Role of Probiotics in the Treatment and Prevention of Common Gastrointestinal Conditions in Children

Abstract

Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. Although recommendations for probiotic use should be strain-specific, many systematic reviews, including recommendations from different societies, recommend probiotic use in general, providing no relevant information for healthcare professionals regarding which probiotic to recommend for which clinical indication, at what dose, and for how long. This narrative review aimed to present the available evidence on the use of probiotics in the prevention and treatment of common gastrointestinal diseases in children, considering the strain and dose used. Furthermore, this study summarizes the evidence on the possible side effects and quality of products containing probiotics.

INTRODUCTION

Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts [1]. In 2014, the International Scientific Association for Probiotics and Prebiotics emphasized that the mode of action of probiotics varies between different genera and species, although some are strain-specific [2]. Unfortunately, many systematic reviews, including recommendations from different societies, recommend probiotic use in general, providing no relevant information for healthcare professionals regarding which probiotic for which clinical indication, at what dose, and for how long. Providing a concrete recommendation is often difficult, as many trials have used different strains at different doses and evaluated different outcomes, making comparisons between them very difficult and sometimes impossible.

Another question is whether the clinical effect is strain-dependent or whether the recommendation at the species level would suffice. A recently published review attempted to answer this question; however, evidence is limited and no head-to-head comparisons are available [3]. Therefore, considering the available evidence and drawing conclusions based on the strain and dose of probiotics used in clinical trials would be prudent.

Another novelty is the recent reclassification of the genus Lactobacillus which is now divided into 25 genera [4]. Therefore, some well-known probiotics have new names; Lactobacillus rhamnosus is Lacticaseibacillus rhamnosus, and Lactobacillus reuteri is Limosilactobacillus reuteri. However, the species and strain designations remain unchanged [4].

Hence, this narrative review aimed to present the available evidence on the use of probiotics in the prevention and treatment of common gastrointestinal diseases in children, considering the strain and dose used. Furthermore, this study summarizes the evidence on the possible side effects and quality of products containing probiotics.

INDICATIONS FOR PROBIOTIC USE

A summary of the probiotic strains and their combinations with the highest levels of evidence is presented in Table 1.

Table 1. Type of probiotic(s) that may be considered in the treatment or prevention of gastrointestinal disease/disorder.

Gastrointestinal disease/disorder	Type of probiotic(s) that may be considered
Acute gastroenteritis – treatment	L. rhamnosus GG
	S. boulardii
	L. reuteri DSM 17938
	Combination of L. rhamnosus 19070-2 and L. reuteri DSM 12246
Antibiotic-associated diarrhea – prevention	S. boulardii
	L. rhamnosus GG
Infantile colics – reduction of crying time	L. reuteri DSM 17938
	B. lactis BB-12
Functional abdominal pain – pain intensity reduction	L. reuteri DSM 17938
Irritable bowel syndrome – reduction of pain frequency and intensity	L. rhamnosus GG
Helicobacter pylori – increase of the eradication rate and reduction of the treatment-related gastrointestinal side effects	S. boulardii

Acute gastroenteritis (AGE)

AGE is a common cause of morbidity and mortality among infants and children worldwide. Malnutrition and unsafe water and sanitation continue to be leading risk factors for diarrhea in developing areas [5]. AGE is an important health issue in developed countries. This leads to frequent visits to primary care physicians, increases the number of emergency department visits and hospital admissions, and consequently, imposes a high financial burden on healthcare and society [5]. Most AGE cases are caused by viral infections, and the mainstay of treatment is rehydration, mainly with oral rehydration solution. Furthermore, avoiding fasting and continuing feeding are important [5,6]. As a causal treatment is not available, studies have assessed the role of different supplement therapies, of which probiotics are one of the most well-studied.

Several randomized controlled trials (RCTs) have investigated the roles of different probiotic strains and their combinations in the treatment of AGE. Consequently, many systematic reviews and expert groups have advocated the use of probiotics in the management of AGE [7,8,9,10]. However, with new evidence from 2019, recommendations have begun to differ, with some societies questioning the efficacy of some strains that previously had positive recommendations [11,12]. This can be mainly observed in two recommendations, both made in 2020; the American Gastroenterology Association (AGA) made a conditional recommendation against the use of probiotics in children from North America with acute infectious gastroenteritis (based on the evaluation of 89 trials) [13]. By contrast, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Working Group (WG) on Probiotics and Prebiotics position paper identified 16 systematic reviews and meta-analyses published from 2010 until September 2020 (more than 150 RCTs included) and made weak recommendations for the use of some probiotic strains and their recommendations (Saccharomyces boulardii, Lacticaseibacillus rhamnosus GG, Limosilactobacillus reuteri DSM 17938 and the combination of L. rhamnosus 19070-2 and L. reuteri DSM 12246 [6]. These recommendations mainly differ because the evidence that recommendations were based on studies from North America, where the two most recent trials questioned the efficacy of probiotics [11,14], and the ESPGHAN considered RCTs published worldwide. A subgroup analysis based on the geographical setting of the RCTs demonstrated a higher efficacy of L. rhamnosus GG in Europe (5 RCTs, n=744, mean deviation [MD] −32 hours, [−49 to −15]) and Asia (6 RCTs, n=1,740, MD −24 hours, [−47 to −1.8]) than in other continents [6]. This could explain the differences between the ESPGHAN WG and AGA recommendations.

Since 2020, several new papers included in the most recent position paper from the ESPGHAN Special Interest Group on Gut Microbiota and Modifications from 2023 have been published [15]. This position paper provides a weak grade of recommendation with a low certainty of evidence for the use of L. rhamnosus GG ATCC 53103 (at a dose of ≥10¹⁰ CFU/day for 5–7 days) and S. boulardii (at a dose of 250–750 mg/day for 5–7 days). A weak grade of recommendation but very low certainty of evidence was provided for the use of L. reuteri DSM 17938 (at daily doses 1×10⁸ to 4×10⁸ CFU for 5 days) and a combination of L. rhamnosus 19070-2 and L reuteri DSM 12246 (at a dose of 2×10¹⁰ CFU for each strain for 5 days) [15]. It should be noted that the main effect was the shortening of diarrhea by approximately one day.

Two combinations had negative recommendations: a combination of L. helveticus R0052 and L. rhamnosus R0011 (certainty of evidence: moderate; grade of recommendation: strong) and Bacillus clausii strains O/C, SIN, N/R, and T (certainty of evidence: very low; grade of recommendation: weak) [15].

Prevention of antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) is a common complication that occurs in up to one-third of all patients treated with antibiotics [16]. Although almost all oral and intravenous antibiotics can cause AAD, the risk is higher with the use of aminopenicillins (with or without clavulanate), cephalosporins, and clindamycin [17]. Although the majority of patients present with mild diarrhea, some may also experience life-threatening fulminant pseudomembranous colitis. Therefore, efforts have been made to prevent AAD, and many RCTs aimed to identify efficacious probiotics.

In 2016, the ESPGHAN WG on Probiotics [18] addressed the prevention of AAD by using probiotics. This review identified two probiotic strains as efficacious: L. rhamnosus GG (recommendation: strong; quality of evidence: moderate) and S. boulardii (recommendation: strong; quality of evidence: moderate). Importantly, if the use of probiotics to prevent C difficile-associated diarrhea is considered, the use of S. boulardii (recommendation: conditional; quality of evidence: low) is recommended [18]. By contrast, the AGA in 2020 failed to formulate any recommendations on the use of probiotics for AAD prevention but conditionally recommended some probiotics for the prevention of C. difficile infection in children receiving antibiotic treatment [13]. A subsequent meta-analysis published in 2021 that included 33 RCTs confirmed the efficacy of S. boulardii CNCM I-745 and L. rhamnosus GG in AAD prevention in outpatients and hospitalized children [19].

Although new data are now available, the recommendations in the new ESPGHAN position paper remain the same [15]. Therefore, if the use of probiotics for AAD prevention is considered owing to the presence of risk factors such as class of antibiotic(s), duration of antibiotic treatment, age, need for hospitalization, comorbidities, or previous episodes of AAD diarrhea, high doses (≥5 billion CFU per day) of S. boulardii or L. rhamnosus GG may be recommended [15]. These strains should be initiated simultaneously with antibiotic treatment in outpatients and hospitalized children (certainty of evidence: moderate; grade of recommendation: moderate) [15].

Functional gastrointestinal disorders (FGID)

FGID, currently known as gut–brain interaction disorders, encompass various disorders in all age groups and are responsible for a large proportion of pediatric gastroenterologist consultations [20]. The definition of different FGIDs became more stringent after the introduction of the Rome criteria, which aimed to provide diagnostic guidance for every specific FGID [20,21]. The most common FGIDs are infantile colic, constipation, functional abdominal pain (FAP) not otherwise specified, and irritable bowel syndrome (IBS).

The etiology of FGID has not been completely elucidated; however, the prevailing focus for FAP disorders is visceral hypersensitivity, altered gastrointestinal motility, and alterations in the brain–gut axis interaction [22]. As the exact causal agent is unknown, different treatment strategies have been proposed, including probiotics [23].

Evidence that these two probiotic strains affect the treatment of infantile colic has been reported. The most-studied probiotic strain for this clinical indication is L. reuteri DSM 17938. Four RCTs (n= 345) were included in the 2018 individual participant data meta-analysis, and in breastfed infants, the use of L reuteri DSM 17938 (1×10⁸ CFU/day) increased treatment success and reduced crying and/or fussing time [24]. However, the role of L. reuteri DSM 17938 in formula-fed infants is unclear [24].

Recently, another strain of Bifidobacterium lactis BB-12 (10⁹ CFU/day), was tested in two RCTs [25,26]. These studies have reported increased treatment success and reduced crying times in the probiotic group.

Therefore, a recent ESPGHAN position paper [15] provided positive recommendations for L. reuteri DSM 17938 (at least 10⁸ CFU/day for at least 21 days) and B. lactis BB-12 (at least 10⁸ CFU/day, for 21–28 days) for the management of colic in breastfed infants (certainty of evidence: moderate; grade of recommendation: weak).

For FAP disorders, recommendations from relevant societies were limited to the AGA 2020 guidelines, and no recommendations were provided for the use of probiotics in symptomatic children and adults with IBS owing to the significant heterogeneity in study design, outcomes, and tested probiotics [13]. A recent ESPGHAN position paper included more recent data and indicated that the only probiotic strains evaluated in more than two RCTs were L. reuteri DSM 17938 (6 RCTs) and L. rhamnosus GG (5 RCTs) [15]. L. reuteri DSM 17938 has resulted in improved abdominal pain in three RCTs [27,28,29], reduced functional disability but not abdominal pain in one RCT [30], and was not better than a placebo in one trial [31]. A 2021 meta-analysis [32] identified six RCTs that evaluated L. reuteri DSM 17938 and three RCTs used L. rhamnosus GG compared to a placebo. L. reuteri DSM 17938 reduced the pain intensity and increased the number of days without pain in patients with FAP. For all the other outcomes, no significant differences were observed between the probiotic and placebo groups.

Another meta-analysis from 2021 evaluated the efficacy of probiotic therapy in children with IBS [33]. Nine RCTs involving 651 participants were included; however, three RCTs included not only patients with IBS, but also those with FAP. This review concluded that probiotics are effective in treating abdominal pain caused by IBS in children. However, the heterogeneity between the studies was high owing to the study design, duration of treatment, and evaluation of outcomes.

Considering available evidence ESPGHAN SIG considers L. reuteri DSM 17938 (at a dose of 10⁸ CFU to 2×10⁸ CFU/day) to reduce pain intensity in children with FAP and L. rhamnosus GG (daily dose from 10⁹ CFU to 3×10⁹ CFU twice daily) to reduce pain frequency and intensity in children with IBS (certainty of evidence: moderate; grade of recommendation: weak) [15].

Functional constipation is considered a widespread FGID in children, with a prevalence of approximately 10% [34]. The etiology of functional constipation is considered multifactorial and includes withholding behavior often observed in children with functional constipation, psychological factors, social conditions, and alterations in the intestinal microbiota [35,36]. The first-line treatment option in children is polyethylene glycol [37]. Unfortunately, for many patients, current treatment options do not provide sustained relief; symptoms often reoccur, and in some patients, last until adulthood; therefore, new treatment strategies have been proposed, including probiotics.

A recent 2021 systematic review and meta-analysis summarized the evidence for probiotic use in chronic constipation [38]. This systematic review identified 13 studies (n=965 children) and two follow-up studies (n=166 children) that compared different probiotic strains to either placebo or laxative treatment. The included RCTs were heterogeneous in study design, duration of treatment, diagnostic criteria, age of the included children, type of strain(s), and clinical outcomes; therefore, no clear conclusions could be drawn. The ESPGHAN 2023 position paper does not recommend the use of probiotics evaluated so far as a single therapy or co-adjuvant with laxatives for the treatment of functional constipation in children (certainty of evidence: moderate; grade of recommendation: weak) [15].

Helicobacter pylori (HP)

HP, a gram-negative microaerophilic bacterium isolated from the gastric mucosa in 1983 [39], commonly causes chronic infections, affecting almost every second person worldwide. A recently published meta-analysis of 73 countries across six continents revealed an overall prevalence of 44.3%, increasing to >80% in underdeveloped countries [40]. Although HP is acquired during childhood, the infection rate is significantly lower in children (32.6% vs. 48.6%), which is ascribed to the birth cohort effect and age-accumulated risk of infection [40].

HP can cause progressive gastric inflammation, contributing significantly to the etiopathogenesis of peptic ulcer, gastric carcinoma, and mucosa-associated lymphoid tissue lymphoma. However, in children, the infection seldom follows the same route, and most infected children are symptom free. Therefore, the latest pediatric guidelines [41,42] do not support a “test and treat” approach recommended for adults but propose an individualized decision adjusted to each infected child.

The treatment consists of at least two antibiotics to which bismuth can be added, in conjunction with a proton pump inhibitor (PPI), provided as a triple, quadruple, sequential, or concomitant treatment, for 7–14 days [41,42]. However, the proclaimed treatment goal of HP eradication in at least 90% of patients [43], is rarely reached because of antibiotic resistance and therapy-associated side effects. A systematic review and meta-analysis performed in the World Health Organization (WHO) regions yielded an unacceptable frequency of primary and secondary resistance to clarithromycin, metronidazole, and levofloxacin, which was >15% in all WHO regions and significantly increased over time in the majority of the regions. Treatment-associated side effects occur in 12–20% of pediatric patients and consist mainly of gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain, precluding treatment compliance in affected children [44].

In the search for a more efficacious treatment that will increase the eradication rate and decrease the frequency of side effects, the addition of probiotics has been addressed because of their potentially beneficial widespread effects, such as competitive exclusion of pathogens, colonization resistance, increased local IgA production, antibacterial substances, and short-chain fatty acid production [2].

Efficacy of probiotic supplementation for HP eradication

The answer to the first question – whether probiotics alone are sufficient to achieve HP eradication in children – was negative. Based on the literature summary, Pacifico et al. [45] concluded that probiotics had a strain-dependent suppressive effect on HP colonization in asymptomatic children, although the most efficacious modalities did not surpass a 22.9% eradication rate; furthermore, the clearance could be a transitory effect as the HP reappeared after a 1-month wash-out period in 80% of children.

The second important question is whether the addition of probiotics to triple therapy increases eradication rates. Based on a literature search until September 2014 and November 2016, both the ESPGHAN and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition [41] and the Japanese Society guidelines [42] stated that the evidence is insufficient to provide an answer on the additional eradication value of adding probiotics as a supplement. However, since then, further randomized controlled trials comparing triple eradication therapy (two antibiotics+PPI) with and without the addition of probiotics have been published and summarized in four consecutive systematic reviews with meta-analyses and a recent position paper of ESPGHAN [15,46,47,48,49]. All the abovementioned systematic reviews concluded that the eradication rate was significantly higher in probiotic-supplemented therapy than in unsupplemented controls, particularly if provided in a high dose and long term (>4 weeks). However, the following restrictions were also apparent. First, the eradication rate, although increased by 8–15%, did not reach the recommended 90%. Second, the most published data are based on evidence obtained from adults. Significant heterogeneity was observed in the three treatment modalities and probiotics used. Except for S. boulardii, none of the probiotics were evaluated in more than one study. The evidence for S. boulardii indicated that in all the participants (18 RCTs, N=3,592; relative risk [RR], 1.09; 95% confidence interval [CI], 1.05–1.13), and also in a subgroup of children (3 RCTs, N=535; RR, 1.14; 95% CI, 1.03–1.25) supplementation to triple therapy significantly improved the eradication of HP [48]. Acknowledging all the abovementioned constraints, the ESPGHAN SIG [15] recommends that S. boulardii may be used along with the HP therapy to increase the eradication rate (certainty of evidence: very low; grade of recommendation: weak).

Role of probiotics in reducing the risk of eradication therapy-related adverse effects

Eradication therapy-related side effects are common, affecting compliance and consequently increasing the risk of eradication failure and antibiotic resistance; therefore, the effect of probiotics on their attenuation was addressed in all systematic reviews cited above. The meta-analysis of Feng et al. [47] (18 RCTs, N=2154; RR, 0.49; 95% CI, 0.38–0.65), and the pediatric subgroup by Lü et al. [46] (2 RCTS; RR, 0.37; 95% CI, 0.21–0.65) has demonstrated that in children, probiotics in general significantly reduced the risk of total therapy-related adverse effects, although the effect differed in terms of type of side effect and probiotic strain used. However, except for S. boulardii, results for all other probiotic strains (single strain or in combination) were limited to a single study only, and therefore cannot be used as a basis for sound recommendations. The most successfully treated adverse effects were diarrhea and vomiting, whereas the least successfully treated ones were headache and abdominal pain. A meta-analysis on the efficacy of Lactobacillus-supplemented triple therapy in children failed to identify a diminished risk of side effects but confirmed a reduced risk of diarrhea [49]. As for S. boulardii, its addition to therapy significantly diminished the risk of side effects in both adults and children (11 RTCs, N=2,464; RR, 0.47; 95% CI, 0.36–0.61), and in particular the risk of diarrhea, nausea, constipation, and bloating. Furthermore, supplementation with S. boulardii significantly diminished the need for HP treatment discontinuation [48]. Based on the evidence presented above, it is plausible to support the recommendation of the ESPGHAN that healthcare professionals may recommend the addition of S. boulardii to standard HP therapy to diminish treatment-related gastrointestinal side effects [15]. Further studies are required on all other probiotic strains.

PROBIOTIC TREATMENT-RELATED SAFETY CONCERNS

In contrast to drugs, probiotics are live microorganisms that colonize the colon and remain viable while exerting beneficial effects on the host. Therefore, safety concerns differ from other medicinal products, foods, and nutraceuticals, and as recently summarized elsewhere, they could be grouped into: production of deleterious metabolites/toxins, transfer of genes to human cells and other members of the gut flora (e.g., those responsible for antibiotic resistance), short- and long-term immunomodulation, and lastly, causing infectious complications in the host [50]. To prevent such developments, legislative and procedural frameworks have been provided by the European Food Safety Authority (EFSA) on how to assess potentially beneficial microorganisms with respect to the abovementioned safety issues [51]. Moreover, inventories of microorganisms with a long track record of safe use in human foods, such as the Qualified Presumption of Safety by the ESFA [52] or Generally Recognized as Safe by the Food and Drug Administration (FDA) in the USA are performed [53].

Once probiotic microorganisms have selected, safety concerns need to be evaluated in scientific studies through post-marketing surveillance, and if possible, through registries created to detect side effects associated with probiotic use. However, the only study aiming to catalog evidence on the safety aspects of six different probiotic strains/genera (Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus, Streptococcus, and Bacillus) was published 10 years ago, including 622 studies, of which only 387 reported adverse events. In conclusion, the risk of adverse events was not increased in patients receiving probiotics in general (RR, 1.00; 95% CI, 0.93–1.07; p=0.999), or concerning gastrointestinal side effects, infections, other adverse events (RR, 1.06; 95% CI, 0.97–1.16; p=0.201), even in non-critically ill patients (RR, 0.79; 95% CI, 0.51–1.22; p=0.286). However, the authors concluded that systematic reporting was lacking, no studies investigated side effects as the primary outcome, interventions were mostly poorly documented, and long-term outcomes were unknown [54]. In the last 5 years, almost 100 systematic reviews on the efficacy of probiotics for the treatment of various clinical conditions have been published in PubMed, and adverse reactions, if reported, have not significantly increased. The same applies to children in the most recently published meta-analyses [55]. Following that, the safety of probiotics might not be an issue. However, Bafeta et al. [56] assessed the reported harm in 384 randomized controlled trials of probiotics (N=265, 69%), prebiotics, and symbiotics published between January 2015 and March 2018. Overall, 28% of the trials did not provide data on eventual harm, and methods for collecting harmful effects were not described in 97% of studies; when reported, the terms used were inadequate and generic, and only nine trials (2%) defined adverse and serious adverse effects and appropriately presented the number and nature of harms. The authors concluded that the evidence at this time was insufficient to answer questions regarding the safety of antibiotics [56].

In contrast to the negligible adverse side effects reported in randomized controlled trials, two recently published systematic reviews summarized cases and case reports of invasive infections associated with treatment with probiotic microorganisms. In the first published article, which included both adults and children, the total number of affected patients was 93, and the most commonly observed harm was fungemia in 35 patients (37.6%), sepsis in 29 (31.2%), bacteremia in 19 (20.4%), and endocarditis, abscess, pneumonia, empyema, and septic arthritis in the rest of the patients. The most frequent cause was Saccharomyces (50.5%), followed by Lactobacillus spp. (27.9%), and Bifidobacterium spp. (12.1%) [57]. An increased risk of infection is significantly associated with young and old age, antibiotic use, and Clostridium difficile infection [57]. Another recent systematic report summarized 49 cases in children: 35% were associated with Lactobacillus, 31% with Bifidobacterium, 29% with Saccharomyces spp., 4% with B. clausii, and 2% with Escherichia coli [58]. Among the 49 pediatric patients only one did not have associated comorbidities, and the most common conditions were prematurity (55%) and use of intravenous catheters (51%) [58]. Nearly 100 patients with diagnosed invasive infections caused by a consumed probiotic might be worrisome. However, this has to be viewed from the perspective of millions of consumers, creating the denominator, and the most common causal genera/species correlate with the most frequently used probiotic microorganisms in particular age groups.

Lastly, three reports were published on cases of infants who developed invasive infections caused by a microorganism that was present as a contaminant in the commercial probiotic product; two infants had sepsis [59,60] and one infant developed fatal gastrointestinal mucormycosis [61]. Problems related to the contamination of commercial probiotic products, post-manufacturing surveillance, and probiotic product quality control are discussed in the next section.

In conclusion, probiotics, as live microorganisms, have the potential for different adverse side effects, and invasive infections are particularly worrisome in patients of very young age (preterm infants), old age, immunocompromised status, and other serious comorbidities. Although side effects are very infrequently reported, which makes them appear safe, the current evidence is of poor quality and cannot answer questions on their safety.

QUALITY OF COMMERCIAL PROBIOTIC PRODUCTS

To confer a beneficial effect on the host, as defined by the International Society of Antimicrobial Chemotherapy [2], probiotic microorganisms must survive the hostile acidity of the stomach, bile in the duodenum, and enzymes in the small intestine and colonize the large bowel in sufficient numbers. Furthermore, concerning the number, viability, and functional capacity, which all have to be retained during the entire product shelf-life, beneficial bacteria must survive manufacturing procedures such as repetitive fermentation, cell harvesting, spray, freeze-drying, mixing with an appropriate matrix, storage conditions such as temperature, pH, oxygen exposure and humidity, and type of packaging, to mention just a few examples of the manufacturing determinants that can affect the biological activity of the final product [50,62,63]. Finally, the commercial product must contain only the strain or a combination that has a scientifically proven benefit for the host while avoiding contamination with other microorganisms. This is particularly important when probiotic products are intended for the treatment of defined gastrointestinal conditions in vulnerable populations, such as those described in this article, and not just to improve the GIT milieu in an otherwise healthy host [2]. Recently published reviews [64,65] have summarized the requirements that need to be considered during the manufacturing process to achieve a final probiotic product that will comply with the standards of relevant organizations, such as the EFSA [66,67] and FDA in the USA [68]. However, in Europe and the USA, probiotic products are mostly categorized as food and dietary supplements, for which the regulatory requirements for continuous monitoring and post-marketing quality control are much less stringent than those for licensed drugs. Therefore, the ESPGHAN raised questions regarding the safety, validity, and quality of commercial probiotic products and performed a literature search to assess these important issues [69]. In conclusion, the results revealed that probiotic products commonly contain species/strains not claimed on the label, sometimes composed of potentially pathogenic genera. Furthermore, the number of viable bacteria is often significantly lower and has decreased functional properties. Contamination is a common and particularly worrisome finding [69]. Following the ESPGHAN position paper, several more recently published reports [70,71], two of which were limited to neonates and children [72,73], also reported missing strains, decreased viability, inadequate resistance to acid and bile, and contamination with potentially pathogenic microorganisms. Therefore, several probiotic products on the market did not match their label claims.

In conclusion, the quality of commercial probiotic products is often unsatisfactory, and more stringent regulatory controls are required, particularly for vulnerable groups such as neonates and children, and when prescribed for defined clinical conditions [69].

CONCLUSION

Currently, available evidence supports the use of probiotics for the following clinical indications (Table 1).

• - Prevention of AGE (L. rhamnosus GG ATCC 53103, S. boulardii, L. reuteri DSM 17938, and a combination of L. rhamnosus 19070-2 and L. reuteri DSM 12246)

• - Prevention of AAD (L. rhamnosus GG ATCC 53103 and S. boulardii)

• - Treatment with infantile colic (L. reuteri DSM 17938 and B. lactis BB-12)

• - Pain intensity reduction in children with FAP (L. reuteri DSM 17938), and pain frequency and intensity reduction in children with irritable bowel syndrome (L. rhamnosus GG)

Increased H. pylori eradication rate and diminished treatment-related gastrointestinal side effects (S. boulardii)