- Email: [email protected]
Probiotics and prebiotics in infectious gastroenteritis
Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
5
Probiotics and prebiotics in infectious gastroenteritis Yvan Vandenplas, MD, PhD, Professor, Head of Department of Paediatrics * UZ Brussel, Department of Paediatrics, Vrije Universiteit Brussel, Brussels, Belgium
a b s t r a c t Keywords: Acute gastroenteritis Diarrhea Gastro-intestinal microbiota Microbiome Prebiotic Probiotic Synbiotic
Acute gastroenteritis (AGE) is worldwide a common problem in infants and children. While AGE is still an important cause of morbidity and mortality in developing countries, it is mainly a problem with high socioeconomic impact in the rest of the world. Oral rehydration solutions (ORS) and rapid refeeding remain the cornerstone of the management. However, ORS does not decrease the duration of diarrhea. There is evidence that selected strains of probiotics decrease the duration of AGE with 24 h, both in ambulatory care and in hospitalized children, resulting also in a decrease of the duration of hospitalization. Synbiotics are equally effective as probiotics alone, but prebiotics are not effective. Both pro- and prebiotics have limited to no efficacy in the prevention of AGE. The administration of pre- and probiotics is considered to be safe, even in newborns. Only these pre-, pro and synbiotics that have been clinically tested can be recommended. © 2015 Elsevier Ltd. All rights reserved.
Introduction Prebiotic oligosaccharides are non-digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system in ways claimed to be beneficial to health. Prebiotics were first identified and named by Marcel Roberfroid in 1995. A prebiotic is a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confers benefits upon host well-being and health.
* UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel.: þ32 24775780. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.bpg.2015.12.002 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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Y. Vandenplas / Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
The word “probiotic” was used for the first time in the 1960s and means “for life” (from the Greek
prο bίο2, pro bios). Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. There are bacterial and yeast probiotics. The best known bacterial probiotics are lactobacilli and bifidobacteria. Saccharomyces boulardii is a non-pathogenic yeast isolated from the lychee fruit and introduced in France for the treatment of diarrhea since 1950. The major indications of probiotics are in the area of the prevention and treatment of gastro-intestinal (GI) related disorders. The number of commercialized products and the number of publications on probiotics in different conditions has literally exploded during recent years. It is accepted that at least two published randomized controlled trials with a commercialized product in the claimed indication are a minimal condition before a claim can be sustained. The commercialized products There are no commercialized prebiotic products for the prevention or treatment of acute gastroenteritis (AGE). Quality control of the commercialized probiotic products is fundamental [1]. Most probiotics are registered as food supplement and do not have to fulfill the regulations and quality requirements that exist for medication. The product label is incorrect in almost half of the probiotic food supplements [2]. Companies can refuse to provide information on the exact strains in the product [3]. Fundamental research on the mechanisms of action of specific strains and clinical trials with commercialized products are mandatory since in vitro effects of a strain may display opposite behavior in vivo [4]. Most used bacterial probiotic strains comprise different lactobacilli (L.) (Lactobacillus casei GG, Lactobacillus reuteri DSM 17938, L. LA5, …) and bifidobacteria (B.) (Bifidobacterium lactis, Bb12, …), but also to a certain extent non-pathogenic Escherichia (E.) coli (E. coli Nissle 1917). The yeast Saccharomyces (S.) boulardii CNCM I-745 is the only non-bacterial probiotic strain evaluated in acute gastroenteritis. Probiotic products in prevention and treatment Prevention of acute infectious diarrhea The study by Saavedra et al. published in 1994 demonstrating that Streptococcus (Str.) thermophilus and Bifidobacterium bifidum (later renamed B. lactis) prevent nosocomial acquired diarrhea in a small group of children admitted in a chronic care institution can be considered as the kick-off study [5]. Since then many studies have been performed with different probiotic strains, with different amounts, added to infant formula or administered separately to evaluate the efficacy of probiotics in the prevention of AGE. Large, randomized controlled trials (RCT), meta-analyses and reviews provide evidence for a very modest effect (statistically significant, but of questionable clinical importance) of some probiotic strains in the prevention of community-acquired diarrhea [6e10]. The American Academy of Pediatrics concluded in 2010: “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” [11]. The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) concluded one year later that there was “insufficient evidence to recommend the use of infant formula enriched with probiotics mainly because the efficacy shown was insufficiently convincing” [12]. However, some studies do show benefit although for different endpoints and the benefit is not always statistically significant. There are also negative studies [13]. Recently, Bifidobacterium animalis subsp. lactis was shown to fail to prevent common infections in hospitalized children [13]. Preliminary data suggest that L. reuteri may be effective in the prevention of some functional gastrointestinal disorders, such as colic and regurgitation, but AGE was not evaluated [14]. Serious adverse events of probiotics added to infant formula were not reported. In summary: there is insufficient evidence to recommend probiotics to prevent AGE in dally routine (added to infant formula) or in at risk situations, such as during hospitalization for an acute disease. However, no study reported a negative outcome. Studies show either a trend of some benefit compared to placebo, or studies show no difference, but no study has a negative outcome. Therefore, the strategy
Y. Vandenplas / Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
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of many infant formula companies to add probiotics to formula is considered safe, although a decrease of AGE cannot be claimed. There is insufficient evidence to recommend the routine administration of probiotics in children hospitalized for acute disease to decrease the risk for nosocomial AGE. Treatment of acute infectious diarrhea The cornerstone of the treatment of AGE (oral rehydration solution (ORS) and rapid realimentation) will not be discussed. Treatment of AGE should focus on the pathophysiological consequences of the condition: compensation of the loss of water and electrolytes and a disturbance of the GI ecosystem. Probiotics address the second pathophysiological aspect of AGE, abnormal GI microbiota. Numerous clinical trials have been published evaluating different probiotics in the treatment of AGE. These trials vary in relation to the strains tested, dosage, methodological quality, diarrhea definitions and outcomes. While some guidelines recommend the use of probiotics in the treatment of AGE, others do not [15]. Most studies show a statistically significant effect that is of moderate clinical benefit, with a greatest effect in viral and watery diarrhea [8]. In general, meta-analyses of published trials conclude in a reduction of diarrheal duration of approximately 24 h (17e30 h) for selected strains of lactobacilli (such as L. casei GG, Lactobacillus acidophilus, Lactobacillus bulgaricus and L. reuteri) and S. boulardii. Freedman et al. concluded in 2013 that “although probiotics appear to be an effective option for the treatment of AGE amongst hospitalized children, outpatient data is lacking and more studies are urgently needed to determine the optimal organism, dosing and duration of treatment” [16]. The ESPGHAN Working Group on Probiotics and Prebiotics published in 2014 recommendations regarding the use of probiotics in the treatment of AGE, recommending Lactobacillus rhamnosus GG, L. reuteri DSM 17938 and S. boulardii CNCM I-745 [17]. In 2014, Szajewska et al. showed benefit in hospitalized patients for L. reuteri DSM 17938 [18]. In the same year, efficacy for L. reuteri DSM 17938 was shown in outpatients [19]. Greater efficacy has been suggested in a few trials if the probiotic is administered early in the disease. However, some authors conclude that mainly business pressures force usage of probiotics (and antisecretory drugs such as racecadotril) as important in the management of AGE while their relevance yet has to be established [20]. However, a 24 h reduction of the duration of AGE will result in a relevant socio-economic benefit. Moreover, adverse effects of probiotics are very seldom. Therefore, we conclude that selected probiotic strains decrease the duration of diarrhea with about 24 h and decrease the duration of hospitalization with a similar duration. The best studied strains are S. boulardii CNCM I-745, L. rhamnosus GG and L. reuteri DSM 17938. The time has come for comparative instead of placebo controlled randomized trials. Trials should compare different strains and/or different dosages, focusing on the question which probiotic strain at which dosage results in the best efficacy. Summarizing Whether or not to recommend probiotics in AGE remains a controversial topic since out of 12 guidelines, five recommend probiotics and seven do not [15]. There is strong and solid proof of efficacy of selected probiotic strains as active treatment in AGE in addition to oral rehydration solutions [15]. The evidence of benefit in the prevention of AGE is much weaker. Prebiotics There are almost no studies with prebiotics in the treatment of AGE. The limited data available are negative [21]. However, a study in Nicaragua in 300 adults with AGE reported an impressive efficacy of a polyphenol-based prebiotic: median time to their last unformed stool was 1.50 h in the treatment arm versus 67.50 h in the control group [22]. Reviews conclude that there is a theoretical potential role for prebiotics in the prevention of AGE [23,24]. However, data available suggest than infants fed infant formula with a specific mixture of short chain galacto-oligosaccharides and long chain fructo-oligosaccharides have less episodes of physiciandiagnosed infections, fever episodes and antibiotic prescriptions than a group fed unsupplemented
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Y. Vandenplas / Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
formula [25]. However, there was no difference in AGE. Later studies could not confirm these findings [26]. Synbiotics There are no studies on the prevention of AGE with synbiotics. Recently, studies have been published with synbiotics in the treatment of infectious AGE showing a comparable effect to probiotics alone [27,28]. Shamir and coworkers showed a reduction in duration of acute GE from 1.96 ± 1.24 to 1.43 ± 0.71 days (p ¼ 0.017) with addition of 109 CFU Str. thermophilus, B. lactis, L. acidophilus, 10 mg zinc and 0.3 g FOS per day [29]. A Turkish study with B. lactis B94 and inulin resulted in a decrease of AGE of 31 h [30]. However, there are no comparative trials showing a benefit of synbiotics compared to probiotics. Conclusion Probiotics and prebiotics added to infant formula have an influence on GI microbiota composition. However, the evidence for a clinically relevant health care benefit of pro- and prebiotics added to infant formula feeding remains limited. Although it has to be acknowledged that i) negative effects have not been shown and ii) the vast majority of the trials show some benefit although not always significant. Nevertheless, the addition of these ingredients to infant formula feeding brings the second choice infant feeding closer to the gold standard, the breastfed baby. The evidence for efficacy of pre- and probiotics in the prevention of AGE is very limited to non-existing. Prebiotics added to infant formula promote the proliferation bifidobacteria. Prebiotics are not helpful for the treatment of AGE. Although probiotics can be helpful for specific disorders, they have been broadly prescribed for disorders without clear evidence to support their use [31]. There is evidence that specific probiotic strains shorten the severity and duration of acute GE with approximately 24 h. Because of strainspecificity, only those organisms that have been clinically tested can be recommended at their published doses. L. GG and S. boulardii have the most compelling evidence of efficacy as they reduced the duration of the disease by 1 day [15].
Practice points The evidence that prebiotics and probiotics do prevent acute gastroenteritis is limited. There is no evidence that prebiotics reduce the duration of acute gastroenteritis, while some strains of probiotics (S. boulardii CNCM I-745, L. rhamnosus GG, L. reuteri DSM 17938) shorten the duration of acute diarrhea with about 24 h. There is no evidence that synbiotics do better than probiotics alone.
Research agenda In treatment, research should focus on comparative and dose-efficacy trials. An additional benefit of synbiotics still needs to be demonstrated. Selection of other prebiotics, probiotics and synbiotics for the prevention of AGE is required.
Conflict of interests Yvan Vandenplas is consultant for ASPEN, Ausnutria, Biocodex and United Pharmaceuticals.
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References [1] Vanheel LME, Goeme F, Nelis HJ, Coenye T. Quality control of fifteen probiotic products containing Saccharomyces boulardii. J Appl Microbiol 2010;109:1745e52. [2] Temmerman R, Pot B, Huys G, Swings J. Identification and antibiotic susceptibility of bacterial isolates from probiotic products. Int J Food Microbiol 2003;81:1e10. [3] Vandenplas Y. Identification of probiotics by specific strain name. Aliment Pharmacol Ther 2012;35:860. [4] Ibnou-Zekri N, Blum S, Schiffrin EJ, von der Weid T. Divergent patterns of colonization and immune response elicited from two intestinal Lactobacillus strains that display similar properties in vitro. Infect Immun 2003;71:428e36. [5] Saavedra JM, Bauman NA, Oung I, Perman JA, Yolken RH. Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;344:1046e9. ska M, Mikołajczyk W. Efficacy of Lactobacillus GG in prevention of [6] Szajewska H, Kotowska M, Mrukowicz JZ, Arman nosocomial diarrhea in infants. J Pediatr 2001;138:361e5. ska M, Mikołajczyk W. Effect of a Lactobacillus GG and breast-feeding in [7] Mastretta E, Longo P, Laccisaglia A, Balbo L, Arman the prevention of rotavirus nosocomial infection. J Pediatr Gastroenterol Nutr 2002;35:527e31. [8] Szajewska H, Setty M, Mrukowicz J, Guandalini S. Probiotics in gastrointestinal disease in children: hard and not-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr 2006;42:454e75. [9] Agustina R, Kok FJ, van de Rest O, Fahmida U, Firmansyah A, Lukito W, et al. Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. Pediatrics 2012;129:e1155e64. [10] Guandalini S. Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol 2011;45(Suppl.):S149e53. [11] Thomas DW, Greer FR. Clinical report: probiotics and prebiotics in pediatrics. Pediatrics 2010;126:1217e31. [12] Braegger C, Chmielewska A, Decsi T, Kolacek S, Mihatsch W, Moreno L, et al., ESPGHAN Committee on Nutrition. Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2011;52:238e50. [13] Hojsak I, Toki c Pivac V, Mo ci c Pavi c A, Pasini AM, Kola cek S. Bifidobacterium animalis subsp. lactis fails to prevent common infections in hospitalized children: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 2015;101:680e4. [14] Indrio F, Di Mauro A, Riezzo G, Civardi E, Intini C, Corvaglia L, et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr 2014;168:228e33. [15] Guarino A, Guandalini S, Lo Vecchio A. Probiotics for prevention and treatment of diarrhea. J Clin Gastroenterol 2015; 49(Suppl. 1):S37e45. [16] Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L. Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries. Evid Based Child Health 2013;8:1123e37. [17] Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr 2014;58:531e9. ska M, Chmielewska A, Indrio F, Kolacek S, Shamir R, et al. Meta-analysis: Lactobacillus reuteri strain [18] Szajewska H, Urban DSM 17938 (and the original strain ATCC 55730) for treating acute gastroenteritis in children. Benef Microbes 2014;5: 285e93. [19] Dinleyici EC, Dalgic N, Guven S, Metin O, Yasa O, Kurugol Z. Lactobacillus reuteri DSM 17938 shortens acute infectious diarrhea in a pediatric outpatient setting. J Pediatr (Rio J) 2015;91:392e6. [20] Alam S, Bhatnagar S. Current status of anti-diarrheal and anti-secretory drugs in the management of acute childhood diarrhea. Indian J Pediatr 2006;73:693e6. [21] Hoekstra JH, Szajewska H, Zikri MA, Micetic-Turk D, Weizman Z, Papadopoulou A, et al. Oral rehydration solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo controlled study on behalf of the ESPGHAN working group on intestinal infections. J Pediatr Gastroenterol Nutr 2004;39: 239e45. [22] Noguera T, Wotring R, Melville CR, Hargraves K, Kumm J, Morton JM. Resolution of acute gastroenteritis symptoms in children and adults treated with a novel polyphenol-based prebiotic. World J Gastroenterol 2014;20:12301e7. [23] Weichert S, Schroten H, Adam R. The role of prebiotics and probiotics in prevention and treatment of childhood infectious diseases. Pediatr Infect Dis J 2012;31:859e62. [24] Vandenplas Y, De Greef E, Hauser B, Devreker T, Veereman-Wauters G. Probiotics and prebiotics in pediatric diarrheal disorders. Expert Opin Pharmacother 2013;14:397e409. [25] Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G. Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr 2008;138:1091e5. [26] van Stuijvenberg M, Eisses AM, Grüber C, Tandoi L, Rizzardi S, Boehm G. Do prebiotics reduce the number of fever episodes in healthy children in their first year of life: a randomised controlled trial. Br J Nutr 2011;106:1740e8. [27] Passariello A, Terrin G, Cecere G, Micillo M, De Marco G, Di Costanzo M, et al. Randomised clinical trial: efficacy of a new synbiotic formulation containing Lactobacillus paracasei B21060 plus arabinogalactan and xilooligosaccharides in children with acute diarrhoea. Aliment Pharmacol Ther 2012;35:782e8. [28] Vandenplas Y, De Hert SG. PROBIOTICAL-study group. Randomised clinical trial: the synbiotic food supplement probiotical vs. placebo for acute gastroenteritis in children. Aliment Pharmacol Ther 2011;34:862e7. [29] Shamir R, Makhoul IR, Etzioni A, Shehadeh N. Evaluation of a diet containing probiotics and zinc for the treatment of mild diarrheal illness in children younger than one year of age. J Am Coll Nutr 2005;24:370e5. € Baysan, Mutlu D, Artan R, et al. The role of Bifidobacterium lactis B94 plus inulin in the _ ¸ lek A, Sayar E, Yılmaz A, BO [30] Is treatment of acute infectious diarrhea in children. Turk J Gastroenterol 2014;25:628e33. [31] NASPGHAN Nutrition Report Committee, Michail S, Sylvester F, Fuchs G, Issenman R. Clinical efficacy of probiotics: review of the evidence with focus on children. J Pediatr Gastroenterol Nutr 2006;43:550e7.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
5
Probiotics and prebiotics in infectious gastroenteritis Yvan Vandenplas, MD, PhD, Professor, Head of Department of Paediatrics * UZ Brussel, Department of Paediatrics, Vrije Universiteit Brussel, Brussels, Belgium
a b s t r a c t Keywords: Acute gastroenteritis Diarrhea Gastro-intestinal microbiota Microbiome Prebiotic Probiotic Synbiotic
Acute gastroenteritis (AGE) is worldwide a common problem in infants and children. While AGE is still an important cause of morbidity and mortality in developing countries, it is mainly a problem with high socioeconomic impact in the rest of the world. Oral rehydration solutions (ORS) and rapid refeeding remain the cornerstone of the management. However, ORS does not decrease the duration of diarrhea. There is evidence that selected strains of probiotics decrease the duration of AGE with 24 h, both in ambulatory care and in hospitalized children, resulting also in a decrease of the duration of hospitalization. Synbiotics are equally effective as probiotics alone, but prebiotics are not effective. Both pro- and prebiotics have limited to no efficacy in the prevention of AGE. The administration of pre- and probiotics is considered to be safe, even in newborns. Only these pre-, pro and synbiotics that have been clinically tested can be recommended. © 2015 Elsevier Ltd. All rights reserved.
Introduction Prebiotic oligosaccharides are non-digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system in ways claimed to be beneficial to health. Prebiotics were first identified and named by Marcel Roberfroid in 1995. A prebiotic is a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microbiota that confers benefits upon host well-being and health.
* UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel.: þ32 24775780. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.bpg.2015.12.002 1521-6918/© 2015 Elsevier Ltd. All rights reserved.
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The word “probiotic” was used for the first time in the 1960s and means “for life” (from the Greek
prο bίο2, pro bios). Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. There are bacterial and yeast probiotics. The best known bacterial probiotics are lactobacilli and bifidobacteria. Saccharomyces boulardii is a non-pathogenic yeast isolated from the lychee fruit and introduced in France for the treatment of diarrhea since 1950. The major indications of probiotics are in the area of the prevention and treatment of gastro-intestinal (GI) related disorders. The number of commercialized products and the number of publications on probiotics in different conditions has literally exploded during recent years. It is accepted that at least two published randomized controlled trials with a commercialized product in the claimed indication are a minimal condition before a claim can be sustained. The commercialized products There are no commercialized prebiotic products for the prevention or treatment of acute gastroenteritis (AGE). Quality control of the commercialized probiotic products is fundamental [1]. Most probiotics are registered as food supplement and do not have to fulfill the regulations and quality requirements that exist for medication. The product label is incorrect in almost half of the probiotic food supplements [2]. Companies can refuse to provide information on the exact strains in the product [3]. Fundamental research on the mechanisms of action of specific strains and clinical trials with commercialized products are mandatory since in vitro effects of a strain may display opposite behavior in vivo [4]. Most used bacterial probiotic strains comprise different lactobacilli (L.) (Lactobacillus casei GG, Lactobacillus reuteri DSM 17938, L. LA5, …) and bifidobacteria (B.) (Bifidobacterium lactis, Bb12, …), but also to a certain extent non-pathogenic Escherichia (E.) coli (E. coli Nissle 1917). The yeast Saccharomyces (S.) boulardii CNCM I-745 is the only non-bacterial probiotic strain evaluated in acute gastroenteritis. Probiotic products in prevention and treatment Prevention of acute infectious diarrhea The study by Saavedra et al. published in 1994 demonstrating that Streptococcus (Str.) thermophilus and Bifidobacterium bifidum (later renamed B. lactis) prevent nosocomial acquired diarrhea in a small group of children admitted in a chronic care institution can be considered as the kick-off study [5]. Since then many studies have been performed with different probiotic strains, with different amounts, added to infant formula or administered separately to evaluate the efficacy of probiotics in the prevention of AGE. Large, randomized controlled trials (RCT), meta-analyses and reviews provide evidence for a very modest effect (statistically significant, but of questionable clinical importance) of some probiotic strains in the prevention of community-acquired diarrhea [6e10]. The American Academy of Pediatrics concluded in 2010: “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” [11]. The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) concluded one year later that there was “insufficient evidence to recommend the use of infant formula enriched with probiotics mainly because the efficacy shown was insufficiently convincing” [12]. However, some studies do show benefit although for different endpoints and the benefit is not always statistically significant. There are also negative studies [13]. Recently, Bifidobacterium animalis subsp. lactis was shown to fail to prevent common infections in hospitalized children [13]. Preliminary data suggest that L. reuteri may be effective in the prevention of some functional gastrointestinal disorders, such as colic and regurgitation, but AGE was not evaluated [14]. Serious adverse events of probiotics added to infant formula were not reported. In summary: there is insufficient evidence to recommend probiotics to prevent AGE in dally routine (added to infant formula) or in at risk situations, such as during hospitalization for an acute disease. However, no study reported a negative outcome. Studies show either a trend of some benefit compared to placebo, or studies show no difference, but no study has a negative outcome. Therefore, the strategy
Y. Vandenplas / Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
51
of many infant formula companies to add probiotics to formula is considered safe, although a decrease of AGE cannot be claimed. There is insufficient evidence to recommend the routine administration of probiotics in children hospitalized for acute disease to decrease the risk for nosocomial AGE. Treatment of acute infectious diarrhea The cornerstone of the treatment of AGE (oral rehydration solution (ORS) and rapid realimentation) will not be discussed. Treatment of AGE should focus on the pathophysiological consequences of the condition: compensation of the loss of water and electrolytes and a disturbance of the GI ecosystem. Probiotics address the second pathophysiological aspect of AGE, abnormal GI microbiota. Numerous clinical trials have been published evaluating different probiotics in the treatment of AGE. These trials vary in relation to the strains tested, dosage, methodological quality, diarrhea definitions and outcomes. While some guidelines recommend the use of probiotics in the treatment of AGE, others do not [15]. Most studies show a statistically significant effect that is of moderate clinical benefit, with a greatest effect in viral and watery diarrhea [8]. In general, meta-analyses of published trials conclude in a reduction of diarrheal duration of approximately 24 h (17e30 h) for selected strains of lactobacilli (such as L. casei GG, Lactobacillus acidophilus, Lactobacillus bulgaricus and L. reuteri) and S. boulardii. Freedman et al. concluded in 2013 that “although probiotics appear to be an effective option for the treatment of AGE amongst hospitalized children, outpatient data is lacking and more studies are urgently needed to determine the optimal organism, dosing and duration of treatment” [16]. The ESPGHAN Working Group on Probiotics and Prebiotics published in 2014 recommendations regarding the use of probiotics in the treatment of AGE, recommending Lactobacillus rhamnosus GG, L. reuteri DSM 17938 and S. boulardii CNCM I-745 [17]. In 2014, Szajewska et al. showed benefit in hospitalized patients for L. reuteri DSM 17938 [18]. In the same year, efficacy for L. reuteri DSM 17938 was shown in outpatients [19]. Greater efficacy has been suggested in a few trials if the probiotic is administered early in the disease. However, some authors conclude that mainly business pressures force usage of probiotics (and antisecretory drugs such as racecadotril) as important in the management of AGE while their relevance yet has to be established [20]. However, a 24 h reduction of the duration of AGE will result in a relevant socio-economic benefit. Moreover, adverse effects of probiotics are very seldom. Therefore, we conclude that selected probiotic strains decrease the duration of diarrhea with about 24 h and decrease the duration of hospitalization with a similar duration. The best studied strains are S. boulardii CNCM I-745, L. rhamnosus GG and L. reuteri DSM 17938. The time has come for comparative instead of placebo controlled randomized trials. Trials should compare different strains and/or different dosages, focusing on the question which probiotic strain at which dosage results in the best efficacy. Summarizing Whether or not to recommend probiotics in AGE remains a controversial topic since out of 12 guidelines, five recommend probiotics and seven do not [15]. There is strong and solid proof of efficacy of selected probiotic strains as active treatment in AGE in addition to oral rehydration solutions [15]. The evidence of benefit in the prevention of AGE is much weaker. Prebiotics There are almost no studies with prebiotics in the treatment of AGE. The limited data available are negative [21]. However, a study in Nicaragua in 300 adults with AGE reported an impressive efficacy of a polyphenol-based prebiotic: median time to their last unformed stool was 1.50 h in the treatment arm versus 67.50 h in the control group [22]. Reviews conclude that there is a theoretical potential role for prebiotics in the prevention of AGE [23,24]. However, data available suggest than infants fed infant formula with a specific mixture of short chain galacto-oligosaccharides and long chain fructo-oligosaccharides have less episodes of physiciandiagnosed infections, fever episodes and antibiotic prescriptions than a group fed unsupplemented
52
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formula [25]. However, there was no difference in AGE. Later studies could not confirm these findings [26]. Synbiotics There are no studies on the prevention of AGE with synbiotics. Recently, studies have been published with synbiotics in the treatment of infectious AGE showing a comparable effect to probiotics alone [27,28]. Shamir and coworkers showed a reduction in duration of acute GE from 1.96 ± 1.24 to 1.43 ± 0.71 days (p ¼ 0.017) with addition of 109 CFU Str. thermophilus, B. lactis, L. acidophilus, 10 mg zinc and 0.3 g FOS per day [29]. A Turkish study with B. lactis B94 and inulin resulted in a decrease of AGE of 31 h [30]. However, there are no comparative trials showing a benefit of synbiotics compared to probiotics. Conclusion Probiotics and prebiotics added to infant formula have an influence on GI microbiota composition. However, the evidence for a clinically relevant health care benefit of pro- and prebiotics added to infant formula feeding remains limited. Although it has to be acknowledged that i) negative effects have not been shown and ii) the vast majority of the trials show some benefit although not always significant. Nevertheless, the addition of these ingredients to infant formula feeding brings the second choice infant feeding closer to the gold standard, the breastfed baby. The evidence for efficacy of pre- and probiotics in the prevention of AGE is very limited to non-existing. Prebiotics added to infant formula promote the proliferation bifidobacteria. Prebiotics are not helpful for the treatment of AGE. Although probiotics can be helpful for specific disorders, they have been broadly prescribed for disorders without clear evidence to support their use [31]. There is evidence that specific probiotic strains shorten the severity and duration of acute GE with approximately 24 h. Because of strainspecificity, only those organisms that have been clinically tested can be recommended at their published doses. L. GG and S. boulardii have the most compelling evidence of efficacy as they reduced the duration of the disease by 1 day [15].
Practice points The evidence that prebiotics and probiotics do prevent acute gastroenteritis is limited. There is no evidence that prebiotics reduce the duration of acute gastroenteritis, while some strains of probiotics (S. boulardii CNCM I-745, L. rhamnosus GG, L. reuteri DSM 17938) shorten the duration of acute diarrhea with about 24 h. There is no evidence that synbiotics do better than probiotics alone.
Research agenda In treatment, research should focus on comparative and dose-efficacy trials. An additional benefit of synbiotics still needs to be demonstrated. Selection of other prebiotics, probiotics and synbiotics for the prevention of AGE is required.
Conflict of interests Yvan Vandenplas is consultant for ASPEN, Ausnutria, Biocodex and United Pharmaceuticals.
Y. Vandenplas / Best Practice & Research Clinical Gastroenterology 30 (2016) 49e53
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