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Inflammation & Allergy - Drug Targets, 2012, 11, 3-14 3A Meta-Analysis and Systematic Review on the Effect of Probiotics inAcute DiarrheaPooneh Salari1, Shekoufeh Nikfar2 and Mohammad Abdollahi*,31Medical Ethics and History of Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran2Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences; and, Food & Drug Laboratory Research Center, Food & Drug Organization, Ministry of Health & Medical Education, Tehran 1314715311, Iran3Faculty of Pharmacy; and Pharmaceutical Sciences Research Center; and Endocrinology & Metabolism ResearchCenter, Tehran University of Medical Sciences, Tehran 1417614411, IranAbstract: Objectives: Diarrhea the second leading cause of death in childhood is caused by a variety of organisms. Rehydration reduces the risk of death but it is not effective in shortening duration of disease. Recently, probiotics have been recommended for prevention or treatment of gastrointestinal disorders including diarrhea. Considering existing documents from different aspects, it seems that results are somehow controversial or non-conclusive. Thus, we aimed to meta-analyze clinical trials to show actual benefit of probiotics in treatment of diarrhea.Methodology: The literature search provided 1228 articles while only 19 articles focusing on the analyses performed on children were eligible to be included in the meta-analysis with a total of 3867 patients enrolled in the study. Studies in adults diarrhea, HIV patients, diarrhea induced by Clostridium difficile, radiation and chemotherapy were also systematically reviewed.Results: The meta-analysis showed that probiotics decrease the duration of diarrhea and fever significantly in children while their effects on the duration of hospitalization, vomiting and number of stools per day were not significant. The results of systematic review on adults diarrhea, amoebiasis, clostridium difficile-associated diarrhea, diarrhea in HIV positive patients, radiation-induced diarrhea, and chemotherapy-induced diarrhea did not support efficacy of probiotics in acute diarrhea.Conclusion: Probiotics may reduce duration of diarrhea and fever in children but their exact efficacy in treatment of diarrhea is not obvious yet.Keywords: Clostridium difficile, diarrhea, meta-analysis, probiotics, systematic review.INTRODUCTIONDiarrhea is considered as one of the most common gastrointestinal (GI) disorders with high economical impact. According to the report of the World Health Organization (WHO), diarrhea is the second leading cause of death in children under 5 years old which kills around 1.5 million every year. Diarrhea is characterized by defecating three or more loose stools per day [1]. Diarrhea can be considered as a symptom of gastrointestinal infections caused by a variety of organisms such as virus, bacteria, and parasites. Most of the time, diarrhea is self-limiting without use of antibiotics. Regardless of the cause of diarrhea, it is primarily treated by fluid replacement therapy to restore nutritional defects and reducing duration of diarrhea. Although, fluid replacement reduces the risk of dehydration and death but it is not effective in shortening duration of diarrhea and vomiting.From 1990s onward, alternative and complementary medicine have been taken into consideration and nowadays*Address correspondence to this author at the Faculty of Pharmacy; and Pharmaceutical Sciences Research Center; and Endocrinology & Metabolism Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran; Tel/Fax: +98 21 66959104;E-mail: Mohammad.Abdollahi@UToronto.Ca

our pharmacies are full of these types of drugs as well as nutritional supplements but scientific evidences behind their usage are insufficient yet. Newly, probiotics have been recommended for treating or preventing a wide range of GI disorders including ulcerative colitis [2-4], Crohns disease [5], and irritable bowel syndrome [6]. Probiotics are live microorganisms such as bacteria and yeast. Probiotics may induce luminal effects or induce trophic and anti- inflammatory properties. Their luminal effects include interacting with pathogens and their toxins, maintaining cellular physiology, and assisting normal microbiota of GI. Probiotics help in recovering fluid maintenance, aid in protein and energy production and maturation of eneterocytes or regulate immune function of the gut [7]. Recently special attention has been paid to their benefits in acute diarrhea however the results of the several clinical trials in this field are controversial.Most of the studies have been carried out on the effectiveness of probiotics in childrens diarrhea and only a few were conducted in adults. Therefore, to clarify efficacy of probiotics in both adults and children, different types of diarrhea that are caused by rota-virus, amoebiasis, Clostridium difficile, chemotherapy, and radiation were evaluated. Furthermore, probiotics were evaluated in the treatment of diarrhea in human immunodeficiency virus1871-5281/12 $58.00+.00 2012 Bentham Science Publishers(HIV) positive patients. Existing trials indicated that only children diarrhea can be meta-analyzed and those of adults should be critically reviewed.METHODSPubMed, Web of Science (ISI), Scopus, and Cochrane databases were searched by keywords such as probiotics, and diarrhea. The search was limited to the randomized clinical trials written in English. The studies entered meta-analysis if they met the inclusion criteria in conduction of trial on children with diarrhea. Three reviewers evaluated each article independently to lessen the probability of duplication, and better analyzing of reviews, case studies and uncontrolled trials. Studies were precluded if they were uncontrolled or their results did not consider our goals.ASSESSMENT OF TRIAL QUALITYJadad score, which indicates the potentiality of the studies based on their description of randomization, blinding, and dropouts (withdrawals) was used to assess the methodological quality of trials [8]. The quality scale ranged from 0 to 5 points with a low quality report of score 2 or less and a high quality report of score at least 3.STATISTICAL ANALYSISData from selected studies were extracted in the form of2 2 tables. Included studies were weighted and pooled. Datawere analyzed using StatsDirect software version 2.7.8. Effect size for weighed mean difference and 95% confidence intervals (95% CI) were calculated using the Hedges-Olkin

and Der Simonian-Laird methods. The Cochrane Q test was used to test heterogeneity. In case of heterogeneity or probability of few included studies in meta-analysis, the random effects for individual and summary of effect size for weighed mean difference was applied. Funnel plot analysis was used as publication bias indicator.RESULTSThe electronic search provided 1228 articles; 176 fromPubMed, 560 from Web of Science, 320 from Scopus, and172 from Cochrane library. Eighty-nine children studieswere provided in full text, of which, 69 trials didnt fulfill inclusion criteria and thus only 20 trials were meta-analyzed (Fig. 1). Totally 3867 subjects enrolled in the study. Summary of each trial is shown in Table 1.EFFICACYDuration of Diarrhea (Day)The summary effect size of duration of diarrhea for all included data for probiotics in comparison to placebo in 19 trials [9-27] was -0.67 with 95% CI= -0.95 to -0.38 (P< 0.0001, Fig. 2a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (P< 0.0001) and could not be combined, thus the random effects for individual and summary for effect size was applied. Regression of normalized effect vs precision for all included studies for duration of diarrhea among probiotics vs placebo therapy was -5.71 (95% CI= -8.99 to-2.45, P= 0.0018), and Kendalls test on standardized effect vsvariance indicated tau= -0.49, P= 0.0024 (Fig. 2b).1228 potentially relevant reports identified and screened for retrieval from electronic search:

560 from Web of Science

176 from PubMed

320 from Scopus

172 from Cochrane library89 reports retrieved

540 excluded because of duplication.

397 excluded because they were reviews.

202 excluded on the basis of title and abstract.

69 reports excluded upon full text search:

n=46: different study design

n=23: did not meet the inclusion criteria20 eligible randomized controlled clinical trials included in the meta-analysisFig. (1). Flow diagram for study selection.Table 1. Summary of Placebo Controlled TrialsAuthorDurationInterventionNo. ofPatientsJadadScore

Chen et al., [9]7 daysBacillus mesentericus, Enterococcus faecalis, Clostridium butyricum/Placebo2935

Moal et al., [10]3 daysLactobacillus acidophilus/Placebo803

Henker et al., [11]10 daysEscherichia coli Nissle 1917 /Placebo995

Syzmanski et al., [12]5 daysLactobacillus rhamnosus /Placebo875

Billoo et al., [13]5 daysSaccharomyces boulardii/Placebo1002

Sarker et al., [14]5 daysLactobacillus paracasei /Placebo2035

Salazar-Lindo et al., [15]5 daysLactobacillus casei strain GG /Placebo1605

Teran et al., [16]5 daysLactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium longum, Saccharomyces boulardii/Placebo755

Narayanappa et al., [17]14 daysBifilac /Placebo802

Basu (1) et al., [18]7 daysLactobacillus rhamnosus /Placebo6645

Villarruel et al., [19]6 daysSaccharomyces boulardii/Placebo724

Khanna et al., [20]3 daysLactobacillus acidophilus /Placebo985

Kurugol et al., [21]5 daysSaccharomyces boulardii /Placebo2004

Thibault et al., [22]5 monthsBifidobactrium breve C50, Streptococcus thermophilus /Placebo9135

Mao et al. [23]not specifiedStreptococcus thermophilus, Bifidobacterium lactis /Placebo2123

Agustina et al., [24]7 daysLactobacillus rhamnosus/Placebo584

Gaon et al., [25]5 daysLactobacillus casei, Lactobacillus acidophillus /Placebo894

Rosenfeldt et al., [26]5 daysLactobacillus rhamnosus, Lactobacillus reuteri/Placebo694

Basu et al., [27]7 daysLactobacillus rhamnosus /Placebo2355

Pashapour et al., [28]not specifiedLactobacillus bulgaris, Streptococcus thernophilus /Placebo801

Bifilac= Streptococcus faecalis, Clostridium butyricum, Bacillus mesentericus, Lactobacillus sporogenes.

Duration of Fever (Hour)The summary effect size of fever for all included data for probiotics in comparison to placebo in 4 trials [9, 16, 21, 26] was -0.18 with 95% CI= -0.34 to -0.02 (P= 0.0246, Fig. 3a). The Cochrane Q test for heterogeneity indicated that the studies are not heterogeneous (P= 0.7116) and could be combined, thus the fixed effects for individual and summary for effect size was applied. Regression of normalized effect vs precision for all included studies for fever among probiotics vs placebo therapy was 1.39 (95% CI= -1.88 to4.66, P= 0.2096), and Kendalls test on standardized effectvs variance indicated tau= 0.67, P= 0.33 (Fig. 3b).Duration of Hospitalization (Day)The summary effect size of hospitalization for all included data for probiotics in comparison to placebo in 10 trials [9, 15, 16, 18, 20, 21, 24, 26-28] was -1.12 with 95% CI= -1.87 to -0.38 (P= 0.0032, Fig. 4a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (P< 0.0001) and could not be combined, thus the random effects for individual and summary for effect size was applied. Regression of normalized effect vs precision for all included studies for hospitalization among probiotics vs placebo therapy was -8.91 (95% CI= -18.84 to 1.01,

P= 0.072), and Kendalls test on standardized effect vsvariance indicated tau= -0.24, P= 0.29 (Fig. 4b).Duration of Vomiting (Day)The summary effect size of vomiting for all included data for probiotics in comparison to placebo in 5 trials [9, 18, 21,26, 27] was -0.18 with 95% CI= -0.41 to 0.04 (P= 0.1151,Fig. 5a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (P= 0.0034) and could not be combined, thus the random effects for individual and summary for effect size was applied. Regression of normalized effect vs precision for all included studies for vomiting among probiotics vs placebo therapy was -1.01 (95% CI= -10.77 to 8.75, P= 0.76), and Kendalls test on standardized effect vs variance indicated tau= -0.2, P=0.4833 (Fig. 5b).Number of Stools Per DayThe summary effect size of number of stools per day for all included data for probiotics in comparison to placebo in 3 trials [9, 20, 25] was -0.81 with 95% CI= -2.05 to 0.44 (P=0.2041, Fig. 6). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (P< 0.0001) and could not be combined, thus the random effects forEffect size meta-analysis plot [random effects]Chen et al., 2010 (9)

Moal et al., 2007 (10)

Henker et al., 2007 (11)

Syzmanski et al., 2006 (12)

Billoo et al., 2006 (13)

Sarker et al., 2005 (14)

Lindo et al., 2004 (15)

Teran et al., 2009 (16)

Narayanappa et al., 2008 (17)

Basu et al., 2007 (1) (18)

Villarruel et al., 2007(19)

Khanna et al., 2005 (20)

Kurugol et al., 2005 (21)

Thibault et al., 2004 (22)

Mao et al., 2008 (23)

Agustina et al, 2007 (24)

Gaon et al., 2003 (25)

Rosenfeldt et al., 2002 (26)

Basu et al., 2007 (2) (27)

-4.0-2.4-0.800.82.4

DL pooled effect size = -0.664639 (95% CI = -0.944865 to -0.384414)Fig. (2a). Individual and pooled effect size for the outcome of duration of diarrhea in the studies considering probiotics comparing to placebo therapy.Standard error0.0

Bias assessment plot0.10.20.30.4

-3 -2 -1 0 1Effect sizeFig. (2b). Publication bias indicators for the outcome of duration of diarrhea in the studies considering probiotics comparing to placebo therapy.Effect size meta-analysis plot [fixed effects]Chen et al., 2010 (9)Teran et al., 2009 (16)Kurugol et al., 2005 (21)Rosenfeldt et al., 2002 (26)-0.61

-0.31 -0.01 0.29 0.59 pooled effect size = -0.182353 (95% CI = -0.341399 to -0.023307)Fig. (3a). Individual and pooled effect size for the outcome of duration of fever in the studies considering probiotics comparing to placebo therapy.Standard error0.10

Bias assessment plot

0.150.200.250.30-1.0 -0.5 0.0 0.5Effect sizeFig. (3b). Publication bias indicators for the outcome of duration of fever in the studies considering probiotics comparing to placebo therapy.Effect size meta-analysis plot [random effects]Chen et al., 2010 (9)Lindo et al., 2004 (15)Teran et al., 2009 (16)Basu et al., 2007 (1) (18)Khanna et al., 2005 (20)Kurugol et al., 2005 (21)Agustina et al, 2007 (24)Pashapour and Lou, 2006 (28)Rosenfeldt et al., 2002 (26)Basu et al., 2007 (2) (27)-6 -4 -2 0 2DL pooled effect size = -1.121195 (95% CI = -1.865857 to -0.376533)Fig. (4a). Individual and pooled effect size for the outcome of duration of hospitalization in the studies considering probiotics comparing to placebo therapy.Standard error0.000

Bias assessment plot0.0750.1500.2250.300

-6 -4 -2 0 2Effect sizeFig. (4b). Publication bias indicators for the outcome of duration of hospitalization in the studies considering probiotics comparing to placebo therapy.Effect size meta-analysis plot [random effects]Chen et al., 2010 (9)Basu et al., 2007 (1) (18)Kurugol et al., 2005 (21)Rosenfeldt et al., 2002 (26)Basu et al,.2007 (2) (27) (mean)(day)-0.90 -0.65 -0.40 -0.15

0 0.10 0.35DL pooled effect size = -0.181045 (95% CI = -0.406223 to 0.044133)Fig. (5a). Individual and pooled effect size for the outcome of duration of vomiting in the studies considering probiotics comparing to placebo therapy.Standard error0.05

Bias assessment plot0.100.150.200.25-0.70 -0.45 -0.20 0.05 0.30 0.55Effect sizeFig. (5b). Publication bias indicators for the outcome of duration of vomiting in the studies considering probiotics comparing to placebo therapy.Effect size meta-analysis plot [random effects]Chen et al., 2010 (9)Khanna et al., 2005 (20)Gaon et al., 2003 (25)-3 -2 -1 0 1DL pooled effect size = -0.80713 (95% CI = -2.052893 to 0.438633)Fig. (6). Individual and pooled effect size for the outcome of number of stools per day in the studies considering probiotics comparing to placebo therapy.individual and summary for effect size was applied. Regression of normalized effect vs precision for all included studies for number of stools per day among probiotics vs placebo therapy could not be calculated because of too few strata.DISCUSSION Diarrhea in ChildrenThe present meta-analysis showed different results interms of duration of diarrhea, duration of hospitalization, duration of fever, duration of vomiting and number of stools per day. Results indicate that probiotics reduce the duration of diarrhea and fever while its effect on the duration of hospitalization, the duration of vomiting and the number of stools per day is not significant. Previously, Szajewska et al. (2006) in a meta-analysis reported significant reduction in the duration of diarrhea, risk of diarrhea, the number of stools per day, and length of hospitalization [29]. Also, the results of an older meta-analysis on children's diarrhea confirmed the benefit of probiotics in reducing the duration of diarrhea and proposed a dose-effect relationship [30] which is in agreement with another meta-analysis conducted in 2002 [31].Obviously in the most of studies (19 studies), the primary outcome was the duration of diarrhea while the number and volume of stools per day were missed. The rest of studies that evaluated other outcomes do not seem adequate to reach a conclusion. Chen et al. reported a decrease in the duration of diarrhea, hospital stay, and presence of gram negative bacteria in the feces as well as down-regulation of tumor

necrosis factor- (TNF- ) and up-regulation of interleukin (IL) IL-10, IL-12, and interferon- (IFN- ) in children who were treated by probiotic [9]. Moreover, probiotics may decrease duration of diarrhea and fever caused by rotavirus [32]. However some studies could not confirm the effect of probiotics on diarrhea [33-35]. Also, none of the studies reported side effects of probiotics. Noteworthy all included studies used different types of probiotics which might differ in their function in the gut. While bifidobacterium colonizes in the human intestinal microflora, Lactobacillus did not cause that. It was suggested that Saccharomyces boulardii may restore healthy microtoba [7]. Regarding these reports and the results of present analysis, it is rational to suggest that probiotics decrease the duration of childrens diarrhea depending on the dose and type of probiotics with no adverse effect.Diarrhea in AdultsThe available studies in adults are limited and the outcomes in these studies are far different from children. Grossi et al. performed a multicenter randomized open-label parallel group controlled study on the effectiveness ofLactobacillus paracasei (Flortec) in comparison withLactobacillus GG (FlorVis) in acute diarrhea for 10 days. Concerning the duration of diarrhea, they didnt find any difference in clinical efficacy of these two bacteria. However91.8% of patients judged in favor of efficacy of Flortec vs83.7% of patients who were in favor of FlorVis [36].In another study, Xiao et al. compared the effect of heat- killed (Lacteol) vs live (Lacidophilin) Lactobacillus acidophilus LB in chronic diarrhea. They observed lowerbowel frequency in the Lacteol group before end of two weeks. At the end of the intervention, improvement in stool consistency, abdominal pain, and distention was significantly higher in the Lacteol group. Obviously, no significant difference was observed when side effects were considered [37]. Margreiter et al. conducted a multicenter parallel group randomized double-blind trial on the therapeutic value of a combination of Lactobacillus gasseri and Bifidobacterium longum vs Enterococcus faecium in acute diarrhea. In both groups, the duration of diarrhea was approximately the same but complete recovery was higher in the bacterium combination group [38]. Therefore, in adult's diarrhea, the results of the performed studies do not show the superiority of probiotics over placebo.In term of preventing travelers diarrhea, consumption of Lactobacillus acidophilus showed beneficial effects [39]. Pereg et al. assigned 541 healthy adult males in a placebo- controlled study on yogurt containing Lactobacillus casei and did not find significant difference between probiotic and control groups in prevention of diarrhea [40]. Conversely in the orthopedic rehabilitation elderly population, probiotic showed significant lower incidence of diarrhea which was more prominent among participants in age of 80 years or older [41].AmoebiasisThe benefits of adding Saccharomyces boulardii to the standard treatment of invasive amoebiasis were investigated by Mansour-Ghanaei et al. In their double-blind clinical trial, the duration of diarrhea, pain and fever decreased in consumers of probiotic while the duration of headache was similar in both groups [42].In an attempt to investigate the anti-diarrheal effect of probiotics in diarrhea caused by amebiasis, Dinleyici et al. compared efficacy of Sacccharomyces boulardii with metronidazole in a randomized open clinical trial. In children with acute bloody diarrhea caused by Entameba histolytica, the duration of diarrhea was significantly shorter in metronidazole plus probiotic along with faster clearance of amebic cysts [43]; however the results of the study of Savas- Erdeve et al. was opposing [44].Clostridium difficileThe clostridium difficile-associated diarrhea is a critical condition which needs special consideration and antibiotic treatment for probably a long period of time. Often, antibiotic regimens fail to prevent recurrence [45, 46]. Therefore restoring the gut microbial flora can prevent colonization by Clostridium difficile which was observed in some studies [47-49]. Concerning the importance of Clostridium difficile-associated diarrhea, Wullt et al. conducted a double-blind placebo-controlled trial on the effect of Lactobacillus plantarum on the recurrent diarrhea caused by clostridium. They could not find significant results [50].The effect of two other types of probiotics (Lactobacillus and Bifidobacterium) in prevention of clostridium difficile- associated diarrhea was studied in a placebo-controlled study in elderly patients receiving antibiotics. Although in this

study the rate of toxin-positive test and diarrheal symptoms was higher in the placebo group, more Clostridium difficile- positive patients were identified in the probiotic group. The authors claimed that their data support toxin neutralization rather than prevention of colonization [51].In vitro studies also show controversial results. Naaber et al. observed strain-specific interaction between Lactobacilli and Clostridium difficile [52].HIVDiarrhea is one of the most common symptoms in HIV patients [53, 54]. Disease advancement and antiretroviral therapy increase the risk of diarrhea [55, 56]. The pathology of diarrhea in HIV patients is unknown and the effectiveness of several treatment modalities on it is uncertain. Therefore, after launching probiotics as effective organisms against diarrhea, limited numbers of investigations were conducted. Salminen et al. performed a randomized placebo-controlled study on the effectiveness of Lactobacillus rhamnosus GG on non-infectious diarrhea in HIV patients and reported no significant difference between probiotic and placebo groups in terms of frequency or consistency of diarrhea, HIV RNA copies, and CD4 cell counts [57]. In a study on HIV-infected children, Trios et al. determined significant increase in the mean CD4 count in children receiving Bifidobacterium bifidum and Streptococcus thermophiles, while no significant change was seen in stool consistency [58]. In contrast to previous studies, Anukam et al. indicated the effect of Lactobacillus rhamnosus and reutri in alleviating diarrhea, flatulence and nausea in HIV when compared to placebo [59].RadiationIn spite of extensive use of highly focused radiation instruments, diarrheal complications are common in lower abdomen radiation therapy. Urbancsek et al. evaluated the efficacy and safety of Lactobacillus rhamnosus in radiation- induced diarrhea and observed significant favorable effects of Lactobacillus in stool consistency, bowel movement, and diarrhea rating in comparison with placebo [60]. The results of the study of Delia et al. confirmed the benefits of probiotics in prevention of radiation-induced diarrhea. They used VSL#3 as a probiotic mixture contained Lactobacillus strains casei, plantarum, acidophilus, delbruekii, and Bifidobacterium strains longum, breve and infantis and one strain of Streptococcus salivarius in a double-blind placebo- controlled trial and reported significant less episodes of diarrhea in patients who underwent radiotherapy [61]. Giralt et al. evaluated the effect of Lactobacillus casei in a multicenter placebo-controlled trial but their significant finding was only seen on stool consistency. According to their observation, Lactobacillus does not affect incidence of diarrhea after radiation [62].In addition to radiotherapy, the effect of probiotics in chemotherapy-induced diarrhea was evaluated by sterlund et al. who concluded that Lactobacillus supplementation for chemotherapy-induced diarrhea may reduce severity of diarrhea, and abdominal discomfort [63].CONCLUSIONObviously there are major differences in design of studies or their results. Our review indicates that number of studies in adults diarrhea or diarrhea caused by radiation, chemotherapy, and HIV is not adequate to reach a convincing conclusion. Although, the present meta-analysis of children studies showed benefits of probiotics in decreasing the duration of diarrhea and fever, it is notable that design of the studies, type and dose of the probiotics can potentially affect the results. From the present review, we learned that researchers need to agree on definition of termination of diarrhea and thus design of studies and their outcome results would be harmonized.Although no adverse effect was reported in most of studies, some investigators had concerns about the risk of fungaemia by S. boulardii especially in HIV or critically ill patients [64-66].It is notable that when animal studies [67, 68] or major reviews [69, 70] are considered, it is clear that diarrhea might be a symptom of a hidden or undiagnosed inflammatory bowel disease. The efficacy of probiotics in such cases return to their potential in regulating body and intestinal immune status.Taken together there is still doubt and no sufficient evidence for the efficacy of probiotics in different types of diarrhea in children or adults. Therefore, further investigations on special types of the probiotics, their origin, their purity, and their combination with prebiotics may be much helpful.ACKNOWLEDGEMENTThis paper is the outcome of an in-house non-financially supported study prepared upon an invitation of Inflammation& Allergy - Drug Targets.REFERENCES[1] Anonymous. http://www.who.int/mediacentre/factsheets/fs330/en/index.html[2] Rahimi, R.; Nikfar, S.; Rezaie, A.; Abdollahi, M. A meta-analysis of the benefit of probiotics in maintaining remission of human ulcerative colitis: evidence for prevention of disease relapse and maintenance of remission. Arch. Med. Sci., 2008, 4(2), 185-190.[3] Elahi, B.; Nikfar, S.; Derakhshani, S.; Vafaie, M.; Abdollahi, M.On the benefit of probiotics in the management of pouchitis inpatients underwent ileal pouch anal anastomosis: a meta-analysis of controlled clinical trials. Dig. Dis. Sci., 2007, 53, 1278-1284.[4] Nikfar, S.; Darvish-Damavandi, M.; Abdollahi, M. 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Received: September 6, 2011 Revised: October 26, 2011 Accepted: November 1, 2011