There are no data on the use of prebiotics.
Extraintestinal Infections and Other Effects
Few studies demonstrating definite beneficial effects of probiotics in the treatment of extraintestinal infections in children including respiratory tract infections and otitis media have been available in recent reviews [14•, 15]. Prophylactic administration of S. salivarius K12 to children with a history of recurrent oral streptococcal disease reduced episodes of streptococcal pharyngeal infections and/or tonsillitis as well as episodes of acute otitis media . Supplementation with synbiotics may have beneficial effects on the incidence of infectious disease and growth in infants . Administration of a follow-on formula containing L. fermentum CECT5716 may be useful for the prevention of community-acquired GI and upper respiratory infections . During a 6-month intervention, antibiotics were prescribed less often in the synbiotic group than in the placebo group (23 % vs. 28 %) . Throughout the follow-up period, respiratory infections occurred less frequently in the synbiotic group (3.7 vs. 4.2 infections) . Specific prebiotics added to standard formula feeding failed to reduce the number of fever episodes in the first year of life . Probiotics directly antagonize pathogens and thus exert beneficial effects without directly affecting the metabolism of the host . Many probiotics have been tested in clinical trials with varying results, but overall show benefit in the prevention and treatment of upper respiratory tract infections and otitis . Controlled administration of B. lactis BB-12 in early childhood may reduce respiratory infections .
Probiotics may offer a safe means of reducing the risk of early acute otitis media and antibiotic use and the risk of recurrent respiratory infections during the first year of life . Spray treatment with S. sanguinis may be effective against secretory otitis media . The probiotics L. rhamnosus GG and LC705, B. breve 99 and Propionibacterium freudenreichii JS did not prevent the occurrence of acute otitis media or the nasopharyngeal carriage of otitis pathogens in otitis-prone children . A tendency for probiotics to reduce recurrent respiratory infections has been shown but needs to be confirmed .
Daily consumption of milk containing probiotic bacteria and fluoride reduced caries in preschool children by 75 % . Although there are some promising results, the lack of studies confirming this finding makes it difficult to draw any conclusions. More studies are needed to identify the most promising probiotic strains and study populations, and to evaluate the mechanisms behind the possible effects of probiotics on otitis media . There is no hard evidence that probiotics decrease extraintestinal infections. Although many studies have shown a benefit, the design and strains were different, so that meta-analyses have not been possible and evidence-based recommendations cannot be made. There is some evidence that some lactobacilli might prevent recurrent urinary tract infection in women. Randomized controlled trials have not shown a decrease in the incidence of urinary tract infections in children who received probiotics . However, data in children are lacking. The same is true for recurrent vulvovaginitis. In a community-based, randomized, double-blind, controlled trial in children, Sazawal et al. showed that milk fortified with prebiotics and probiotics was able to prevent morbidity . In adults and children, probiotics were better than placebo in reducing the number of subjects experiencing episodes of acute upper respiratory tract infections and in reducing antibiotic use . Supplementation of infant formula with prebiotics showed some contradictory results: a decrease of respiratory tract infections and antibiotic use in some studies and no benefit in others [14, 15].
Prebiotics have a long-lasting bifidogenic effect . No effect of prebiotic supplementation on vaccination-specific antibody levels was found in children up to the age of 12 months. The vaccine-specific antibody levels in infants fed the study prebiotics or a control diet were similar during the first year of life . Natural prebiotics, human milk oligosaccharides, competitively interact with HIV for receptor binding sites in vitro .
Purified phytases from B. longum subsp. infantis and B. pseudocatenulatum reduced the contents of phytate as compared to control samples (untreated or treated with fungal phytase) and led to increased levels of myoinositol triphosphate . This is the first example of the application of purified bifidobacterial phytases in food processing and shows the potential of these enzymes for use in products for human consumption . Lactic acid bacteria improve the synthesis of vitamins B2, B11 and B12 and have the potential strategies to increase B-group vitamin contents in cereal-based products . Vitamin-producing lactobacilli have led to the development of novel fermented functional foods .
The vast majority of studies have shown some benefit of probiotics in the treatment of extraintestinal infections. However, the benefit found has not always been statistically significant, and results of different studies can be contradictory. Studies have had different designs, and have used different methods and different primary endpoints making it impossible to formulate evidence-based recommendations. On the other hand, adverse events in these studies have not generally been reported, and the beneficial trend may be justification for adding prebiotics, probiotics or synbiotics to infant formula or for administering them as a preventive measure.
Safety and Side Effects
Probiotics have a long record of safety, which relates primarily to lactobacilli and bifidobacteria [108•]. Experience with other forms of probiotic is more limited. There is no such thing as zero risk, particularly in the context of certain forms of host susceptibility [108•]. Probiotics are “generally regarded as safe” and side effects in ambulatory care have very seldom been reported. Administration during pregnancy and early infancy is considered safe . Probiotic compounds may contain hidden food allergens and may not be safe in subjects with allergy to cows’ milk or hens’ eggs . Invasive infections in infants and children are exceedingly rare. Plasmid transfer of antibiotic resistance has been shown to be clinically possible. Long-term use of probiotics under antibiotic selection pressure could cause antibiotic resistance, and the resistance gene could be transferred to other bacteria [111••].
Translocation from the GI tract to the systemic circulation has not been reported. The case reports on sepsis emphasize that probiotic supplementation should be used with caution in children with indwelling central venous catheters, prolonged hospitalization, and recognized or potential compromise of gut mucosal integrity [112, 113]. Probiotic administration is even recommended as protection against sepsis in immunocompromised preterm newborns . There is poor public understanding of the concept of risk in general, and risk/benefit analysis in particular [108•]. Uncertainty persists regarding the potential for transfer of antibiotic resistance with probiotics, but the risk seems to be low with currently available probiotic products [108•]. As with other forms of therapeutic agents, the safety of probiotics should be considered on a strain-by-strain basis [108•]. The potential benefits of supplementation should be weighed against the risk of developing an invasive infection from probiotic therapy.
Probiotics and prebiotics affect the GI flora composition. However, despite extensive research on the subject, clear indications for their use in treatment and prevention remain scarce even though their administration seems safe and negative effects are rare. It is difficult to translate heterogeneous study results, which are mainly because of differences in genera, strains, doses, study settings and measured outcomes, into evidence-based recommendations .
A recent review analyzed the data from studies of synbiotics (3 studies, 475 infants), probiotics (10 studies, 933 infants) and prebiotic (12 studies, 1,563 infants) added to infant formula . Probiotics did not lower the incidence of diarrhea, colic, regurgitation, crying, restlessness or vomiting. Prebiotics in formula did increase weight gain. Prebiotics increased stool frequency but had no effect on stool consistency, the incidence of colic, spitting up/regurgitation, crying, restlessness or vomiting. There was no impact of prebiotics on infections or GI microflora. There is not enough evidence to state that supplementation of term infant formula with synbiotics, probiotics or prebiotics results in improved growth or clinical outcomes in term infants . There are no data available to establish if synbiotics are superior to probiotics or prebiotics .
During the last decade, evidence from many good quality clinical research studies shows that prebiotics, probiotics and synbiotics can no longer be neglected. However, future research has to focus on specificity, safety, dosage, and combinations.
Conflict of Interest
Dr. Y. Vandenplas has been a consultant for United Pharmaceuticals and Biocodex.