Review of the Literature

Role of Probiotics in Pediatric Patients with Helicobacter pylori Infection:A Comprehensive Review of the LiteratureElena Lionetti,*Flavia Indrio,†Lorenzo Pavone,*Giorgia Borrelli,†Luciano Cavallo†andRuggiero Francavilla†*Department of Paediatrics,University of Catania,Catania,Italy,†Department of Paediatrics,University of Bari,Bari,ItalyHelicobacter pyloriDespite the fact that Helicobacter pylori was discov-ered more than25years ago and that the Nobel Prize in Medicine or Physiology was awarded to Marshall and Warren few years ago,H.pylori infection is still a challenging subject for many researchers and physicians especially when it deals with treatment.It is well known that childhood is an important period for acquisition of H.pylori infection although several recent articles have reported a decline in the prevalence of H.pylori infection in children over the last10years[1].Intrafamiliar transmission of the infection,especially from mother to child,has been hypothesized as the major mode of dissemination[2]. Poor socioeconomic conditions remain a significant risk factor for infection,while exclusive breast-feeding (longer than4months)and higher socioeconomic status have been reported as protective factors for the infection[3].H.pylori is considered to be the major cause of chronic gastritis and duodenal ulcer in childhood and an important cofactor in the development of gastric cancer[4].Indeed this bacterium is able to influence gastric cell proliferation and apoptosis[5]and to increase the biosynthesis of polyamine[6].Treatment studies on children are limited by the small number of infected children in each individual center and a recent publication of the PERTH study shows that27different treatment regimens were used in22different European pediatric hospitals[7].The Maastricht III Consensus Report recommends,asfirst choice treatment,a triple therapy using a proton pump inhibitor(PPI)with clarithromycin and amoxicillin or metronidazole given twice daily for7–14days[8].This regimens have the disadvantages of being expensive,KeywordsChildren,Helicobacter pylori,probiotics, therapy.Reprint requests to:Elena Lionetti,MD, Department of Paediatrics,University of Catania,Via S.Sofia,78,95125–Catania,Italy. E-mail:elenalionetti@inwind.it AbstractBackground:The current guidelines suggest the use of triple therapy asfirst choice treatment of Helicobacter pylori infection,although the eradication failure rate is more than30%.Current interest in probiotics as therapeutic agents against H.pylori is stimulated not only by the clinical data showing efficacy of some probiotics in different gastrointestinal diseases but also by the increasing resistance of pathogenic bacteria to antibiotics,thus the interest for alternative therapies is a real actual topic.Aim:To review in vitro and in vivo studies on the role of probiotics in H.pylori infection focusing on the paediatric literature.Materials and methods:Pre-clinical and clinical paediatric studies in English assessing the role of probiotics in H.pylori infection identified by MEDLINE search(1950–2009)were reviewed.Results:In vitro studies demonstrated an inhibitory activity of probiotics on H.pylori growth and that this effect is extremely strain specific.Available data in children indicate that probiotics seems to be efficacious for the prevention of antibiotic associated side-effects,and might be of help for the prevention of H.pylori complications by decreasing H.pylori density and gastritis,and for the prevention of H.pylori colonization or re-infection by inhibiting adhesion to gastric epithelial cells.There is no clear evidence that probiotics may increase the H.pylori eradication rate.Conclusion:Both in vitro and in vivo studies provide evidence that probio-tics may represent a novel approach to the management of H.pylori infection.Helicobacter ISSN1523-5378risking poor compliance,causing side-effects and in particular encouraging resistance emergence,both in H.pylori and commensal organisms exposed gratu-itously[9].Moreover,as most of the colonized children remain asymptomatic the administration of antibiotic treatments is not ethically acceptable.Other factors limiting the administration of such treatments in devel-oping countries is their high cost for the families from the low socioeconomic stratum(the most affected by the infection)and the relative inefficiency of the anti-biotics due to the fact that,when treated,children tend to be rapidly re-colonized[3].Therefore,recent review studies report eradication rates of standard triple therapy in children below75% [7,10].Our group reported that a novel10-day sequen-tial treatment consisting of omeprazole plus amoxicillin for5days followed by omeprazole,clarithromycin and tinidazole for the next5days,was highly efficacious in eradicating H.pylori infection in children[11]. Nowadays,there is considerable interest in alternative therapies(e.g.targeting urease,a known virulence factor)or adjunctive treatment against H.pylori[12]to reduce some of the drawbacks associated with the anti-biotic consumption.To these aims,probiotics have been included as‘‘possible’’tools for management of the infection[13]and a considerable amount of reports have currently been carried out on their possible role in the treatment and prophylaxis of H.pylori infections. ProbioticsAccording to the currently adopted definition by FAO⁄WHO,probiotics are:‘‘Live microorganisms which when administered in adequate amounts confer a health bene-fit on the host’’[14].Several controlled clinical trials have shown in children beneficial outcomes for the use of probiotics in some different conditions as rotavirus infections,antibiotic-associated diarrhea,irritable bowel syndrome and inflammatory bowel disease[15–17]. Microorganisms most commonly used in clinical prac-tice are lactic acid-producing bacteria such as Lacto-bacillus spp,and microorganisms belonging to genus Bifidobacterium and Bacillus.Other less commonly used probiotic microorganisms are strains of Streptococcus, Escherichia coli,and Saccharomyces[16].Different biologic effects have been described for probiotics,including the synthesis of antimicrobial substances as lactic acid, hydrogen peroxide and bacteriocins,the competitive interaction with pathogens for microbial adhesion sites, andfinally the modulation of the immune response of the host[18,19].Research efforts into the clinical effects of probiotics in man are increasing rapidly.Afield in which particular interest is arising represents the H.pylori infection.Pre-clinical StudiesProbiotics and H.pylori InhibitionSeveral in vitro studies have shown that various lacto-bacilli can inhibit H.pylori growth.Strains with this ability include Lactobacillus acidophilus:L.acidophilus strain CRL639[20],L.acidophilus in a liophilized culture (Lactisyn)[21],L.acidophilus LB[22],L.acidophilus strain NAS and DDS-1[23];L.casei rhamnosus dairy starter[24]; L.johnsonii La1[25];L.salivarius WB1004[26].Lacto-bacilli are known to produce by catabolism relatively large amounts of lactate,and this has been considered as the inhibitory and⁄or the bactericidal factor by some authors[24,27].Indeed,lactic acid could inhibit the H.pylori urease[28]and in addition could exert its anti-microbial effect resulting from the lowering of the pH, although in opposition with this hypothesis it has been recently shown that lactic acid released by gastric mucosa enhances the growth of H.pylori[29].Other authors have clearly shown that for some strains a substance other than lactate also contributes to the antibacterial effects[20,22,25,30–32].In detail,Lorca et al.[20] showed that L.acidophilus CRL639may exert its anti-H.pylori action through the secretion of an autolysin,a proteinaceous compound released after cell lysis.In-vitro studies have demonstrated that L.reuteri ATCC55730 exert a significant inhibitory effect on H.pylori growth [30].A substance named reuterina is responsible for this effect.The probiotic strain Bacillus subitilis3has also been shown to inhibit the growth of H.pylori by the secretion of bacteriocins similar to anticoumacins,belonging to isocoumarin group of antibiotics[31].Other probiotic bacteria,such as L.acidophilus LB[22],L.casei strain Shirota[32],and L.johnsonii La1[25]were shown to exert an inhibitory effect on H.pylori by a lactic acid-and pH-independent mechanism.However,the exact nature of antimicrobial substances secreted by these strains remains to be determined.Probiotics and H.pylori Adhesion to Gastric Cells Some probiotic strains such as L.reuteri[33]or Weissella confusa[34]can inhibit H.pylori growth by competing with adhesion sites.H.pylori can bind tightly to epithe-lial cells via multiple bacterial surface components[35]. There is increasing evidence in animal models that this adhesion is relevant in determining outcome in H.pylori-associated disease[36].In this context,a study from Mukai et al.is particularly interesting[33].Probiotics in H.pylori Infection Lionetti et al.These investigators showed that two of nine L.reuteri strains,JCM1081and TM105,were able to bind to asialo-GM1and sulphatide and to inhibit binding of H.pylori to both glycolipids.Also W.confusa strain PL9001,was shown to inhibit the binding of H.pylori to the human gastric cell line MKN-45[34].These results suggest that selected probiotics strains could be of help in preventing the infection in an early stage of coloni-zation of the gastric mucosa by H.pylori[36].A pro-biotic that shares glycolipid-binding specificity with H.pylori may compete with pathogens for the receptor site making it possible to hypothesize a future applica-tion as anti-adhesion drugs[37].We have recently shown that,two years after H.pylori eradication,30% of children became reinfected[38]therefore the possi-bility to reduce this phenomenon by the simple admin-istration of a probiotic is fascinating.Probiotics and the Mucosal BarrierH.pylori is known to suppress MUCI and MUC5A gene expression in a human gastric cell line[39].In vitro studies have shown that L.plantarum strain299v and L.rhamnosus GG increase the expression of MUC2and MUC3genes[40]and the subsequent extracellular secretion of mucin by colon cell cultures[41].This prop-erty can mediate the ability of these strains to restore the mucosal permeability of gastric mucosa or inhibit the adherence of pathogenic bacteria,including H.pylori [28].Pantoflikova et al.have shown a significant increase of mucus thickness after long-term probiotic intake(L.jonhsonii Lj1)both in antrum and corpus[42]. Probiotics and the ImmunomodulationThe inflammatory response to H.pylori cause an increase of IL8leading to release of TNF a and IL1–6that stimulate CD4+cells to produce IFN c and IL4,-5,-6 that leads to gastric inflammation[43].Probiotics could modify the immune response of the host[28].L.salivarius WB1004has shown in vitro to reduce IL-8secretion by gastric epithelial cells[27]and in animal studies certain lactic acid bacteria(L.casei, L.acidophilus,L.rhamnosus,L.delbrueckii subsp.bulgaricus, L.plantarum,Lactococcus lactis and Streptococcus thermophi-lus)were been able to increase the number of IgA pro-ducing cells associated to the lamina propria of small intestine[44].However,the specific interaction of pro-biotics with the immune system and the mechanism by which they can exert a beneficial effect are still unclear; moreover,the immunoadjuvant capacity observed would be a property of the strain assayed and can not be generalized to genus or species.The reduction of inflammation has been demon-strated directly on gastric biopsies by Pantoflikova et al.[42]and indirectly by the decrease of serum gastrin-17 in H.pylori infected patients after probiotic dietetic supplementation[45](L.jonhsonii Lj1and L.rhamnosus GG,L.rhamnosus LC705,Propionibacterium freudenreichii JS,Bifidobacterium lactis Bb12,respectively).Recent studies have defined potentially new probiot-ic strains of L.reuteri,a small minority of which showed strong anti-inflammatory combined with anti-pathogen effects.L.reuteri ATCC PTA6475produces and exports substances that can interfere with TNF a production in human macrophages[46]and sup-presses NFKB activation affecting apoptosis[47]whilst still retaining its basic anti-pathogen activity during both planktonic and biofilm growth[48].Initial human studies on this strain in our clinic show good safety and tolerance(personal data).Clinical studies on a combination of the anti-inflammatory effects of this strain with the earlier known anti-H.pylori effect of L.reuteri DSM17938is currently under investigation.Clinical StudiesProbiotics and H.pylori-Induced Gastritis in Man On the basis of the above mentioned results,three stud-ies in adults directly assessed the effect of the adminis-tration of probiotics on H.pylori gastritis by the histological examination of gastric biopsies showing that L.johnsonii La1[42,49]and L.acidophilus La5and ctis Bb12contained in the yogurt[50]resulted effective in both reducing the density of H.pylori colonization,and the gastric mucosal inflammation.No study has been performed in children to explore this issue.Probiotics Alone and H.pylori Loads:13C-Urea Breath TestIn most adult studies,the effect of probiotic treatment on the level of H.pylori infection has been estimated indirectly by the13C-urea breath test(13C-UBT)delta over baseline value,a well known semi quantitative measurement of the bacterial load[51].In detail subjects treated either with L.johnsonii La1[25,52], L.brevis CD2lyophilized bacteria[53],yogurts contain-ing L.acidophilus La5and ctis Bb12[50],L.gasseri OLL2716[54],a milk containing B.bifidum BF-1[55], a drink consisting of equal doses of L.rhamnosus GG, L.rhamnosus LC705,P.freudenreichii JS and ctis Bb12[45],or with L.reuteri ATCC55730[56]showed a significant decrease in13C-UBT values.Lionetti et al.Probiotics in H.pylori InfectionIn children,two studies have been performed(by the same investigators)to evaluate the ability of probiotics to interfere with the intragastric bacterial load (see Table1).First,Cruchet et al.performed a random-ized,double blind,controlled study on326asymptom-atic children screened for H.pylori by the13C-UBT[57];H.pylori-colonized subjects were distributed intofive groups to receive a product containing live L.johnsonii La1or L.paracasei ST11,heat-killed La1or L.paracasei ST11,or just vehicle everyday for4weeks.A second 13C-UBT was carried out at the end of this period.The authors detected a moderate but significant difference in13C-UBT values in children receiving live La1()7.64 per thousand;95%CI:)14.23to)1.03),whereas no differences were observed in the other groups.Subse-quently,in a randomized open trial,Gotteland et al.[58]randomized182asymptomatic H.pylori-positive children to receive either7-day triple therapy,or Saccharomyces boulardii as a symbiotic simultaneously with inulin or L.acidophilus LB daily for8weeks.An additional81asymptomatic H.pylori-positive children were followed for8weeks without any treatment.A significant decrease in13C-UBT values(repeated after 8weeks)was observed in the antibiotic group ()26.6%;95%CI:)33.9to)19.3%)and in the S.boulardii group()6.31;95%CI:)11.84to)0.79)but not in the L.acidophilus LB group(+0.70;95%CI: )5.84to+7.24).No changes in13C-UBT values were observed in untreated children.These results suggest that anti-H.pylori activity is species and strain specific, with some probiotics,such as S.boulardii and L.johnso-nii La1,interfering with H.pylori in vivo more actively than others(L.acidophilus LB,L.paracasei ST11).This ability of some probiotics strains may represent an interesting alternative to modulate H.pylori coloni-zation in children infected by this pathogen through a regular ingestion of the beneficial microorganisms.No studies in adults have been able to demonstrate the eradication of H.pylori infection by probiotic treat-ment.In children two studies evaluated whether pro-biotics may eradicate alone the H.pylori infection.Gotteland et al.showed that H.pylori eradication was successful in66%of children treated with antibiotic,in 12%of the S.boulardii plus inulin and in 6.5%of L.acidophilus LB group(v2=51.1,p<.001);no sponta-neous clearance was observed in children without treat-ment[58].The fact that the13C-UBT was carried out immediately after treatment(in the case of probiotic supplementation)limits the conclusion on a real eradi-cation of the bacterium.A further multicentre random-ized,controlled,double-blind trial has been recently carried out in295asymptomatic H.pylori positive children[59].Subjects have been allocated into four groups to receive one of the following dietary treat-ments daily for3weeks:cranberry juice and La1 (CB⁄La1),placebo juice and La1(La1),cranberry juice and heat-killed La1(CB),or placebo juice and heat-killed La1(control).After treatment H.pylori eradica-tion rates significantly differed in the four groups:1.5% in the control group compared with14.9,16.9,and 22.9%in the La1,CB,and CB⁄La1groups,respectively (p<.01);the latter group showed the highest eradica-tion rate.However,a third13C-UBT performed after a 1-month washout showed a recrudescence of the infection in80%of those children who had resulted negative,suggesting just a temporary inhibition of H.pylori that disappeared once the administration of the inhibiting factors was interrupted[59].Probiotics Plus Antibiotic Treatment and H.pylori Eradication RateIt has been suggested that the use of probiotics as an adjuvant to eradicating regimens could improve the success of H.pylori eradication.Several clinical trials have been carried out both in adults and children,pro-viding conflicting results[60–77].Overall,in adults three studies[60,64,74]reported significantly improved eradication rates,the remaining10showing no improvement[61–63,65–69,71–73,75].Table2summarizes the clinical trials performed in children on the effect of probiotics on H.pyloriTable1Summary of clinical trials of probiotics in Helicobacter pylori infection in children:effects on breath test values Reference and type of study Type of patient Number of children Regimen ResultsCruchet et al.,2003 [57];DB,R,P Asymptomatic326screened,252randomizedL.johnsonii La1or L.paracaseiST11for4wksBreath test values reducedin the La1group aGotteland et al.,2005 [58];O,R,C Asymptomatic254screened,182randomizedSaccharomyces boulardii plusinulin(SbI)or L.acidophilusLB for8weeksBreath test valuesreduced in theSbI group aa Statistically significant(p<.05)vs controls.DB,double-blind;R,randomized;P,placebo controlled;O,open;C,controlled.Probiotics in H.pylori Infection Lionetti et al.eradication rates.Sykora et al.supplemented a standard triple therapy with a fermented milk containing L.casei DN-114001for14days in86H.pylori positive patients and showed a significantly higher eradication rate in the probiotic as compared to the placebo group(84.6vs 57.5%;p=.0045)[70].Hurduc et al.demonstrated that the addition of S.boulardii to a standard triple therapy in90symptomatic children confers a12% nonsignificant enhanced therapeutic benefit on H.pylori eradication(93.3vs80.9%;p=NS)[76].In contrast, Goldman et al.tested the efficacy of a commercial yogurt containing B.animalis and L.casei as an adjuvant to triple therapy in65children and found no difference in H.pylori eradication rates between probiotic and placebo group(45.5vs37.5%;p=NS)[71].In a study of our group,aimed to evaluate the efficacy of pro-biotics to reduce antibiotic side effects,we found no differences in the eradication rates according to the presence⁄absence of the probiotic:treatment was suc-cessful in17of20patients supplemented with L.reuteri ATCC55730(SD2112)as compared to16of20patients in the placebo group(85vs80%;p=NS)[72]. Recently,in a double-blind placebo-controlled random-ized clinical trial performed in66children no difference was found with respect to H.pylori eradication rates between children receiving standard triple therapy supplemented with L.rhamnosus GG or placebo(69vs 68%;p=NS)[77].Pooled data,derived from children and adults’studies on more than1900treated patients,show eradication rates of82.5%(95%CI:80.1–84.7%)in patients with probiotic supplementation as compared to73.7% (95%CI:71–76.4%)in patients receiving placebo(RR: 1.11;95%CI:1.07–1.17).These data do not represent convincing evidence to support the use of probiotics as an adjunct with the aim of increasing the H.pylori erad-ication rate.Nevertheless,further studies are needed to clarify their role in this particular issue.The major limit to establish whether a probiotic is able to significantly increase the eradication rate is represented by the power of the study.Indeed,due to the high eradication rates that we mostly achieve with standard antibiotic treatment,to detect a10%increase in eradication(sec-ondary to the use of a probiotic strain),given a power of al least80%and an alpha error level of5%,150 patients in each arm are needed to be enrolled. Probiotics and H.pylori-Related Dyspeptic SymptomsIn our own experience on40adults,we were able to demonstrate a favorable effect of L.reuteri ATCC55730 (SD2112)on dyspeptic symptoms induced by H.pylori [56].In this study,L.reuteri administration was followed by a significant decrease in the Gastrointesti-nal Symptom Rating Scale(GSRS)as compared to pre-treatment value(7.9±4.1vs11.8±8.5;p<.05)that was not observed in patients receiving placebo (9.7±8.7vs11.4±9.7;p<NS)[56].Not all probiotic strains are able do decrease dyspeptic symptoms[53] suggesting that the effect is strain specific.No data are available in the pediatric age.Probiotics and Antibiotic-Associated Gastrointestinal Side Effects During H.pylori Eradication TherapyBacterial resistance and antibiotic’side-effects represent the most frequent cause for anti-H.pylori treatment failure in clinical practice[9].Table2Summary of clinical trials of probiotics in Helicobacter pylori infection in children:effects on eradication ratesReference and typeof study Eradication therapy Probiotic regimen Eradication rate inprobiotics groupEradication ratein control group RRSykora et al.,2005 [70];DB,R,P Omeprazole,amoxicillin,clarithromycin for1weekL.casei DN-114001for14days33⁄39(84.6%)a27⁄47(57.4%) 1.47Goldman et al.,2006 [71];DB,R,P Omeprazole+,amoxicillin+,clarithromycin for1weekB.animalis+L.caseifor3months15⁄33(45.4%)12⁄32(37.5%) 1.21Lionetti et al.,2006 [72];DB,R,P Omeprazole,amoxicillin,clarithormycin,tinidazole(sequential therapy)for10daysL.reuteri ATCC55730for20days17⁄20(85%)16⁄20(80%) 1.06Hurduc et al.,2009 [76];O,R,P Omeprazole,amoxicillin,clarithromycin for1weekSaccharomyces boulardiifor4weeks45⁄48(93.7%)34⁄42(80.9%) 1.15Szajewska et al.,2009 [77];DB,R,P Omeprazole,amoxicillin,clarithromycin for1weekL.rhamnosus GGfor1week23⁄34(67.6%)22⁄32(68.7%)0.98a Statistically significant(p<.05)vs controls.DB,double-blind;R,randomized;P,placebo controlled;O,open.Lionetti et al.Probiotics in H.pylori InfectionSeveral studies evaluated whether probiotic supple-mentation might help to prevent or reduce drug-related side effects during H.pylori eradication therapy in adults [61,63,64,66,68,69,72–75,78–80].All showed that diar-rhea,nausea and taste disturbances were significantly reduced by probiotics and overall they were superior to placebo for side effect prevention.The rationale of coupling a probiotic to any antibiotic treatment stem from the result of a recent study show-ing that daily supplementation with viable probiotic bacteria during and post antibiotic therapy reduces the extent of disruption of the intestinal microbiota as well as the incidence and total numbers of antibiotic-resistant strains in the re-growth population,suggesting that a probiotic should be always associated to an anti-biotic[81].Our group has recently performed thefirst trial in children to determine whether adding probiotics to an anti-H.pylori regimen could be of help to prevent or minimize the gastrointestinal side-effects burden[72] (see Table3).Forty H.pylori-positive children were consecutively treated with10-day sequential therapy, they were blindly randomized to receive either L.reuteri ATCC55730(SD2112)or placebo(maltodextrin)for 20days starting from thefirst day of the anti-H.pylori regimen.Overall,in all probiotic supplemented children as compared to those receiving placebo,there was a sig-nificant reduction in the GSRS score during eradication therapy(4.1±2.0(95%CI:2.9–5.9)vs6.2±3.0(95% CI:5.2–8.3);p<.01)which became markedly evident at the end of follow-up(3.2±2.0(95%CI:2.4–4.0)vs 5.8±3.4(95%CI:4.8–6.9);p<.009).In detail,chil-dren receiving L.reuteri complained of epigastric pain less frequently during eradicating treatment(15vs 45%;p<.04)as well as abdominal distension(0vs 25%;p<.02),belching(5vs35%;p<.04),disorders of defecation(15vs45%;p<.04)and halitosis(5vs 35%;p<.04)thereafter.In a randomized open trial performed in90symp-tomatic H.pylori positive children,the occurrence of antibiotic associated side-effects was significantly reduced by the addition of S.boulardii compared with the placebo supplemented group(8.3vs30.9%; p=.047)[76].However,the authors concluded that it couldn’t be excluded that the incidence and interpreta-tion of side-effects was influenced by the fact that it was an open trial.Finally,in a double-blind placebo-controlled random-ized clinical trial preformed by Szayeska et al.in66 H.pylori positive children the supplementation of standard triple therapy with L.rhamnosus GG did not significantly alter the incidence of antibiotic associated side-effects(52.9vs40.6%;p=NS)[77].Given the results from these studies,probiotic treat-ment seems to be able to reduce H.pylori therapy asso-ciated side-effects;however,it is evident that not all probiotics are created equal,that the beneficial effects are strain specific,and each strain must be evaluated individually.Conclusions and PerspectivesBoth in vitro and in vivo studies provide evidence that probiotics may represent a novel approach to the management of H.pylori infection.Despite the fact that there is no clear evidence that the addition of probiotics to the eradicating therapy increases the eradication rates,it seems to be efficacious for the prevention of antibiotic associated side-effects.Moreover,the persis-tent strains specific ability,although weak in some cases, of some probiotics to decrease H.pylori density and gastritis could be of help in reducing the risk of H.pylori-associated complication later in life[82].Finally,as a perspective it is fascinating the hypothesis of using pro-biotics to inhibiting H.pylori adhesion to gastric epithe-lial cells thus preventing H.pylori colonization especiallyTable3Summary of clinical trials of probiotics in Helicobacter pylori infection in children:effects on antibiotic-associated gastrointestinal side-effectsReference and type of study Type ofpatient Number Eradication therapy Probiotic regimen ResultsLionetti et al.,2006 [72];DB,R,P Dyspeptic40children Omeprazole,amoxicillin,clarithromycin,tinidazolefor10daysL.reuteri ATCC55730for20daysEpigastric pain,abdominaldistension,belching,halitosissignificantly less in PRHurduc et al.,2009 [76];O,R,P Dyspeptic90children Omeprazole+,amoxicillin+,clarithromycin for1weekS.boulardiifor4weeksOverall incidence of side effectssignificantly reduced in PRSzajewska et al.,2009 [77];DB,R,P Dyspeptic66children Omeprazole+,amoxicillin+,clarithromycin for1weekL.rhamnosus GGfor1weekNo significant differencebetween PR and placeboDB,double-blind;R,randomized;P,placebo controlled;O,open;PR,probiotic group.Probiotics in H.pylori Infection Lionetti et al.。