Saccharomyces boulardii in childhood,Review
REVIEW
Saccharomyces boulardii in childhood Yvan Vandenplas&Oscar Brunser&Hania Szajewska
Received:10August2008/Revised:27October2008/Accepted:4November2008 #Springer-Verlag2008
Abstract
Introduction Probiotics are live microorganisms which confer a health benefit on the host.Saccharomyces boulardii,a yeast,has been found to be an effective probiotic in double-blind placebo-controlled randomized clinical studies.
Materials and methods We reviewed the established mech-anisms of actions and clinical efficacy in children of S. boulardii.
Conclusions The mechanisms of action of S.boulardii depend mainly on the inhibition of some bacterial toxins, anti-inflammatory effects,and on stimulating effects on the intestinal mucosa such as trophic effects on the brush border enzymes and immunostimulatory effects.At present, in pediatric populations,there is evidence that S.boulardii is beneficial for the treatment of acute gastroenteritis and the prevention of antibiotic-associated diarrhea.More data are needed in other indications such as traveller’s diarrhea, Helicobacter pylori eradication,and inflammatory bowel disease.S.boulardii is a yeast strain that has been extensively studied in vitro and in vivo.Recent data have opened the door for new therapeutic indications.Keywords Child.Diarrhea.Gastroenteritis.Probiotic. Saccharomyces boulardii.Yeast
Introduction
The gastrointestinal(GI)microflora,the so-called micro-biota,is an extremely complex ecosystem that coexists in equilibrium with the host.There is increasing evidence that this microbiota is a major regulator of the immune system, also outside the gut.Probiotic is derived from Greek and means“for life.”“Probiotics”are defined as living microorganism(bacteria and yeast)resistant to digestion and reaching the colon alive and,when ingested in adequate amounts,have a health benefit for the host[44]. Fermented food—and as a consequence“good”bacteria—has been very popular worldwide during centuries.Until a few years ago,probiotics were discussed primarily in the context of alternative medicine,but they are now entering mainstream medical practice[85].
Yeasts are also part of the residual microbial system that makes up<0.1%of the microbiota.Most yeast isolates from the GI tract are Candida albicans,although others are occasionally found.The cell size of yeast is many times larger than that of bacteria(Fig.1).Saccharomyces boulardii(S.boulardii)is a yeast isolated from the skin of lychees grown in Indochina and belongs to the same species as Saccharomyces cerevisiae(S.cerevisiae),al-though it definitively has different taxonomy,physiological, metabolic and genetic characteristics.A unique and specific microsattelite allele was described distinguishing S.bou-lardii from other strains of S.cerevisiae[56].Whereas most S.cerevisiae strains grow and metabolize best at a temperature of30°C,S.boulardii is a thermotolerant yeast that grows optimally at37°C[45].
Eur J Pediatr
DOI10.1007/s00431-008-0879-7
Y.Vandenplas(*)
Universitair Ziekenhuis Kinderen Brussel,
Vrije Universiteit Brussel,
Laarbeekl101,
1090Brussels,Belgium
e-mail:Yvan.Vandenplas@uzbrussel.be
O.Brunser
Institute of Nutrition and Food Technology(INTA),U.of Chile, Santiago,Chile
H.Szajewska
The Medical University of Warsaw,
Warsaw,
Poland
The improved understanding of the mechanisms of action of probiotics is fundamental for the scientific acceptance of their potential benefit,and include regulation of intestinal microbial homeostasis,interference with the ability of pathogens to colonize and infect the mucosa,modulation of local and systemic immune responses,stabilization of the gastrointestinal barrier function,inhibi-tion of procarcinogenic enzymes,and induction of enzy-matic activity favoring absorption and nutrition.
Pharmacodynamics and pharmacokinetics
In lyophilized form,S.boulardii survives gastric acid and bile and can be detected alive throughout the entire digestive system (if ingested daily in freeze-dried form).S.boulardii is also resistant to proteolysis.After 3days of administration,a stable concentration in the intestinal content is reached.Within 1week after stopping the administration,S.boulardii becomes undetectable [11].As is the case with all yeasts,S.boulardii is naturally resistant to antibiotics.Simultaneous oral intake of amoxicillin and S.boulardii doubles the number of S.boulardii surviving in the gastrointestinal tract [61].A significant correlation between the density of S.boulardii in the feces and the therapeutic activity has been shown in patients with repetitive Clostridium difficile infection:those who did not relapse had higher fecal presence of S.boulardii (1×106cells per gram)compared to those who did (2.5×104per gram)[40].The higher the dose of S.boulardii adminis-tered,the higher the survival rate of mice infected with C.difficile [39].Nystatin completely eliminates S.boulardii from the gastrointestinal tract.However,if there is a time interval of 4to 6h between the ingestion of S.boulardii
and fluconazole,the antifungal has no effect on the intestinal survival of the yeast [41].The epithelial barrier
The basic principle that a probiotic should adhere to the gastrointestinal mucosa has been considered in the past as extremely important.The epithelium of the gastrointestinal mucosa forms a barrier inhibiting the passage of commen-sal and pathogenic microorganisms.In some diseases,such as in inflammatory bowel disease (IBD),this natural barrier function is likely to be disrupted.Adherence of the bacteria in the gastrointestinal tract to the intestinal mucosa may not be of extreme relevance.Adherence of S.boulardii to the gastrointestinal tract mucosa has not been convincingly documented.
Effect on enteric pathogens
Probiotics may also have effects on epithelial barrier function via cellular mechanisms that have little to do with adherence or with Toll-like receptor signaling.S.boulardii does interact strongly with the gastrointestinal microflora.A strong direct antagonist effect has been demonstrated for S.boulardii against a number of pathogens.In vitro studies have shown that S.boulardii reduces the growth of C.albicans ,Escherichia coli ,Shigella ,Salmonella typhimurium ,Pseudo-monas aeruginosa ,Staphylococcus aureus ,and Entamoeba histolytica .In in vitro studies,it was shown that S.boulardii inhibits cell invasion by S.typhimurium and Yersinia enter-ocolitica [31].S.typhimurium and E.coli of the serogroup O 157are bound to the surface of S.boulardii [47](Figs.1,2).In vivo studies have shown that S.boulardii reduces in rats significantly the number of E.histolytica and the severity of symptoms [74].In mice,S.boulardii reduces the number of C.albicans 20to 50times.S.boulardii reduces mortality of mice infected with virulent S.typhimurium or Shigella [76].A study using T84cells infected with enteropathogenic E.coli concluded that S.boulardii is able to increase the transepithelial resistance to pathogens through the preserva-tion of the integrity of tight junctions [29].Otherwise,preliminary data from Brunser shows how S.boulardii alters the structure of Helicobacter pylori (Fig.3)[13].
Several studies using animal and/or cell models indicated two main mechanisms of action against enteric pathogens:production of factors that compete with bacterial toxins and modulation of the host cell signaling pathways implicated in proinflammatory response during bacterial infection [30].Secretion of enzymatic proteins
S.boulardii produces two proteins,one of 120kDa and another of 54kDa.The 54-kDa serine protease inhibits
the
Fig.1Scanning electron micrographs of T84cells exposed to S.boulardii and S.typhimurium (micrograph:D.Czerucka,Facultéde Médecine,UniversitéNice-Sophia Antipolis,Nice)
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enterotoxic and cytotoxic activities of C.difficile by proteolysing toxin A and its receptor.Pothoulakis et al.have demonstrated in an in vivo model that the 54-kDa protein inhibits water and electrolyte secretion but has no effect on the cellular lesions caused by C.difficile [24,72].Nevertheless,intestinal permeability to mannitol is reduced by 93%in the presence of S.boulardii .Castagliuolo et al.demonstrated that the 54kDa protease inhibits the binding of toxin A and B to their receptors on the membranes of the intestinal villi [25,26,74].
The 120kDa protein has a nonproteolytic activity,competes specifically with the hypersecretion caused by the toxins of Vibrio cholera decreasing cyclic adenosine monophosphate in the intestinal cells.The metabolic changes in the intestinal mucosa caused by cholera toxin are decreased if S.boulardii is ingested prior to the cholera toxin.The 120-kDa protein acts directly on enterocytes and includes signal transduction pathways involved in the regulatory secretion [32].
S.boulardii also synthesizes a phosphatase that dephos-phorylates endotoxins such as lipopolysaccharide of E.coli 055B5and inactivates its cytotoxic effects [22].Modification of host cell signaling
The infection of T84cells by enteropathogenic E.coli (EPEC)and enterohemorrhagic E.coli (EHEC)share common
pathogenic mechanisms characterized by bacterial adhesion to the intestinal mucosa and subsequent widening of the tight junctions and activation of signaling different pathways involving mitogen-activating protein (MAP)kinases:extra-cellular regulating protein kinases 1and 2(ERK-1and ERK-2),p38MAP kinase,and JUN-kinase.These kinases do not stimulate attachment of the probiotic to the intestinal mucosa and do not change intestinal permeability.S.boulardii reduces the number of infected cells and stimulates the growth and differentiation of intestinal cells in response to trophic factors (such as insulin and IgF-1)by activating the ERK-1and -2kinases.The p38MAP kinase is involved in cellular apoptosis.All these mechanisms are related to interleukin-8synthesis,stimulating a Th-1response.If S.boulardii has been in contact with the intestinal mucosa prior to the EPEC or EHEC,decrease in transepithelial resistance was prevented,and secretion of IL-8was decreased or inhibited.The observation that the yeast did not modify the number of adherent bacteria prompted research on the effects of S.boulardii on host cell signaling.S.boulardii prevents apoptosis and synthesis of tumor necrosis factor alpha (TNF α)in EHEC infection [29,33,35].
Similar effects have been reported in Shigella flexneri and S.typhimurium infection.But again,this protective effect is not linked to a reduction in the degree of intestinal overgrowth of these bacteria [76].Effects on the intestinal tract Trophic effects
In adult healthy volunteers,S.boulardii has no effect on the thickness of the small intestinal mucosa.However,
the
Fig.3Relationship between co-incubated S.boulardii and Helico-bacter pylori .The ultrastructure of the individual Helicobacter pylori is altered:their structure is profoundly altered,especially in those microorganisms closest to the yeast;some of the bacteria are vesiculating.The body occupying the lower part of the picture is S.boulardii .There are some empty vesicles and part of a flagellum.Membranes stained with ruthenium red.×56,000[13
]
Fig.2Adherence of enterohemorrhagic E.coli serogroup 0157:H to the surface of S.boulardii .Electron microscopic photograph,magnitude ×5,000[47]
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enzymatic activities(lactase,alpha-glucosidase,alkaline phosphatase)do increase over baseline values in healthy adult volunteers.S.boulardii stimulates the expression of disaccharidases,enzymes involved in nutrient digestion (Fig.4).S.boulardii stimulates the secretion of a sucrase at levels high enough to be effective in the treatment of congenital sucrase-isomaltase deficiency[19].More recent-ly,the intraluminal secretion of a leucine aminopeptidase belonging to the zinc-metalloprotease family enhancing proteolysis has been shown[21].In rats,S.boulardii also improves D-glucose absorption after a proximal enter-ectomy of more than50%[20].
S.boulardii stimulates the production of glycoproteins in the brush border of microvilli such as hydrolases,trans-porters,secretory IgA,and the receptor for polymeric immunoglobulins[15].
The production of intestinal polyamines induced and stimulated by S.boulardii is one of its most relevant and specific mechanisms of action.The polyamines spermidine, spermine,and putrescine enhance the expression of brush border enzymes(such as hydrolases,proteases,and transport molecules)[18].
In pigs with a reduced gastrointestinal flora because of administrations of antibiotics,S.boulardii restores normal levels of colonic short chain fatty acids(SCFA)[12].A similar effect was shown in patients on total parenteral nutrition.SCFAs are important metabolites produced by the anaerobic flora and are relevant for colonic absorption of water and electrolytes[77].These effects may be especially relevant in the management of antibiotic-associated diarrhea.
The antisecretory effect of S.boulardii may be related to the capacity to modulate the nitrogen oxide pathway through the inhibition of the iNOS[49].
Anti-inflammatory and immunological effect
The innate immune system is the first line of defense against microbial aggression.Probiotics decrease inflam-mation by exerting positive effects on the epithelial cell and mucosal immune system dysfunctions that constitute the basis of the inflammatory processes.Peptoglycans, lipopolysaccharides,and lipotheichoic acid,which are present in bacteria,and phospholipomannan,phosphope-tidomannan,and glycan,which are present in yeast,are all pathogen-associated molecular pattern antigens and are recognized by different pattern-recognition receptors and thus may account for different responses to these microorganisms[59].
Some experiments suggest that probiotics may decrease gastrointestinal inflammation through their effects on enter-ocyte functions,including barrier function,cytokine secre-tion,and their antibacterial effects related to the colonization of the epithelial layer[30].In addition,there are emerging data suggesting that probiotics stimulate regulatory T cells and thus inhibit the effector T cells that would otherwise induce inflammation[37].
S.boulardii inhibits MAP kinase and NF-κB signal transduction pathways and decreases the secretion of the proinflammatory cytokine IL-8.S.boulardii also secretes a small(<1kDa)heat-stable and water-soluble anti-inflam-matory factor termed S.boulardii anti-inflammatory factor that inhibits the NF-κB-dependent signaling pathway in the presence of C.difficile toxin[78](Fig.5).
S.boulardii also decreases enterocyte apoptosis,proba-bly as a result of the decrease of the synthesis of TNFα[33].
Probiotic administration does lead to the increased elaboration of regulatory cytokines,and these play a major role in their protective effects.It seems likely that probiotics bring about these effects through their interactions with mucosal dendritic cells which produce regulatory cytokines or induce T cells with these capabilities.It has been recently postulated that S.boulardii inhibits dendritic cell-induced activation of na?ve T cells[6].It also modifies the migration of lymphocytes in a model of chronic IBD[34].Recent research demonstrated that the supernatant of S.
boulardii Fig.4Changes in mucosal spe-
cific activity of sucrase,lactase,
and maltase after14days of oral
treatment with S.boulardii
(seven volunteers).The values
are mean±SE,*p<0.05(Wil-
coxon matched-pairs signed-
ranks test)[16]
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cultures modifies the capacity of lymphocytes to adhere to endothelial cells,leading to improved cell rolling and adhesion [34].
Recent experimental studies have confirmed the anti-inflammatory properties of S.boulardii using different models of inflammation (C.albicans [60]or Citrobacter rodentium -infected mice [90]or S.flexneri -infected T84cells [69]).
There is a very clear and marked stimulation of IgA production as demonstrated by the increased content in the intestinal lumen and in crypt cells.This may be explained by a trophic effect exerted on the mucosa or by direct immunostimulation [15](Fig.6).
Clinical applications of S.boulardii Introduction
An increasing number of potential health benefits are being attributed to probiotic treatments [1,80].However,only a limited number have been confirmed in well-designed and conducted randomized controlled trials (RCTs)and even less in the pediatric population.Antibiotic-associated diarrhea
Antibiotic-associated diarrhea (AAD)is defined as other-wise unexplained diarrhea that occurs in association with the administration of antibiotics [4]The bacterial agent most commonly associated with AAD is C.difficile [3].Almost all antibiotics,particularly those that act on anae-robes,can cause diarrhea,but the risk is higher with the aminopenicillins,the combination of aminopenicillins and clavulanate,the cephalosporins,and clindamycin [2,67].AAD occurs in approximately 5–30%of patients between the initiation of therapy and up to 2months after the end of
treatment [68,89].The incidence of diarrhea in children receiving broad-spectrum antibiotics ranges from 11%to 40%[84,42].Measures to prevent AAD include the use of probiotics.
S.boulardii for the prevention of AAD
We found three RCTs [7,43,62]aimed at determining whether S.boulardii prevents AAD in children (Table 1).In the first trial [62],269children (age,6months to 14years)with otitis media and/or respiratory tract infections were enrolled in a double-blind (DB),randomized placebo-controlled trial in which they received standard antibiotic treatment plus 250mg of S.boulardii (experimental group,n =132)or a placebo (control group,n =137)orally twice daily for the duration of the antibiotic treatment.Analyses were based on the treatment allocated and included data from 246children.Patients receiving S.boulardii had a lower prevalence of diarrhea (≥3loose or watery stools/day for ≥48h,occurring during or up to 2weeks after the antibiotic therapy)than those receiving the placebo (9/119[7.5%]vs 29/127[23%];relative risk,RR 0.3;95%confidence interval,CI 0.2–0.7).S.boulardii also reduced the risk of AAD (diarrhea caused by C.difficile or unexplained diarrhea)compared with placebo (4/119[3.4%]vs 22/127[17.3%];RR 0.2;95%CI 0.07–0.5).No adverse events were observed.The risk of C.difficile diarrhea was lower in the group receiving S.boulardii .The second trial was conducted in Turkey [43].In this controlled clinical trial,S.boulardii (250mg/day)was compared to no treatment in 466children 1to 5years of age treated with sulbactam-ampicillin or azi-thromycin.Children in the S.boulardii group had a reduced risk of diarrhea defined as ≥3watery stools on any day of antibiotic treatment (14/224vs 42/222;
RR
Inflammation
Cytoplasm
Nucleus
Gene expression of
IL 8
NF-κB
NF-κB
S.b.
B α
Soluble Anti-Inflammatory F actor
Fig.5S.boulardii inhibits NF-κB inflammation pathway through the secretion of a soluble anti-inflammatory factor (adapted from Sougioultzis et al.[78])
INTESTINAL MUCOSA
DUODENAL FLUID
S C ( g .g m u c o s a -1)(m e a n ± S E )
s I g A (n g .m g p r o t e i n -1)(m e a n ± S E )
Controls (n=16)Treated (n=15)
p<0.05p<0.01
μFig.6Stimulation of IgA and Secretory component by S.boulardii [15]
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0.3;95%CI 0.2to 0.5;number needed to treat [NNT]8,95%CI 6to 14).
C.difficile -associated diarrhea
All randomized placebo-controlled studies evaluating C.difficile infection-associated diarrhea were performed in adults.There are only very limited data from one small observational trial in children suggesting that S.boulardii may be effective in C.difficile -associated enteropathies [17].
In summary,the evidence from several prospective controlled trials shows that S.boulardii is effective in preventing AAD in children.The likely advantages of co-administration of the yeast with antibiotics include ease of administration and potential cost/benefits.
Future trials should address the efficacy of S.boulardii in preventing AAD caused specifically by C.difficile in children or those antibiotics that are most likely to cause diarrhea,as well as the effectiveness of S.boulardii in treating AAD in children.Acute diarrhea
Diarrhea is defined as a change in bowel movements in an individual with an increase in the water content,volume,and —usually —frequency of stools [73,88].In the vast majority of cases,acute diarrhea is the result of a gut infection —mostly viral in the developed countries.The mainstay of therapy for dehydrating gastroenteritis is oral rehydration.However,water and electrolyte replacement does not result in substantial shortenings of the diarrheal episodes nor in reductions in stool volume,prompting a growing interest in adjunctive treatments.S.boulardii for the treatment of acute diarrhea
One meta-analysis aimed at evaluating the effectiveness of S.boulardii in treating acute infectious diarrhea in children [81].The following electronic databases were searched through August 2006for studies relevant to acute infectious diarrhea and S.boulardii :MEDLINE,EMBASE,CINAHL,and The Cochrane Library;additional references were obtained from reviewed articles.Data from five RCTs [10,27,54,63,86](619participants)were included (Table 2).Combined data from four RCTs showed that S.boulardii significantly reduced the duration of diarrhea compared with the control.The pooled weighted mean difference was ?1.1days (95%CI ?1.3to ?0.8)with a fixed model and remained significant in a random-effect model.S.boulardii significantly reduced the risk of diarrhea on days 3,6,and 7.In addition,the risk of diarrhea lasting >7days was
T a b l e 1C h a r a c t e r i s t i c s o f r a n d o m i z e d c o n t r o l l e d t r i a l s e v a l u a t i n g t h e e f f e c t o f S .b o u l a r d i i i n t h e p r e v e n t i o n o f a n t i b i o t i c -a s s o c i a t e d d i a r r h e a
A u t h o r [r e f ]
A l l o c a t i o n c o n c e a l m e n t
B l i n d i n g I T T F U N u m b e r (e x p e r i m e n t a l /c o n t r o l )A g e (y e a r s )S B D o s e (p e r d a y )
C o n t r o l g r o u p
D u r a t i o n o f i n t e r v e n t i o n F o l l o w -u p
A n t i b i o t i c s t u d i e d
D e f i n i t i o n A A D
N u m b e r o f p a t i e n t s w i t h A A D
S B
C o n t r o l
K o t o w s k a [62]
U n c l e a r
D B
Y e s Y e s
119/127
6m o –14y e a r s
500m g P l a c e b o F o r t h e d u r a t i o n o f a n t i b i o t i c t r e a t m e n t (e x p e r i m e n t a l g r o u p 7.8±1d a y ;c o n t r o l g r o u p 8.1±1d a y )2w e e k s V a r i o u s
D i a r r h e a :≥3l o o s e o r w a t e r y s t o o l s p e r d a y f o r a m i n i m u m o f 48h d u r i n g a n d /o r u p t o 2w e e k s a f t e r t h e e n d o f a n t i b i o t i c t r e a t m e n t 4/119(3.36%)22/127(17.32%)B e n h a m o u [7]
U n c l e a r D B
N o
163/779
327/289
1–5y e a r s 4.5b i l l i o n C F U /d a y D i o s m e c t i t e 6g /d a y (1–2y e a r s ),9g /d a y (>2y e a r s )?
L e n g t h o f a n t i b i o t i c i n t e r v e n t i o n
N o t s p e c i f i e d >3l i q u i d s t o o l s /d a y 25/327(7.6%)16/289(5.5%)
E r d e v e [43]
I n a d e q u a t e
N o N o
187/653
224/222
1–15y e a r s 5b i l l i o n C F U /d a y
N o t r e a t m e n t ?N o t s p e c i f i e d S a l b a c t a m -a m p i c i l l i n ,a z i t h r o m y c i n
≥3w a t e r y s t o o l s o n a n y d a y o f a n t i b i o t i c t r e a t m e n t 14/224(5.7%)
42/222(18.9%)
I T T i n t e n t i o n -t o -t r e a t a n a l y s i s ,F U c o m p l e t e n e s s o f f o l l o w u p ,D B d o u b l e -b l i n d ,S B S .b o u l a r d i i
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T a b l e 2C h a r a c t e r i s t i c s o f r a n d o m i z e d c o n t r o l l e d t r i a l s e v a l u a t i n g t h e e f f e c t o f S .b o u l a r d i i i n t h e t r e a t m e n t o f a c u t e d i a r r h e a (a d a p t e d f r o m S z a j e w s k a e t a l .[81])
A u t h o r (r e f )A l l o c a t i o n c o n c e a l m e n t 1
B l i n d i n g I T T F U (%)
N u m b e r (e x p e r i m e n t a l /c o n t r o l )
I n c l u s i o n c r i t e r i a A g e D o s e (p e r d a y )D u r a t i o n o f i n t e r v e n t i o n D e f i n i t i o n o f t e r m i n a t i o n o f d i a r r h e a E t i o l o g y o f d i a r r h e a
B i l l o o
[10]
U n c l e a r N o Y e s 100
50/50A c u t e d i a r r h e a m i l d t o m o d e r a t e s e v e r i t y 2m o n t h s –12y e a r s 500m g 5d a y s N o t r e p o r t e d
H R V 18%B a c t e r i a 19%
C e t i n a -S a u r i [27]U n c l e a r Y e s
Y e s 100b 65/65A c u t e n o n b l o o d y d i a r r h e a 3–36m o
600m g 4d a y s
E f f i c a c y :<4s t o o l s i n 24h a n d a b s e n c e o f l i q u i d s t o o l s N o d a t a
H a f e e z [54]
I n a d e q u a t e N o N o a 9351/50A c u t e w a t e r y d i a r r h e a m i l d t o m o d e r a t e s e v e r i t y
6m o n t h s –5y e a r s 500m g 6d a y s
N o t r e p o r t e d
N o d a t a
K u r u g o l [63]
N o t r e p o r t e d Y e s
N o a 86100/100
A c u t e d i a r r h e a (l i q u i d o r m u c o u s o r b l o o d y s t o o l s p a s s e d a t l e a s t t w i c e a s f r e q u e n t l y t h a n u s u a l f o r a m i n i m u m o f 24h b e f o r e a d m i s s i o n b u t n o t l o n g e r t h a n 7d a y s )3m o n t h s –7y e a r s
250m g 5d a y s (f o l l o w u p 14d a y s )T i m e f r o m t h e s t a r t o f t h e t r e a t m e n t u n t i l t h e a p p e a r a n c e o f t h e f i r s t n o r m a l s t o o l s
H R V 41.5%B a c t e r i a /p a r a s i t e s 10%U n s p e c i f i e d 48.5%V i l l a r r u e l [86]
A d e q u a t e Y e s
N o a 8844/44A c u t e m i l d t o m o d e r a t e d i a r r h e a ≥3l i q u i d o r l o o s e s t o o l s i n t h e l a s t 24,b u t <7d a y s d u r a t i o n ,o u t p a t i e n t s
3–24m o n t h s <1y e a r s 250m g >1y e a r 500m g
6d a y s N o t r e p o r t e d
N o d a t a
I T T ,i n t e n t i o n -t o -t r e a t a n a l y s i s F U ,c o m p l e t e n e s s o f f o l l o w u p ,H R V h u m a n r o t a v i r u s a
A v a i l a b l e c a s e a n a l y s i s (a s s e s s e d b y t h e r e v i e w e r s )b U n c l e a r h o w m a n y p a r t i c i p a n t s w e r e r a n d o m i z e d a t t h e s t a r t o f t h e s t u d y
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significantly reduced in the S.boulardii group vs control group(one RCT,n=88;RR0.25;95%CI0.08–0.83;NNT 5,95%CI3–20).Thus,this meta-analysis of data from RCTs showed that,in otherwise healthy infants and children with acute infectious gastroenteritis,the use of S. boulardii compared with a control treatment is associated with a moderate therapeutic benefit that is reproducible regardless of the outcome measure studied(i.e.,duration of diarrhea,chance of cure or risk of diarrhea at certain point intervals,number of stools,and length of hospital stay) (Tables2,3,Fig.7).
More recently,Italian investigators conducted a multi-center,randomized,clinical trial[23].The study aimed at comparing the efficacy of five probiotic preparations (including S.boulardii)in children aged3–36months, randomly assigned to receive either an oral rehydration solution(ORS)alone(control group)or the ORS plus one of five probiotic preparations(Lactobacillus rhamnosus strain GG;S.boulardii;Bacillus clausii;mix of Lactoba-cillus delbrueckii var bulgaricus,Streptococcus thermophi-lus,Lactobacillus acidophilus,and Bifidobacterium bifidum;or Enterococcus faecium SF68).Five hundred seventy-one children were allocated to the intervention groups.The mean duration of the treatment with ORS alone was115.5h.There was no difference between S.boulardii and the control group.However,this study is not without limitations,the main being the absence of blinding.This,as well as several other factors(European trial,ambulatory care),may contribute to explain why S.boulardii had no effect in this study.
Another recent trial was carried out in Myanmar[58].In this RCT involving100children with acute diarrhea,S. boulardii reduced the duration of diarrhea compared with placebo(3.08±0.95vs4.68±1.23days,respectively).
Given these new data,the previous mentioned meta-analysis was updated.Based on the pooled results of six RCTs involving 756children,S.boulardii,compared to placebo or no intervention,reduced the duration of diarrhea by22h(weight-ed mean difference[WMD]?22,CI?26to?18;Fig.8).
In summary,the findings demonstrate that S.boulardii is effective for treating children with acute gastroenteritis(AGE).
S.boulardii for the prevention of acute diarrhea
One RCT from Pakistan involving100children with acute watery diarrhea reported significant difference in the incidence of episodes of diarrhea in the group receiving S. boulardii compared with the control group during2months follow-up(0.32vs0.56,p=0.04;Fig.9)[10].
Recommendations from professional pediatric societies
Recently,the European Society for Paediatric Gastroenter-ology,Hepatology and Nutrition and European Society of Paediatric Infectious Diseases Expert Working Group addressed the clinical efficacy of probiotics in the manage-ment of acute gastroenteritis[53].It stated that selected probiotics may be an effective adjunct to the management of diarrhea.However,because there is no evidence of efficacy for many preparations,only probiotic strains with proven
Table3Summary of the results on the effectiveness of S.boulardii vs control for the treatment of acute infectious diarrhea(adapted from Szajewska et al.[81])
Comparison or outcome RCT(s)Number Statistical method Effect size NNT(if applicable) Cure On day21130RR4(1.75to9.14)4(3–8)
On day81130RR 1.96(1.4to2.75)3(2–5)
Diarrhea On day31101RR0.71(0.56to0.90)4(3–12)
On day4188RR0.73(0.5to1.05)NS
On day61101RR0.49(0.24to0.99)6(3–98)
On day7188RR0.39(0.20to0.75)4(3–11)
>7days188RR0.25(0.08to0.83)5(3–20)
Number of stools On day11130WMD?0.32(?1.07to0.43)
On day33331WMD?1.25(?1.87to?0.63)
On day42218WMD?1.13(?1.62to?0.64)
On day62201WMD?1.7(?2.38to?1.02)
On day7188WMD?0.90(?1.37to?0.43)
Hospitalization(d)1200WMD?1(?1.38to?0.62)
Duration of vomiting(d)1200WMD?0.1(?0.34to0.14)
If the95%CI for a RR crosses1or for a WMD crosses0,it indicates that there is no statistically significant difference between the experimental and control group—equivalent to p<0.05
RCT randomized controlled trial,RR relative risk,WMD weighted mean difference(negative values indicate that the outcome was shorter(or reduced)in the S.boulardii group than in the control group),NNT number needed to treat,CI confidence interval
Eur J Pediatr
clinical efficacy and in appropriate dosage are recommended as an adjunct for the management of children with AGE to rehydration https://www.360docs.net/doc/6f4854341.html,ctobacillus GG and S.boulardii constituted examples of probiotics that showed benefit.Persistent diarrhea
While most episodes of diarrhea last less than 1week,some children may develop persistent diarrhea.WHO defines this as an episode which starts acutely but which persists for 14days or longer.The main dangers of persistent diarrhea are malnutrition and severe nonintestinal infections [87].The morbidity and mortality of persistent diarrhea and the magnitude of the problem,particularly in the developing world,justify any attempt to improve treatments.
To determine whether treatment with S.boulardii improves outcomes in children with persistent diarrhea,
researchers from Argentina [46]randomized in a double-blind trial 89children (age range 6–24months)to receive pasteurized cow ’s milk supplemented with two viable lyophilized strains Lactobacillus casei and L.acidophilus strains CERELA 1010–1012CFU/g (n =30),or lyophilized S.boulardii 1010–1012CFU/g (n =30),or pasteurized cow ’s milk as placebo (n =29),twice a day for 5days.Enteric pathogens (rotavirus,E.coli ,Salmonella ,Shigella )were isolated from the stools in 40%of the patients,27%had https://www.360docs.net/doc/6f4854341.html,ctobacillus and S.boulardii significantly reduced the number of stools per day (p <0.001)and diarrheal duration (p <0.005).Similarly,both probiotics significantly (p <0.002)reduced vomiting as compared with placebo.There were no differences between treatments depending on rotavirus status.
Another trial was carried out in Cuba [26].Forty children (aged 6to 36months)with diarrhea of 3or 4weeks duration were randomized to receive S.boulardii at a dose of 500mg/day (n =20)or placebo (n =20)for 1month.All patients received either tinidazole for Giardia lamblia (87.5%)or trimetoprim plus sulfamethoxazole for Shigella just prior to the intervention.Both groups had similar baseline characteristics.At the end of the study,the percentage of children with only one to three bowel movements per day was significantly higher in the S.boulardii group compared with the placebo group (65%vs 15%,p =0.002).More patients in the S.boulardii group had a histologically normal mucosa,but the difference was not statistically significant (35%vs 15%,p =0.2).Despite the study ’s limitations (e.g.,small sample size,lack of allocation concealment,no intention to treat analysis),the findings are sufficiently promising in both clinical and economic terms to warrant a larger,more extensive study
RR = 0.25 (0.07 - 0.82)
Placebo
S.b.
2530201510
5
27.2
6.8
Placebo + ORS
S.b.+ ORS
% o f p a t i e n t s
Fig.7S.boulardii decreases the percentage of patients presenting with prolonged diarrhea [86
]
Control
Cl
Cl
Fig.8Summary of the results on the effectiveness of S.boulardii vs control for the treatment of acute infectious diarrhea.Mean duration of diarrhea (hours).Up-date of meta-analysis by Szajewska et al.[81]
Eur J Pediatr
on the effect of S.boulardii for treatment of persistent diarrhea.
In conclusion,these results indicate that S.boulardii is useful in the management of persistent diarrhea in children.However,studies with larger populations are needed to determine whether S.boulardii therapy alone is also effective in children with persistent diarrhea.H.pylori infection
The role of the Gram-negative bacillus H.pylori in the pathogenesis of chronic gastritis and peptic ulcer in adults and children and as a risk factor for gastric malignancy in adults is widely accepted.Several studies have shown that various lactobacilli (e.g.,Lactobacillus johnsonii La1,L.acidophilus CRL 639,L.casei )or their metabolic products inhibit or kill H.pylori in vitro [8,9],suggesting that probiotics may have a place as adjunctive treatment for H.pylori infection.
A recent systematic review evaluated the role of pro-biotics in H.pylori eradication and side effects during treatment of H.pylori infection [83].Fourteen randomized controlled trials (RCT)of various methodological quality involving 1,671patients were identified.In patients with H.pylori infection,probiotic supplementation improved erad-ication rates.In two RCTs that studied patients with previous eradication failure,probiotic supplementation improved eradication rates.Probiotics reduced treatment-related side effects and individual symptoms such as diarrhea,epigastric pain,nausea,and taste disturbances.In this meta-analysis,only one RCT evaluated S.boulardii and found that it decreased the risk of diarrhea when given concomitantly to patients receiving H.pylori triple eradi-cation therapy [38].Subsequently published RCTs carried out in adults also found that S.boulardii supplementation reduced posttreatment dyspepsia independent of H.pylori status.However,S.boulardii had no significant effect on the rate of H.pylori eradication [28].
In pediatric populations,there have been only three RCTs evaluating whether consumption of lactic acid bacteria,i.e.,L.casei DN-114001(one RCT)[79],yogurt containing Bifidobacterium animalis and L.casei (1RCT)[50],and Lactobacillus reuteri ATCC 5573(one RCT)[64]could increase H.pylori eradication and reduce the side effects of treatment,but the results are conflicting [79].S.boulardii plus inulin could hold promise as an adjunctive agent to the triple therapy.This is based on the results on one open RCT [51]evaluating whether consumption of either the combination of S.boulardii plus inulin or of L.acidophilus LB would affect H.pylori eradication in the pediatric population.Two hundred and fifty-four asymp-tomatic children,who were positive for H.pylori infection by the 13C urea breath test,were allocated to one of three groups:(1)an 8-day course of eradication triple therapy with lanzoprazole,amoxicillin,and clarithromycin,(2)L.acidophilus LB,and (3)a synbiotic (S.boulardii plus inulin).H.pylori was eradicated in 66%(30/45),12%(6/51),and 6.5%(3/46)of the children from the antibiotic group,synbiotic group,and probiotic groups,respectively (p <0.001).Although the eradication rate of H.pylori with S.boulardii is low,further studies elucidating the mecha-nisms by which S.boulardii with or without additional inulin may inhibit H.pylori would be of interest.
Safety
No adverse effects were observed in any of the trials.However,the administration of S.boulardii is not without risk.One caveat about S.boulardii is that it can cause fungemia,more specific in patients with central venous lines [5,75,91].Sporadic cases of fungemia have been reported,and these occurred in patients with severe general or intestinal disease who had an indwelling catheter [55].Up to now,almost 100cases of fungemia have been reported [71].However,S.cerevisiae might as well be responsible for a number of these fungemias,since identification of the strain S.boulardii is difficult [36].There is indeed confusion between fungemia with S.boulardii and S.cerevisiae [52].Once the diagnosis is made,fungemia with S.boulardii can effectively be treated with antimycotic medication,although treatment failure with fluconazole has been reported [14].
Chronic stress induces mucosal dysfunction manifested as increased epithelial ion secretion and permeability,enhanced binding of luminal bacteria to the enterocytes,increased uptake of luminal antigens,and mucosal inflam-mation.The incidence of bacterial translocation in burn injury is enhanced by antibiotics,and this is decreased by S.boulardii ,which also decreases the incidence of antibiotic-induced bacterial translocation [57].These effects are
month 01
month 02
0.60.5
0.70.40.30.20.1
0.64
0.26
p = 0.001
0.56
Group ORS
0.32
p = 0.004
Group ORS +S.b.
N u m b e r o f e p i s o d e s o f d i a r r h e a
Fig.9S.boulardii decreases the occurrence of new episodes of diarrhea [10]
Eur J Pediatr
strain-specific since pretreatment with Lactobacillus fer-mentum had no substantial effect on improving gut barrier integrity[65].Translocation of commensal bacteria to the mesenteric lymph nodes is a physiological event.It is possible that,in chronic stress,the increased bacterial translocation results from the decreased clearance of the bacteria in the lamina propria and that probiotics prevent this phenomenon.Translocation was not observed by electron microscopy in rats that were given S.boulardii [48],a well-tolerated and safe probiotic.
The absence of transfer of genetic material between bacteria and yeast is relevant,especially in antibiotic-associated https://www.360docs.net/doc/6f4854341.html,mensal bacteria,even lactobacilli, may act as reservoirs for antibiotic resistance genes similar to those found in pathogens.In other words,these bacteria might transfer their resistance genes to pathogenic bacteria [66,82].
The use of S.boulardii should be carefully assessed in immunosuppressed or critically ill patients[70].However, fungemia with S.boulardii has,to the knowledge of the authors,not been reported in ambulatory care in patients with a normal functioning immune system. Conclusions
S.boulardii mediates pharmacodynamic effects which resemble the protective effects of the normal healthy gut flora.The mechanisms of action of S.boulardii depend mainly on the inhibition of some bacterial toxins,anti-inflammatory effects,and on stimulating effects on the intestinal mucosa such as trophic effects on the brush border enzymes and immunostimulatory effects.
At present,in pediatric populations,there is evidence that S.boulardii is beneficial for the treatment of acute gastroenteritis and the prevention of antibiotic-associated diarrhea.More data are needed for other indications. References
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