Chen. M SR and Three Level MA

’ Systematic Review and/or Meta-analysis
Probiotics for the management of irritable bowel

syndrome: a systematic review and three-level
meta-analysis
Min Chen, MD, PhDa, Lu Yuan, MDb, Chao-Rong Xie, MDb, Xiao-Ying Wang, MDb, Si-Jia Feng, MDb,
Xin-Yu Xiao, MDb, Hui Zheng, MD, PhDb,*
Objective: Previous systematic reviews demonstrated a potentially beneficial effect of probiotics on irritable bowel syndrome (IBS).
However, these studies are either affected by the inclusion of insufficient trials or by the problem of dependent data across multiple
outcomes, and an overall effect size has not been provided. We aimed to determine the effect of probiotics on IBS through a three-
level meta-analysis and clarify potential effect moderators.
Methods: We searched MEDLINE, Embase, and Web of Science, screening for randomized controlled trials (RCTs) that examine
the effect of probiotics on IBS. The primary outcome was the improvement in the severity of global IBS symptoms at the end of
treatment. The secondary outcomes were the improvement in abdominal pain and the quality of life. The effect sizes of the probiotics
were measured by using the standardized mean difference (SMD) and pooled by a three-level meta-analysis model.
Results: We included 72 RCTs in the analysis. The meta-analysis showed significantly better overall effect of probiotics than
placebo on the global IBS symptoms (SMD − 0.55, 95% CI − 0.76 to − 0.34, P < 0.001), abdominal pain (SMD − 0.89, 95% CI
− 1.29 to − 0.5, P < 0.001) and quality of life (SMD 0.99, 95% CI 0.45 to 1.54, P < 0.001), respectively. Moderator analysis found that
a treatment duration shorter than 4 weeks was associated with a larger effect size in all the outcomes, and Bacillus probiotics had
better improvement on the abdominal pain.
Conclusions: Probiotics had a short-term effect and a medium effect size on the global IBS symptoms. Treatment duration and
types of probiotics affected the effect size of probiotics, and shorter durations and Bacillus probiotics were associated with better
treatment effects.
Registration: Open Science Framework.
Keywords: irritable bowel syndrome, multi-level meta-analysis, probiotics, systematic review
Introduction
HIGHLIGHTS
Irritable bowel syndrome (IBS) is a disorder of the brain–gut axis
characterized by frequent abdominal pain, bloating, flatulence, • Despite the previous reports of several systematic reviews
and change of bowel habits – constipation or diarrhea. The global and meta-analyses examining the effect of probiotics for
prevalence of IBS was 9.2% but varied across different regions; irritable bowel syndrome (IBS), the general effect size of
the prevalence was similar in Western countries, which is between probiotics on IBS symptoms and the essential effect
8.6 and 9.5% when the Rome III criteria were adopted and is moderators are unknown.
• In this meta-analysis incorporating 72 randomized con-
trolled trials (RCTs), probiotics showed a medium effect
a
Department of Colorectal Diseases, Hospital of Chengdu University of Traditional size on the improvement of global IBS symptoms (standar-
Chinese Medicine and bAcupuncture and Tuina School, Chengdu University of dized mean difference, − 0.55, 95% CI − 0.76 to − 0.34)
Traditional Chinese Medicine, Chengdu, People’s Republic of China
compared with placebo.
Sponsorships or competing interests that may be relevant to content are disclosed at • A treatment duration shorter than 4 weeks and Bacillus
the end of this article.
probiotics were associated with larger effect sizes.
*Corresponding author. Address: No. 1166 Liutai Avenue, Wenjiang District,
Chengdu 610000, People’s Republic of China. Tel./fax: + 860 288 768 9918.
E-mail: zhenghui@cdutcm.edu.cn (H. Zheng).
between 4.5 and 4.7% with Rome IV[1], and the prevalence was
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open access article distributed under the Creative Commons Attribution License 4.0 as high as 21.2% in Japan when the Rome III criteria were
(CCBY), which permits unrestricted use, distribution, and reproduction in any adopted[2]. IBS affects the quality of life substantially to the same
medium, provided the original work is properly cited. degree as inflammatory bowel diseases[3]. The high prevalence
International Journal of Surgery (2023) 109:3631–3647 and heavy disease burden urge the development of treatments for
Received 14 June 2023; Accepted 24 July 2023 patients with IBS.
Supplemental Digital Content is available for this article. Direct URL citations are Owing to the complexity of IBS pathophysiology and the long
provided in the HTML and PDF versions of this article on the journal's website, disease duration, dietary supplements and alternative treatments
www.lww.com/international-journal-of-surgery. are supposed to be more appropriate than pharmacological
Published online 10 August 2023 treatments since they are acknowledged to be harmless or with
http://dx.doi.org/10.1097/JS9.0000000000000658 few adverse events. However, dietary supplements, like
3631
Chen et al. International Journal of Surgery (2023) International Journal of Surgery
probiotics, are in the conundrum of ‘no harm, might help’[4]. Headings) terms and keywords were developed for the search in
Numerous systematic reviews and meta-analyses were published the databases. The search strategies were shown in eTables 1–3
to examine the effect of probiotics on IBS, and most of them (Supplemental Digital Content 4, http://links.lww.com/JS9/A877)
suggested a beneficial effect[5–8], but convincing evidence cannot We also searched previously published systematic reviews and
be reached owing to the small sample size, single-center design, read the reference lists of the reviews, trying to find out missing
and high risk of bias of the included trials. Additionally, the RCTs from our literature search. One author (C.-R.X.) performed
diverse outcome assessments and differential assessment time the literature search, and two authors (L.Y. and X.-Y.X.) inde-
points hinder a general evaluation of the effect size of the pro- pendently screened the retrieved articles. The inclusion and
biotics. The previously published meta-analyses normally selec- exclusion criteria are listed below.
ted a specific time point and one of the outcomes to pool, which RCTs were included if they (1) recruited participants who aged
caused a loss of information – many of the outcomes are corre- over 18 years and were diagnosed with IBS or any of its subtypes;
lated and should be included for analysis[9]. In addition, numer- (2) tested the effect of probiotics by comparing them with a pla-
ous factors might affect the effect size of probiotics, and previous cebo; (3) measured any of the following outcome: improvement
reviews concluded that specific strains of the probiotics had larger of IBS symptoms, improvement of abdominal pain, or quality
effects than the others[7]. Other effect moderators like treatment of life.
duration and the patient’s characteristics are rarely evaluated. RCTs were excluded if they (1) also recruited other gastro-
Based on these grounds, we raised two clinically relevant ques- intestinal diseases (e.g. functional dyspepsia, inflammatory bowel
tions – what is the overall effect size of probiotics in the man- diseases); (2) published as letters that had insufficient information
agement of IBS, and what are the major effect moderators that to judge the exact type of probiotics and their controls, or
significantly affect the size of the probiotic effect? insufficient information on the types of outcomes.
One problem, not being fully settled in previously published
meta-analyses on the topic, is that the effect sizes reported by the Outcome assessments
included trials might not be independent. For example, the studies
The primary outcome of this study was the severity of global IBS
conducted in the same region (i.e. European countries) might
symptoms, which normally include abdominal pain, discomfort
report similar results, which introduces dependence. A three-level
in the abdominal region (i.e. bloating, urgency, indigestion), and
meta-analysis is developed to solve this problem, which treats
changed bowel habits (constipation, diarrhea, or diarrhea alter-
effect sizes nested within a study as dependent variables and
nating with constipation). These symptoms could be assessed by
examines the source of heterogeneity within a study and between
asking questions with yes-or-no answers like ‘Are your global IBS
studies – avoiding the inflation of type I error[10]. In addition, a
symptoms relieved?’ or by adopting scales such as the IBS-SSS
three-level meta-analysis can include effect moderators in the
(Irritable Bowel Syndrome Severity Scoring System) scale.
model and assess the impact of the moderators on the effect sizes, Secondary outcomes included the severity of abdominal pain
which gives a better explanation for the effect of an intervention and the improvement in quality of life. Abdominal pain is one of
than the conventional meta-analysis. We aimed to assess the the most essential symptoms of IBS, and it is usually separately
overall effect of probiotics on the improvement of IBS symptoms reported. The severity of abdominal pain could be assessed by
and find out the important effect moderators through the three- using binary outcomes indicating whether relief of pain was
level meta-analysis. achieved or by rating scales such VAS (Visual Analog Scale)
score. The quality of life in IBS patients is assessed by scales like
Methods IBS-QoL (Irritable Bowel Syndrome Quality of Life). Our study
included all these scales.
Study overview
We performed a systematic review and multi-level meta-analysis, Data extraction
and this work had been reported in line with Preferred Reporting Two reviewers (X.-Y.W. and S.-J.F.) independently extracted
Items for Systematic Reviews and Meta-Analyses (PRISMA)[11] study data from the included studies. Characteristics of the study
(Supplemental Digital Content 1, http://links.lww.com/JS9/A874, design, participants, intervention, controls, and outcomes were
Supplemental Digital Content 2, http://links.lww.com/JS9/A875) separately extracted, and the characteristics were also coded and
and AMSTAR (Assessing the methodological quality of sys- prepared for moderator analysis, which was described in detail in
tematic reviews) Guidelines[12] (Supplemental Digital Content 3, the statistical analysis section.
http://links.lww.com/JS9/A876). The review was registered in
Open Science Framework prior to conduction. The meta-analysis Risk of bias assessment
used aggregate-level data from published randomized controlled
trials (RCTs). Ethical approvals and patient informed consent We assessed the risk of bias (RoB) using the revised Cochrane
were acquired in each participating center of the RCTs. The work RoB tool (RoB 2.0), in which five domains – bias arising from the
has been reported. randomization process, bias due to deviation from intended
interventions, bias due to missing outcome data, bias in the
measurement of an outcome, and bias in the selection of the
Literature search and study selection
reported result – were assessed and an overall RoB (low/high RoB
We searched MEDLINE, Embase, and Web of Science from or some concerns) was provided for each study. The certainty of
inception to 12 November 2022, aiming to screen for RCTs that the evidence was assessed by using the Grading of
examined the efficacy of probiotics on IBS. Comprehensive search Recommendations, Assessment, Development, and Evaluations
strategies with the combination of MeSH (Medical Subject (GRADE) approach.
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Chen et al. International Journal of Surgery (2023)
Statistical analysis Seventy studies compared probiotics with placebo controls. More
detailed information is shown in Table 1. Of the 72 included RCTs,
We estimated the effect size of probiotics versus placebo by using
nine were classified with a low risk of bias, two were with a high
the standardized mean difference (SMD, also known as Cohen’s d).
risk of bias, and 61 with some concerns; the assessment of each
Based on the assumption that the underlying continuous mea-
domain was presented in eFigure 1 (Supplemental Digital Content
surements in each intervention group follow a logistic distribution
4, http://links.lww.com/JS9/A877) The GRADE assessment for all
and that the variability of the outcomes is the same in both the
three outcomes showed low certainty of the evidence. The summary
intervention and control groups, the odds ratios (ORs) can be re-
of the GRADE table is shown in eTable 4 (Supplemental Digital
expressed as an SMD according to the following simple
√3 Content 4, http://links.lww.com/JS9/A877). Figure 2 shows the
formula[13,14]: SMD = ln(OR). The effect size was inter-
π concept of the three-level meta-analysis and the results of the meta-
preted as small, medium, and large with the cut-off points of 0.2,
analyses on the three outcomes – the severity of global IBS symp-
0.5, and 0.8, respectively[15]. To ensure the consistency of the
toms, the severity of abdominal pain, and the quality of life
direction of outcome measurements, the category outcomes were
assessment.
measured with the ORs of participants with failures of improve-
ment, while continuous outcomes were measured with the change The severity of global IBS symptoms
in the severity of the global IBS symptoms or abdominal pain.
We used a three-level random-effects meta-analysis model to The three-level meta-analysis – included 63 studies[17–22,25–34,
36–48,50,52,53,55–58,60–69,71–76,78–81,83–87]
pool the effect sizes, estimated the heterogeneity within-study and generated 217 effect
(level 2) and between-study (level 3), and used Cochran’s Q test sizes – showed an overall effect of probiotics was significantly
to evaluate whether the heterogeneity was statistically significant superior over placebo (SMD − 0.55, 95% CI − 0.76 to − 0.34,
(defined as P < 0.05). We compared the traditional two-level P < 0.001; Fig. 2), but with significant heterogeneity (Cochran’s
meta-analysis with the three-level model by evaluating the AIC Q = 2906.24, P < 0.001). We further analyzed within-study and
(Akaike Information Criterion) and BIC (Bayesian Information between-study variance and found a total I2 of 96.3%, a within-
Criterion) of the models and estimated the significance of the study I2 of 79.5%, and a between-study I2 of 16.8%. We then
difference by the likelihood ratio test – which also used a cut-off compared the traditional two-level meta-analysis model with the
point of 0.05. To assess potential publication bias, we generated three-level model and found the three-level model reduced AIC
funnel plots for the three outcomes to perform a visual assessment from 913.7 to 906 and the BIC from 920.4 to 916.2, and the
for asymmetry[16]. likelihood ratio test (LRT) demonstrated a significant difference
We further performed moderator analyses to find out which between the two models (chi-squared (χ2) = 9.652, P = 0.002) –
factors substantially affected the effect size by using the meta- showing the three-level model provided a better fit. The funnel
regression model. Four groups of factors were analyzed. The first plot showed no signs of publication bias (eFigure 2, Supplemental
group was study-design-related: countries hosting the studies, Digital Content 4, http://links.lww.com/JS9/A877).
types of RCT (single vs. multicenter design), number of study The moderator analyses showed that participants from dif-
sites, and the total study duration (measured by weeks). The ferent continents reported differential effects, while participants
second group was participant-related: age, proportion of females, from the Asia region reported the largest effect size (Fig. 3A).
the proportion of participants who dropped out from the study, Additionally, we found that study duration affected the effect
duration of disease, and diagnostic criteria. The third group was size, and a longer study duration was associated with a smaller
intervention-related: duration of the intervention (measured by effect size (Fig. 3B). We also found that longer treatment duration
weeks) and the types of probiotics (classified as Bacillus, was associated with a smaller effect size (Fig. 3C). The type of
Bifidobacterium, Enterococcus, Escherichia coli, Lactobacillus, outcome impact also had an impact, and probiotics had a larger
effect size on abdominal discomfort (SMD − 1.55, 95% CI − 2.97
Saccharomyces, and a combination of differential probiotic
to − 0.15, P = 0.017; Fig. 3D). Other factors had no significant
strains). The fourth group was outcome-related: the type of data
impact on the effect sizes of the probiotics (Table 2).
(continuous vs. categorical data) and types of outcome definition
(i.e. global IBS symptoms could be further classified as adequate
The severity of abdominal pain
relief of symptoms, any relief of global symptoms, bloating,
bowel habit, abdominal discomfort, and defecation urgency). The model – included 48 studies[17–22,24–34,36,37,39,40,43–46,49,52,
54,55,57,62–67,69,72,74,75,77–81,84,87,88]
The analysis was performed in the R environment (version 4.2.2) and generated 92 effect sizes –
and the metafor package (version 4.2-0). showed probiotics reduces the severity of abdominal pain (SMD
− 0.89, 95% CI − 1.29 to − 0.5, P < 0.001; Fig. 2), but with sig-
nificant heterogeneity (Cochran’s Q = 1923.12, P < 0.001). We
Results found a total I2 of 98.4%, a within-study I2 of 74.7%, and a
between-study I2 of 23.7%. A slightly reduced AIC (from 363 to
Trial characteristics
360.5) was found in the three-level model when compared with the
We identified 72 RCTs[17–88] after screening for 2725 pieces of traditional one, the LRT test was still significant (χ2 = 4.1825
articles and included a total of 8581 participants. The process of P = 0.034). The funnel plot showed no signs of publication bias
screening is shown in Figure 1. The included population had a (eFigure 3, Supplemental Digital Content 4, http://links.lww.com/
mean age of 41.7 years and a mean proportion of 65.8% of JS9/A877).
females. Sixty-seven (93.1%) of the included studies adopted the In the moderator analysis, we found that the study duration
Rome criteria as the diagnostic standard, and 53 (73.6%) of the affected the effect sizes. RCTs with a study duration shorter than
studies recruited at least two subtypes of IBS. Of the 18 studies that 4 weeks (SMD, − 1.71, 95% CI − 2.62 to − 0.8) had significantly
focused on a single subtype, 13 studied diarrhea-predominated IBS. larger effect sizes than other RCTs with a study duration longer
3633
Figure 1. The study flowchart. WoS, Web of Science.
than 4 weeks (P < 0.001; Table 2). The proportion of females also containing Bacillus and Bifidobacterium showed significantly
affected the effect sizes, RCTs with a higher proportion of females larger effect sizes than those containing Saccharomyces (Table 2).
were associated with smaller effect sizes (coefficient estimate
0.02, 95% CI 0.001–0.046, P = 0.04). For other factors, no sig-
nificant impact was found (Table 2). Discussion
By pooling all the effect sizes from the included RCTs, we found a
Quality of life assessment general medium effect size (with an SMD larger than 0.5) of
probiotics on the improvement of IBS symptoms compared with
The model – included 23 studies[20,22,23,28,33,36–38,40,43,48,56, placebo, and a large effect size (with an SMD larger than 0.8) of
60,61,63,66,68,71,78,80,83,85,88]
and generated 71 effect sizes – probiotics on the abdominal pain and the scores of quality-of-life
showed that probiotics significantly improved the quality of life in assessments. We found that the treatment duration and study
patients with IBS (SMD 0.99, 95% CI 0.45–1.54, P < 0.001; duration were the most important moderators of effect, and a
Fig. 2), but with significant heterogeneity (Cochran’s Q = 788.7, longer study duration or treatment duration was associated with
P < 0.001). The total I2, within-study I2, and between-study I2 a smaller effect size. When the treatment duration was longer
were 98%, 41.8%, and 56.2%, respectively. Compared with the than 8 weeks and the study duration was longer than 12 weeks,
traditional meta-analysis model, the three-level model had sig- the effect sizes dropped to − 0.02 and 0.02 (extremely small effect
nificantly reduced AIC (268.2–257.5) and BIC (272.7–264.2) size), respectively.
(LRT = 12.7, P < 0.001). The funnel plot showed signs of pub- Our meta-analysis included a larger number of studies than the
lication bias (eFigure 4, Supplemental Digital Content 4, http:// previous and recent systematic reviews that assessed the efficacy
links.lww.com/JS9/A877); one study[37] demonstrated a larger of probiotics for IBS[6,7] because we used the transformation
size than other studies. between odds ratios and SMDs, which has been suggested and
The moderator analysis showed that the treatment duration reported in the Cochrane handbook[16] and methodological
and the types of probiotics affected the effect size. A treatment reports[9,14] to increase the statistical strength of the meta-ana-
duration within 4 weeks showed a significantly larger effect than lysis. The ability to include more studies might also be attributed
a treatment duration between 4 and 8 weeks and a treatment to the application of the three-level meta-analysis model, which
duration longer than 8 weeks (Table 2). The probiotic strains prompts the estimation of the general effect of the probiotics on
3634
Table 1
Trial characteristics
Sample size Group
Country, study (%female, allocation The probiotics and their Control, dosage and The main efficacy
Author* design mean age) BMI (I, P)† Diagnosis; Subtypes components‡ Dose and duration duration outcomes
Gade et al.[17] Denmark, RCT, 54 (77.8, 34) NA 32, 22 Others; IBS‑D, IBS‑C Enterococcus; Streptococcus faecium 4 tablets b.i.d. for 4 Placebo; 4 tablets b.i.d.; Improvement in IBS
Thirteen weeks 4 weeks Symptoms
centers
Nobaek et al.[18] Sweden, RCT, 60 (69.2, 48.5) NA 25, 27 Rome criteria; IBS‑D, IBS‑C Lactobacillus; Lactobacillus plantarum 400ml (5 × 107 CFU/ml/ Placebo; 400ml q.d.; Significant improvements
Single center DSM 9843 drink) q.d.for 4 weeks. 4 weeks. in the IBS Symptoms
Niedzielin et al.[19] Poland, RCT, 40 (80,43.5) 23.7 20, 20 Clinical diagnosis; 2.5% IBS- Lactobacillus; Lactobacillus plantarum 200ml (5 × 107CFU/ml)
Single center D, 52.5% IBS-C, 45% 299V
IBS‑M
bid for 4 weeks Placebo; 200ml Improvement in
bid; 4 weeks Global IBS
symptoms
Kim et al.[20] USA, RCT, Single 25 (72,42.8) NA 12, 13 Rome II; 100% IBS‑D Combination; VSL#3 One packet (containing Placebo; One packet b.i. Satisfactory relief of IBS
center 225 billion bacteria/ d.; 8 weeks symptoms for 50% of
packet) b.i.d. for 8 weeks
weeks
Kim et al.[22] USA, RCT, Single 48 (93.8,43) NA 24, 24 Rome II; 42 % IBS‑D, 33% Combination; VSL#3 One product b.i.d. (31 Placebo; One product b.i. Satisfactory relief of IBS
center IBS‑C, 25% IBS‑M patients for 4 weeks d. (31patients for 4 symptoms for 50% of
and 17 patients for 8 weeks and 17 patients weeks
3635
weeks) for 8 weeks).

Kajander et al.[21] Finland, RCT, 103 (76.5,45.5) 25.1 52, 51 Rome I and II; 47 .6% IBS‑D, CombinationLactobacillus rhamnosus One capsule (8-9 × 109 Placebo; one capsule o. Relief of global symptom
Single center 23.3% IBS-C, 29.1% IBS- GG, Lactobacillus Rhamnosus CFU/capsule) o.d. for d.; 24 weeks score
M LC705, Bifidobacterium breve Bb99 24 weeks
and Propionibacterium
freudenreichii ssp.
Niv et al.[23] Israel, RCT, Two 54 (66.7,45.7) NA 27, 27 Rome II; 37% IBS‑D, 18.5% Lactobacillus; Lactobacillus reuteri One product (1 × Placebo; One tablet b.i.d; Global symptoms score;
centers IBS-C 44.4% IBS‑M ATCC 55730 108colony-forming 22 weeks. Adverse events
units/tablet), q.i,d. for
1week, then tid.
Kim et al.[24] Korea, RCT, 40 (26.5,39.4) 23.7 20, 20 Rome II; 70 % IBS‑D, 30% Combination; Bacillus Subtilis and One capsule t.i.d.; 4 Placebo; One capsule t.i. Abdominal pain
Single center IBS‑M Streptococcus faecium weeks. d.; 4 weeks
Whorwell et al.[25] UK, RCT, Twenty 362 (100,41.9) 26.7 270, 92 Rome II; 55.5% IBS-D, 20.7% Bifidobacterium; Bifidobacterium (1 × 106 live bacteria/ Placebo; One capsule o. Relief of overall IBS
centers IBS-C, 23.8% IBS-M, infantis 35624 capsule, 1 × 108 live d.; 4 weeks symptoms
bacteria/capsule, or
1 × 1010 live bacteria/
capsule) o.d. for 4
weeks
Guyonnet et al.[26] France, RCT, 274 (74.5,49.3) NA 135, 132 Rome II; 100% IBS‑C Combination; Fermented milk One pot containing 125g. Placebo; One pot b.i.d.; 6 Improvement at least
Thirty-five containing Bifidobacterium animalis (1.25 × 1010 CFU/ weeks 10% discomfort
centers DN1 73010 Streptococcus 125g) or (1.2 × 109 dimension score
thermophilus and Lactobacillus CFU/125g) b.i.d. for 6
bulgaricus weeks
Drouault-Holowacz France, RCT, 106 (76,45.4) NA 48, 52 Combination; Bifidobacterium longum One sachet q.d. for 4 Placebo (of identical com- Satisfactory relief of
et al.[27] Single center LA 101 (29%), Lb.acidophilus LA weeks position except for the overall IBS symptoms
Table 1
(Continued)
Sample size Group
Rome II; 29% IBS-D, 29% 102 (29%), Lactobacillus lactis LA bacteria); One sachet
IBS-C, 41% IBS-M, 1% 103 (29%), and Streptococcus q.d.; 4 weeks
IBS-U thermophilus LA 104 (13%)
Enck et al.[28] Germany, RCT, 297 (73.5,49.6) 24.2 149, 148 0.75 ml (3.0-9.0 × 107 Placebo (identical in taste
Clinical criteria; IBS-D, IBS-C, I Combination; Enterococcus faecalis Have at least a 50%
ten centers BS-M DSM16440 and Escherichia coli CFU/1.5ml) t.i.d. for 1 and Texture); The same decrease in global
DSM17252 week, then 1.5 ml t.i.d. dose; 8 weeks. symptom score
for weeks 2 and 3, then
2.25 ml t.i.d. for weeks
3–8
Kajander et al.[29] Finland, RCT, 86 (93,48) 26.2 43, 43 Rome II; 45% IBS-D, 25% Combination; probiotic milk containing One drink for 1.2 dL (1 Placebo; One drink of 1.2 Global IBS symptoms
Single center IBS-C, 30% IBS-M Lactobacillus rhamnosus GG (ATCC × 107 CFU/ml) q.d. for dL q.d. for 14 weeks. score
53103, LGG), Lactobacillus 14 weeks.
rhamnosus Lc705 (DSM 7061),
Propionibacterium freudenreichii
ssp. Shermanii JS (DSM 7067) and
Bifidobacterium animalis ssp. lactis
Bb12 (DSM 15954)
Sinn et al.[30] Korea, RCT, 40 (65,44.7) 22.2 20, 20 Rome III; 10% IBS‑D, 27 .5% Lactobacillus; Lactobacillus One capsule (2 × 109 Placebo; One capsule b.i. Reduction in abdominal
3636
Single center IBS‑C, 62.5% IBS‑M acidophilus-SDC 2012 and 2013 CFU/ml) b.i.d. for 4 d; 4 weeks. pain score
weeks
Zeng et al.[31] China, RCT, 30 (34.5,45.2) NA 14, 15 Rome II; 100% IBS‑D Combination; Fermented milk 200ml (1 × 108 CFU/ml Placebo (containing no Global IBS scores in GSRS
Single center containing Streptococcus or 1 × 107 CFU/ml) b.i. bacteria); 200mL b.i.d.;
thermophilus, Lactobacillus d.for 4 weeks 4 weeks
bulgaricus, Lactobacillus
acidophilus, and Bifidobacterium
longum
Agrawal et al.[32] UK RCT, Single 38 (100,39.5) 24.8 17, 17 Rome III; 100% IBS‑C Combination; A fermented milk One pot (1.25 × 1010 Placebo; One pot q.d.; 4 Global symptoms score
center containing Bifidobacterium lactis CFU/ pot or 1.2 × weeks.
DN-173010, Streptococcus 109CFU/pot) q.d. for 4
thermophilus, and Lactobacillus weeks.
bulgaricus
Enck et al.[33] Germany, RCT, 298 (49.3,49.6) 24,2 148, 150 Others; IBS‑D, IBS‑C, IBS‑M Escherichia coli; Escherichia coli 0.75ml (1.5‑4.5 × 107 Placebo; 0.75ml drops t.i. Adequate relief of IBS
Twelve (DSM17252) CFU/ml) drops t.i.d. for d. for one week, then core symptoms
International Journal of Surgery

centers one week, then 1.5ml t. 1.5ml t.i.d. for weeks
i.d. for weeks 2‑8 2‑8
Hong et al.[34] Korea, RCT, 70 (32.9,37) NA 36, 34 Rome III; 45.7% IBS-D, 20% Combination; Bifidobacterium Bifidum One sachet (20 Billi Placebo; One sachet b.i. Reduction of symptom
Single center IBS‑C, 8.5% IBS‑M,25.8% BGN4, Bifidobacterium lactis bacteria/sachet) b.i.d. d.;8 weeks score by at least 50%
IBS‑U AD011, Lactobacillus acidophilus for 8 weeks
AD031, and Lactobacillus casei
IBS041
Hun et al.[35] USA, RCT, Single 50 (82,48) NA 22, 22 Rome II;100% IBS-D Bacillus; Bacillus coagulans GBI-30, One preparation q.d. for 8 Placebo; One preparation IBS symptoms (abdominal
center 6086 weeks q.d.; 8 weeks pain and bloating
scores)
Williams et al.[36] 56 (86.5,39) NA 28, 28
Combination; Lactobacillus acidophilus One capsule (2.5 × 1010

UK, RCT, Single Rome II; 11.5% IBS-D, 27% Placebo; One capsule q. IBS Symptom Severity
center IBS-C, 61.5% IBS-M CUL-60 (NCIMB 30157) and CUL‑21 CFU/capsule) q.d. for 8 d.; 8 weeks Score
(NCIMB 30156), Bifidobacterium weeks
bifidum CUL‑20 (NCIMB 30153),
and Bifidobacterium lactis CUL‑34
(NCIMB 30172)
Simren et al.[37] Sweden, RCT, 74 (70.3,43) NA 37, 37 Rome II; 35.1% IBS-D, 14.9% Combination; Fermented milk 200 ml (5 × 107 CFU/ml) Placebo; 200 ml Adequate relief of IBS
Single center IBS‑C, 50% IBS‑M containing Lactobacillus paracasei, b.i.d. for 8 weeks nonfermented milk b.i. symptoms at least 50%
ssp. paracasei F19, Lactobacillus d.; 8 weeks
acidophilus La5 and Bifidobacterium
lactis Bb12
Choi et al.[38] Korea, RCT, 90 (46,40.4) 23.1 45, 45 Rome II; 71.6 % IBS‑D, Saccharomyces; Saccharomyces One capsule (2 × 1011 Placebo; One capsule b.i. Overall improvement in
Three centers 28.4% IBS‑M boulardii live cells/capsule) b.i.d. d.; 4 weeks IBS-QOL
for 4 weeks
Guglielmetti et al.[39] Germany, RCT, 122 (67.2,38.9) 24.3 60, 62 Rome III; 21.3% IBS‑D, Bifidobacterium; Bifidobacterium One capsule (1 × Placebo; One capsule q. Relief of overall IBS
Multicenter 19.7% IBS-C, 59% IBS‑M Bifidum MIMBb75 109CFU/capsule) q.d. d.; 4 weeks symptoms
for 4 weeks.
Michail et al.[40] USA, RCT, Single 24 (66.7,21.8) NA 15, 9 Rome III; 100% IBS-D Combination; VSL#3 One packet (900 billion Placebo; One packet q.d; Global symptoms score (a
center bacteria/packet) q.d for 8 weeks clinical rating scale
8 weeks GSRS)
Ringel-Kulka et al.[41] USA, RCT, Single 33 (72,45.4) NA 16, 17 Rome III; 100% IBS-D Combination; Lactobacillus (2 × 1011CFU/day) for 8 Placebo; 8 weeks Global relief of GI
center acidophilus NCFM (L-NCFM) weeks symptoms, Satisfaction
and Bifidobacterium with treatment, HR-
animalis subsp. lactis Bi-07 (B- QOL
LBi07)
3637
Sondergaard et al.[42] Sweden, RCT, 64 (75,51.2) 24.8 27, 25 Rome II; Subtype not reported Combination; Fermented milk 250ml (5 × 107 CFU/ml) Placebo; Acidified milk Adequate relief of IBS
Two centers containing Lactobacillus paracasei b.i.d. for 8 weeks. 250 ml b.i.d; 8 weeks symptoms
ssp paracasei F19, Lactobacillus
acidophilus La5 and Bifidobacterium
lactis Bb12
Cha et al.[43] Korea, RCT, 50 (48,39.7) 23 25, 25 Rome III; 100% IBS-D Combination; Lactobacillus One capsule (0.5 × 1010 Placebo; One capsule b.i. Adequate relief of their
Single center acidophilus, Lactobacillus CFU/capsule) b.i.d. for d.; 8 weeks. IBS symptoms at least
plantarum, Lactobacillus 8 weeks. 50% of the weeks
rhamnosus, Bifidobacterium breve,
Bifidobacterium lactis,
Bifidobacterium longum, and
Streptococcus thermophilus
Cui et al.[44] China, RCT, 60 (70,44.7) 21.2 37, 23 Rome III; 48.3% IBS-D, 30% Combination; Bifidobacterium longum 200mg t.i.d. for 4 weeks Placebo; Two capsules t.i. Improvement in IBS
Single center IBS‑C, 11.7% IBS-M, 10% DSM 20219 and Lactobacillus d.; 4 weeks symptoms
IBS-U acidophilus DSM 20079.
Dapoigny et al.[45] France, RCT, 52 (70,47.1) 24 25, 25 Rome III; 30% IBS-D, 22% Lactobacillus; lactobacillus casei One capsule 250 mg (2 × Placebo; 250 mg t.i.d.; 4 IBS severity Score
Four centers IBS-C, 34% IBS-M, 14% rhamnosus LCR35 108 CFU/capsule) t.i.d. weeks
IBS-U for 4 weeks
Ducrotte et al.[46] France, RCT, 214 (29.4,37.3) NA 108, 106 Rome III; 62% IBS-D, 38% Lactobacillus; Lactobacillus plantarum One capsule (10 billion Placebo; One capsule q. Relief of IBS Symptoms
Four centers non-classified 299V DSM 9843 CFU/capsule) q.d. for 4 d.; 4 weeks
weeks.
Farup et al.[47] Norway, RCT, 16 (69,50) 24 / Rome II; 37.5% IBS‑D 6.25% Lactobacillus; Lactobacillus plantarum One capsule (1 × Placebo; One capsule q. Global symptoms score
Single center IBS‑C 56.25% IBS‑M MF 1298 1010CFU/capsule) q.d. d.; 6 weeks.
for 6 weeks.
Kruis et al.[48] Germany, RCT, 120 (76.7,45.7) NA 60, 60 Rome II; 45% IBS-D, 29.2% Escherichia coli; Escherichia coli One capsule (2.5-25 × Placebo; The same
Single center IBS-C, 25.8%IBS-M/U Nissle1917 109 CFU/capsule) o.d. protocol; 12 weeks
Table 1
(Continued)
Sample size Group
for 4 days then b.i.d. for Clinical response (Patients
12 weeks Reported satisfied in
treatment)
Murakami et al.[49] Japan, Single 35 (56.5,16.2) NA / Rome III; subtype not reported Lactobacillus; One capsule containing (≥1.0 × 1010 CFU/ Placebo; One capsule q.d; Relief of IBS symptoms,
center KB290 (freeze-dried KB290 bodies capsule) q.d for 8 for 8 weeks Quality of life (QOL)
weeks
Begtrup et al.[50] Denmark, RCT, 131 (30,30.5) 24.5 67, 64 Rome III; 40.5% IBS‑D, Combination; Lactobacillus paracasei Two capsules (1.3 × 1010 Placebo; Two capsules b. Adequate relief of global
Single center 19.1% IBS‑C, 38.2% ssp paracasei F19, Lactobacillus CFU/capsule) b.i.d. for i.d.; 24 weeks IBS symptoms
IBS‑M, 2.2% IBS‑U acidophilus La5, and 6 months
Bifidobacterium Lactis Bb 12
Charbonneau et al.[51] USA, RCT, Single 76 (81.7,45.1) 30.2 39, 37 Rome II; subtype not reported Bifidobacterium; Bifidobacterium. One capsule (1 × 109 Placebo; One capsule q. Relief of IBS symptoms
center infantis 35624 CFU/capsule) q.d. for 8 d.; 8 weeks.
weeks
Ko et al.[52] Korea, RCT, 26 (63.3,37.3) 22.8 13, 40 Rome III; 100% IBS‑D Combination; Bifidobacterium brevis, One capsule (5 billion Placebo; One capsule t.i. Adequate relief of overall
Single center Bifidobacterium lactis, bacteria/capsule) t.i.d. d.; 8 weeks. IBS symptoms
Bifidobacterium longum, for 8 weeks.
Lactobacillus acidophilus,
Lactobacillus plantarum,
3638
Lactobacillus rhamnosus, and

Streptococcus thermophilus
Roberts et al.[53] UK, RCT, 179 (85,44.2) 26.3 88, 91 Rome III; 100% IBS‑C or Combination; Bifidobacterium lactis I- One pot (1.25 × 1010 Placebo;One pot b.i.d.; for Subjective global
Thirteen IBS‑M 2494 (previously known as CFU/pot or 1.2 × 109 12 weeks assessment of
centers DN173010) Streptococcus CFU/pot) b.i.d. for 12 symptom relief
thermophilus I-1630, and weeks
Lactobacillus bulgaricus I‑1632 and
I‑1519
Abbas et al.[54] Pakistan, RCT, 72 (26.4,35.4) 35.4 37, 35 Rome II; 100 % IBS‑D Saccharomyces; Saccharomyces 750 mg q.d for 6 weeks Placebo; 6 weeks (week Abdominal pain
Single center boulardii (week 3-8) 3-8).
Jafari et al.[55] Iran, RCT,Single 108 (60.2,36.7) NA 51, 46 Rome III; subtype not reported Combination; Bifidobacterium animalis One capsule (4 × 108 Placebo; b.i.d.; 4 weeks Relief of IBS symptoms
center subsp. lactisBB‑12®, Lactobacillus CFU/capsule) b.i.d. for
acidophilus LA‑5®, Lactobacillus 4 weeks
delbrueckii subsp. bulgaricus
LBY‑27, and Streptococcus

thermophilus STY‑31
Lorenzo-Zuniga et al.[56] Spain, RCT, Two 84 (63.1,46.8) 25.6 55, 29 Rome III; 100% IBS-D Combination; Lactobacillus plantarum High dose (1-3 × 1010 Placebo; One capsule q.d. Relief of IBS symptoms
centers CECT7484, Lactobacillus plantarum CFU/capsule) q.d. or for 6 weeks
CECT7485, and Pediococcus Low dose (3-6 ×
acidilactici CECT7483 109CFU/capsule) t.i.d.
for 6 weeks
Ludidi et al.[57] Netherlands, 40 (67.5,40.5) 25.5 21, 19 Rome III; 42.5% IBS‑D, 10% Combination; Bifidobacterium lactis One sachet (5 × 109 CFU/ Placebo; One sachet (5 g) Mean symptom
RCT, Single IBS‑C, 30% IBS‑M, 17 .5% W52, Lactobacillus casei W56, sachet) o.d. for 6 o.d. for 6 weeks composite score
center IBS‑U Lactobacillus salivarius W57, weeks
Lactococcus lactis W58,
Lactobacillus acidophilus NCFM, and
Lactobacillus rhamnosus W71
Pedersen et al.[58] Denmark, RCT, 123 (73.2,37.3) 22.7 41, 40 Rome III; 40.7% IBS-D, Lactobacillus; Lactobacillus rhamnosus One capsule b.i.d. for 6 Low FODMAP diet for 6 Reduction of IBS-SSS
Single center 15.4% IBS-C 38.2% IBS-M GG weeks weeks; Normal Danish/
Western diet for 6 weeks
Rogha et al.[59] Iran, RCT, Single 85 (78.6,39.8) NA 33, 39 Rome III; 12.5% IBS-C 32% Bacillus; Bacillus Coagulans and One tablet (15 × 107 Placebo; One tablet t,i,d,; Relief of IBS symptoms
center IBS-D 50% IBS-M Fructo-oligosaccharides (100 mg). Spores) t,i,d, for 12weeks 12 weeks
Sisson et al.[60] UK, RCT, Single 186 (69.4,38.3) NA 124, 62 Rome III; 37 .6% IBS‑D, Combination; Lactobacillus rhamnosus 1 ml (1 × 1010 CFU/50 Placebo (containing inert IBS-SSS
center 21.5% IBS-C, 35.5% IBS‑M, NCIMB 30174, Lactobacillus ml) q.d. for 12weeks flavorings and water); 1
5.4% IBS‑U plantarum NCIMB 30173, ml q.d.; 12 weeks
Lactobacillus acidophilus NCIMB
30175, and Enterococcus faecium
NCIMB 30176
Stevenson et al.[61] South Africa, 81 (97.5,47.9) 28.9 54, 27 Rome III; 37.6% IBS-D, Lactobacillus; Lactobacillus plantarum Two capsules (5 × 109 Placebo; Two capsules q. IBS symptom severity
RCT, Single 21.5% IBS-C 299v CFU/capsule) q.d. for 8 d.; 8 weeks Scores
center weeks
Yoon et al.[62] Korea, RCT, 49 (65.3,44.5) NA 25, 24 Rome III; 53.1% IBS-D, Combination; Bifidobacterium bifidum One capsule (5 × Placebo; One capsule b.i. Global relief of IBS
Single center 40.8% IBS-C, 6.1% IBS-M KCTC 12199BP, Bifidobacterium 109viable cells/capsule) d.; 4 weeks Symptoms
Lactis KCTC 11904BP, Bifidobacteriu b.i.d. for 4 weeks
Longum KCTC 12200BP, Lactobacillus
acidophilus KCTC 11906BP,
Lactobacillus rhamnosus KCTC
12202BP, and Streptococcus
thermophilus KCTC 11870BP
Pineton de Chambrun France, RCT, 200 (86,44) NA 93, 86 Rome III; 28.5% IBS-D, Saccharomyces; Saccharomyces One capsule (8 × 109 Placebo; One capsule q. Improvement of
et al.[63] Single center 46.9% IBS‑C, 24.6% IBS‑M cerevisiae CNCMI‑3856 CFU/capsule) q.d. for 8 d.; 8 weeks abdominal pain adverse
weeks event
3639
Wong et al.[64] Singapore, RCT, 42 (45.2,47) NA 20, 22 Rome III; IBS‑M Combination; VSL#3 Four capsules (225 billion Placebo;four capsules b.i. Overall IBS symptom
Single center bacteria/capsule) b.i.d. for d.; 6 weeks scores
6 weeks
Yoon et al.[65] Korea, RCT, 81 (46.3,59.3) NA 39, 42 Rome III; 48.1% IBS-D, Combination; Bifidobacterium bifidum One capsule (5 × 109 Placebo; One capsule b.i. Adequate relief of overall
Single center 18.5% IBS-C, 21%IBS-M, (KCTC 12199BP,) Bifidobacterium viable cells/capsule) b.i.d. d.; 4 weeks IBS symptoms
12.4%IBS-U lactis (KCTC11904BP), for 4 weeks.
Bifidobacterium Longum (KCTC
12200BP), Lactobacillus acidophilus
(KCTC 11906BP), Lactobacillus
rhamnosus (KCTC 12202BP), and
Streptococcus thermophilus (KCTC
11870BP)
Lyra et al.[66] Finland, RCT, 391 (74.7,47.9) 24.7 260, 131 Rome III; 38.9% IBS‑D, Lactobacillus; Lactobacillus acidophilus One capsule (low dose: 1 Placebo;One capsule q. IBS symptom severity
Two centers 16.6% IBS‑C, 44% IBS‑M, NCFM (ATCC 700396) × 109 CFU/capsule; high d.; 12 weeks Scores
0.5% IBS‑U dose: 1 × 1010 CFU/
capsule) q.d. for 1 2
weeks
Spiller et al.[67] UK, RCT, Single 379 (83.6,45.4) NA 192, 187 Rome III; 20.8 % IBS-D, 47.5 Saccharomyces; Saccharomyces. 1000 mg (8 × 109 CFU/g) Placebo (calcium Improvement of 50% of
center % IBS‑C, 31.7% IBS‑M cerevisiae I-3856 q.d. for 12 weeks phosphate and the weekly average
maltodextrin) q.d.; 12 "intestinal pain/
weeks discomfort score"
Thijssen et al.[68] Holland, RCT, 80 (68.8,41.8) 25.1 39, 41 Rome II, 30% IBS-D, 25% A fermented milk drink (65ml per One bottle (6.5 × 109 Placebo; One bottle Mean symptom score
Four centers IBS-C, 28.75% IBS-M, bottle); Lactobacillus CFU/bottle) b.i.d. for 8 (65ml) b.i.d.; 8 weeks decrease of at least 30%
16.25% IBS-U weeks
Hod et al.[69] 107 (100,29.5) 22.3 54, 53 Rome III; 100% IBS-D b.i.d. for 8 weeks Placebo; b.i.d.; 8 weeks
Table 1
(Continued)
Sample size Group
Israel, RCT, Combination; Lactobacillus rhamnosus Abdominal pain, overall
Single center LR5, Lactobacillus casei LC5, responder rates
Lactobacillus Paracasei.LPC5,
Lactobacillus plantarum LP3,
Lactobacillus acidophilus LA1,
Bifidobacterium Bifidum BF3,
Bifidobacterium Longum BG7,
Bifidobacterium breve BR3,
Bifidobacterium infantis BT1,
Streptococcus, thermophilus ST3,
Lactococcus bulgaricus LG1, and
Lactococcus Lactis SL6
Pinto-Sanchez et al.[70] Canada, RCT, 44 (54,43.3) 24.9 22, 22 Rome III; 61.4% IBS‑D, Bifidobacterium; Bifidobacterium (1.0 × 1010 CFU/gram Placebo; 6 weeks Adequate relief of IBS
Single center 38.6% IBS‑M longum, NCC3001 powder with maltodextrin) symptoms
for 6 weeks.
Staudacher et al.[71] UK, RCT, two 104 (67.5,35.5) 24.5 / Rome III; 66.3% IBS-D, Combination; VSL#3 4 weeks Placebo, sham diet; 4 Adequate relief of IBS
centers 23.1% IBS-M, 10.6% IBS-U weeks symptoms
Shin et al.[72] Korea, RCT, 60 (56.9,36.5) 23.4 27, 24 Rome III; 100% IBS‑D, Lactobacillus; Lactobacillus. gasseri Two capsules b.i.d. for 8 Placebo; Two capsules b. Relief of IBS symptoms
3640
Single center BNR17 weeks i.d.; 8 weeks

Catinean et al.[73] Romania, RCT, 90 (60,39.4) 25.2 30, 60 Rome III; 100 % IBS-D Bacillus; MegaSporeBiotic a mixture of q.d. for 1 week, then b.i. Ten-days rifaximin IBS-SSS Score
Single center spores of five Bacillus spp d. for 24 days. treatment followed by
either a nutraceutical
agent or a Low FODMAPs
for 24 days
Madempudi et al.[74] India, RCT, 136 (27.8,43.4) 24.8 53, 55 Rome III; IBS-D, IBS‑C, IBS‑M, Bacillus; Bacillus coagulants Unique One capsule (2 billion Placebo;One capsule q. Relief of abdominal pain,
Single center IBS‑U IS2 CFU/capsule) q.d. for 8 d.; 8 weeks Satisfactory relief of IBS
weeks symptoms
Oh et al.[75] Korea, RCT, 55 (72,32.8) 21.5 26, 24 Rome III; 42% IBS‑D,20% Combination; Lactobacillus species, q.d. for 4 weeks. Placebo; q.d.; 4 weeks. Relief of IBS Symptoms
Single center IBS‑M, 38% IBS‑U Lactobacillus paracasei, Lactobacillus
salivarius, and Lactobacillus
plantarum.
Andresen et al.[76] Germany, RCT, 443 (69.5,41.4) 24.6 221, 222 Rome III; 40% IBS‑D, 24.1% Bifidobacterium; Bifidobacterium Two capsules (1 × 109 Placebo; q.d.; 8 weeks Adequate relief of IBS
twenty-center IBS‑C, 7.7% IBS‑M, 28.2% bifidum MIMBb75 cells/capsule) q.d. for 8 symptoms

IBS‑U weeks
Gayathri et al.[77] India, RCT, 100 (34,41) NA 52, 48 Rome III;65 % IBS-D, 24 % Saccharomyces; Saccharomyces One capsule (2 × 109 Placebo; One capsule b.i. Abdominal pain score
Single center IBS‑C, 11% IBS‑M cerevisiae CNCM I-3856 CFU/capsule) b.i.d. for 8 d.; 8 weeks.
weeks
Kim et al.[78] Korea, RCT, 63 (74.6,36) NA 32, 31 Rome II; 100% IBS-D Combination; Bifidobacterium longum One capsule (5 × Placebo; One capsule t.i. Relief of IBS symptoms
Single center BORI, Bifidobacterium bifidum BGN4, 109viable cells/capsule) t. d.; 8 weeks
Bifidobacterium lactis AD011, i.d. for 8 weeks
Bifidobacterium infantis IBS007, and
Lactobacillus acidophilus AD031
Lewis et al.[79] Canada, RCT, 285 (77.7,42) NA 167, 81 Rome III; 15.1% IBS-D, Placebo; One capsule q. IBS Symptom Severity
Single center 11.2% IBS-C, 73.7%IBS-M d.; 8 weeks. Score
One capsule (10 × 109

Lactobacillus or Bifidobacterium;
Lactobacillus paracasei HA-196 or CFU/capsule) q.d. for 8
Bifidobacterium longum R0175 weeks.
Martoni et al.[80] USA, RCT, 336 (49.5,39.5) 24 224, 112 Rome III; Subtype not reported Lactobacillus or Bifidobacterium; One capsule (1 × Placebo; q.d.; 6 weeks Relief of IBS symptoms
Twelve-center Lactobacillus acidophilus DDS- 1010 CFU/capsule) q.d. score
1 or Bifidobacterium lactis UABla‐12 for 6 weeks.
Sadrin et al.[81] France, RCT, 80 (71,48.9) NA 40, 40 Rome III; Subtype not reported Lactobacillus; Lactobacillus acidophilus Two capsules (5 × Placebo;Two capsules b.i. Relief of IBS symptoms
Multicenter NCFM and Lactobacillus acidophilus 109CFU/capsule) b.i.d. for d.; 8 weeks score
subsp. Helveticus LAFTI L10 8 weeks
Wilson et al.[82] UK, RCT, Single 69 (55.1,34.1) 24.7 24, 45 Rome III; 65% IBS-D Bifidobacterium; Bifidobacterium q.d. for 4 weeks. Placebo; q.d.; 4 weeks. Relief of IBS Symptoms
center bifidum NCIMB 41171
Barraza-Ortiz et al.[83] México, RCT, 55 (67.2,45.5) 25.2 37, 18 Rome IV; 52.7% IBS-D 47.3% Combination; Lactobacillus plantarum t.i.d for 6 week Placebo; t,i,d, 6 weeks Response rate in QoL,
Single center IBS-M CECT 7484, Lactobacillus plantarum Abdominal pain
CECT 7485, and Pediococcus
acidilactici CECT 7483
Gupta et al.[84] India, RCT, 40 (30,35.5) 23.8 20, 20 Rome IV; Subtype not reported Bacillus; Bacillus coagulants LBSC t.i.d for 80 days Placebo; t,i,d,; 80 days
IBS-SSS, Change in stool
Single center consistency
Skrzydło- Poland, RCT, 51 (64.5,43.1) 25.9 25, 23 Rome III; 100% IBS-D Combination; Bifidobacterium, One capsule b.i.d. for 8 Placebo; One capsule b.i. IBS-SSS, Global
Radomańska et al.[85] Single center Lactobacillus, and Streptococcus weeks d.; 8 weeks Improvement Scale (IBS-
thermophilus GIS)
Mack et al.[86] Germany, RCT, 389 (69,46.4) 26 191, 198 Rome III; 16.1% IBS-C 39.8% Combination; Escherichia coli (DSM 10 drops (0.71 mL) 3 × Placebo; The same dose IBS Global Assessment of
Multicenter IBS-D 36,2% IBS-M 17252) and Enterococcus faecalis /day during week 1, 20 and duration Improvement Scale (IBS-
(DSM 16440) drops (1.42 mL) 3 × /day GAI), Abdominal pain
during week 2, 30 drops
(2.14 mL) 3 × /day during
3641
week 3, and 30 drops 3 ×

/day until week 26
Moeen-Ul-Haq et al.[87] Pakistan, RCT, 120 (41.7,35.9) NA 55, 53 Rome III; 25.9% IBS-C 30.6% Lactobacillus; Lactobacillus plantarum (5x1010 CFU) for 4 weeks Placebo (comprised Daily frequency of
Single center IBS-D 43,5% IBS-M 299v micro-crystalline cellulose abdominal pain,
powder); 4 weeks Improvement in the
severity of abdominal
pain, The severity of
bloating
Mourey et al.[88] France, RCT, 456 (86,40.5) NA 230, 226 Rome IV; 100% IBS-C Saccharomyces; Saccharomyces Two capsules (8 × 109 Placebo; q.d.; 8 weeks Global IBS symptoms
Four centers cerevisiae CNCM I-3856 CFU/capsule) q.d. for 8
weeks
BMI, body mass index; B.i.d, twice a day. CFU, colony forming units; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; GSRS, gastrointestinal symptom rating scale; IBS, irritable bowel syndrome; IBS-C, constipation-predominant irritable bowel
syndrome; IBS-D, diarrhea-predominant irritable bowel syndrome; IBS-M, mixed irritable bowel syndrome; IBS-U, un-subtyped irritable bowel syndrome; IBS-SSS, irritable bowel syndrome symptom severity score; IBS-QOL, evaluation of the irritable bowel syndrome quality of life;
O.d, once every two days. Q.d, four times a day; RCT, randomized controlled trial; T.i.d, three times a day. VSL#3, a combination of three types of Bifidobacterium (Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium breve).
*This column is arranged according to years.
†
(I, P) refers to the sample sizes for probiotics and control groups, respectively, whereas the I refers to the probiotic group and the P refers to the control group.
‡
This column lists numerous abbreviations for the probiotic components which were named as the article reported or according to the nomenclature or naming system for bacteria suggested by the International Committee on Systematics of Prokaryotes.
Figure 2. The three-level meta-analysis concept and results. IBS, irritable bowel syndrome; SMD, standardized mean difference. Note: The figure shows the
concept of the three-level meta-analysis model and the results of the three outcomes. The three-level meta-analysis was conceived and developed to solve the
problems of correlated data and missing information, which were unsatisfactorily settled in the traditional meta-analysis model[9]. For example, the severity of global
IBS symptoms was assessed by differential scales at differential time points, and in most circumstances in traditional meta-analyses, data from one specific scale
measured at one time point would be selected, which induced loss of information. We adopted the three-level model to synthesize all data from the relevant scales
measured at defined time intervals, and we provided a general effect size using the SMD. According to previous literature, an absolute value of SMD larger than 0.5
would indicate a medium size of effect[15], meeting the standard of recommendation for clinical practice. Our meta-analysis demonstrated that all SMDs for the three
outcomes exceeded that cut-off point of 0.5.
IBS and confirms a medium effect size of probiotics on the that longer treatment duration might be associated with better
improvement of global IBS symptoms (SMD 0.56) – suggesting a efficacy in the treatment of IBS with probiotics[90], while the
possible generalization to routine practice. other two studies showed that a shorter treatment duration of
Shorter treatment duration or study duration being asso- probiotics would be more efficacious[91,92]. Our meta-analysis,
ciated with larger treatment effects of probiotics was one of the with a larger number of included trials and the inclusion of
major findings of our meta-analysis. A network meta-analysis more efficacy data (through a third-level model), confirmed
published in 2022 reported that treatment duration could that shorter treatment duration was associated with a larger
affect the efficacy of probiotics in the relief of abdominal pain treatment effect. Several hypotheses were proposed for this
and strain, and it showed that using Bacillus coagulans for 8 phenomenon. First, trials with small sample sizes and single-
weeks was the most efficacious[89]. Dale and colleagues found center design were more likely to have short treatment
A B
C D
Figure 3. The moderators of the probiotic effects on global IBS symptoms. IBS, irritable bowel syndrome. SMD, standard mean difference. Note: The figure shows
that (A) continents, (B) study duration, (C) treatment duration, and (D) types of outcome definition are the most important moderators of the probiotic effects. (A) The
study population in Asia, Europe, and North America had larger effect sizes than in Africa. (B) and (C), shorter study duration (< 4 weeks) and treatment duration (< 4
weeks) were associated with larger effect sizes. (D) The outcome of abdominal discomfort was associated with larger effect sizes than other outcomes.
3642
Table 2
Moderator analysis of the outcome measurements.
Global IBS symptoms Abdominal pain QoL assessment
Moderators Estimate P* Estimate P* Estimate P*

Continents
Africa 1.51 (− 0.44 to 3.46) Reference NA NA − 0.23 (− 3.38 to 2.92) Reference
Asia − 1.06 (− 1.51 to − 0.61) 0.012 − 1.44 (− 2.24 to − 0.64) Reference 2.71 (0.72 to 4.7) 0.118
Europe − 0.46 (− 0.76 to − 0.23) 0.05 − 0.91 (− 1.58 to − 0.23) 0.314 0.98 (− 0.07 to 2.02) 0.466
North American − 0.74 (− 1.41 to − 0.07) 0.033 − 0.2 (− 1.78 to 1.38) 0.167 0.76 (− 0.99 to 2.52) 0.58
Assessment time points
Within 8 weeks − 0.7 (− 0.93 to − 0.48) Reference − 0.97 (− 1.36 to − 0.59) Reference 1.18 (0.56 to 1.79) Reference
9–16 weeks 0.06 (− 0.46 to 0.57) 0.05 − 0.85 (− 1.79 to 0.08) 0.807 0.53 (− 0.28 to 1.34) 0.128
17–24 weeks − 0.26 (− 1.1 to 0.59) 0.316 − 0.54 (− 2.62 to 1.53) 0.686 0.65 (− 1.9 to 3.19) 0.68
> 24 weeks 1.48 (− 0.89 to 3.86) 0.07 NA NA NA NA
RCT types
Single center − 0.66 (− 0.96 to − 0.37) 0.672 − 1.15 (− 1.74 to − 0.55) Reference 1.3 (0.1 to 2.49) Reference
Multicenter − 0.55 (− 0.97 to − 0.14) 0.614 − 0.82 (− 1.68 to 0.04) 0.534 0.99 (− 0.16 to 2.15) 0.715
Multi-nation 0.18 (− 2.67 to 3.04) Reference NA NA NA NA
Number of study sites 0.02 (− 0.02 to 0.04) 0.375 0.04 (− 0.034 to 0.107) 0.305 − 0.03 (− 0.28 to 0.22) 0.824
Study duration
< 4 weeks − 1.02 (− 1.48 to − 0.57) Reference − 1.71 (− 2.62 to − 0.8) Reference 6.58 (4.09 to 9.07) Reference
4–12 weeks − 0.6 (− 0.89 to − 0.31) 0.126 − 0.75 (− 1.37 to − 0.13) 0.086 0.95 (0.31 to 1.58) < 0.001
> 12 weeks 0.02 (− 0.62 to 0.66) 0.009 − 0.94 (− 2.45 to 0.57) 0.387 0.54 (− 0.27 to 1.35) < 0.001
Age 0.02 (− 0.02 to 0.06) 0.44 − 0.006 (− 0.1 to 0.09) 0.895 − 0.25 (− 0.51 to 0.006) 0.055
Proportion of female 0.005 (− 0.008 to 0.02) 0.463 0.02 (0.001 to 0.046) 0.04 − 0.05 (− 0.1 to 0.008) 0.088
Proportion of drop-outs 0.008 (− 0.004 to 0.02) 0.205 0.02 (− 0.02 to 0.05) 0.347 − 0.007 (− 0.05 to 0.03) 0.748
Disease duration 0.03 (− 0.06 to 0.122) 0.523 0.11 (− 0.78 to 1) 0.791 − 0.11 (− 0.62 to 0.39) 0.635
Diagnostic criteria
Others − 0.78 (− 1.78 to 0.25) Reference − 1.07 (− 2.82 to 0.67) Reference 1.18 (− 3.03 to 5.4) Reference
Rome − 0.25 (− 2.4 to 1.91) 0.667 − 0.39 (− 3.42 to 2.65) 0.697 NA NA
Rome II − 0.61 (− 1.1 to − 0.16) 0.784 − 1.37 (− 2.41 to − 0.32) 0.774 1.55 (0.23 to 2.87) 0.866
Rome III − 0.62 (− 0.94 to − 0.3) 0.781 − 1 (− 1.65 to − 0.35) 0.936 0.85 (− 0.46 to 2.16) 0.88
Rome IV − 0.56 (− 1.91 to − 0.79) 0.807 − 0.38 (− 2.58 to 1.83) 0.623 0.33 (− 3.13 to 3.79) 0.753
Treatment duration
< 4 weeks − 1 (− 1.37 to − 0.63) Reference − 1.45 (− 2.24 to − 0.65) Reference 6.58 (4.13 to 9.02) Reference
4–8 weeks − 0.56 (− 0.88 to − 0.24) 0.08 − 0.89 (− 1.56 to − 0.22) 0.286 0.99 (0.44 to 1.54) < 0.001
> 8 weeks − 0.02 (− 0.57 to 0.54) 0.004 − 0.26 (− 1.87 to 1.35) 0.19 0.1 (− 0.94 to 1.14) < 0.001
Types of probiotics
Bacillus − 0.58 (− 1.62 to 0.46) Reference − 2.23 (− 4.31 to − 0.14) Reference NA NA
Bifidobacterium − 0.77 (− 1.42 to − 0.12) 0.757 − 0.44 (− 1.54 to 0.65) 0.136 0.77 (− 0.27 to 1.81) Reference
Combination − 0.65 (− 0.96 to − 0.34) 0.901 − 1.24 (− 1.85 to − 0.63) 0.37 1.18 (0.65 to 1.71) 0.487
Enterococcus − 0.51 (− 2.07 to 1.06) 0.939 − 1.38 (− 4.44 to 1.69) 0.651 NA NA
Escherichia coli − 0.59 (− 2.06 to 0.87) 0.987 − 0.65 (− 3.97 to 2.67) 0.427 0.61 (− 0.92 to 2.15) 0.866
Lactobacillus − 0.6 (− 1.07 to − 0.13) 0.969 − 1.04 (− 1.78 to − 0.31) 0.29 0.12 (− 0.49 to 0.73) 0.285
Saccharomyces − 0.09 (− 1.21 to 1.03) 0.529 0.41 (− 0.93 to 1.75) 0.037 6.45 (4.36 to 8.55) < 0.001
Types of outcomes
Continuous − 0.5 (− 0.82 to − 0.18) Reference − 1.08 (− 1.55 to − 0.6) Reference 1.4 (0.56 to 2.24) Reference
Categorical − 0.71 (− 0.97 to − 0.44) 0.301 − 0.59 (− 1.37 to 0.18) 0.279 1.23 (0.06 to 2.4) 0.895
Types of outcome definition NA NA NA NA
Adequate relief − 0.51 (− 1.06 to 0.05) Reference
Bloating − 0.77 (− 1.2 to − 0.35) 0.445
Bowel habits − 0.49 (− 0.9 to − 0.07) 0.953
Abdominal discomfort − 1.56 (− 2.23 to − 0.89) 0.017
Global symptoms − 0.51 (− 0.81 to − 0.2) 0.999
Urgency 0.27 (− 2.03 to 2.57) 0.518
NA, not available; QoL, quality of life.
*The P values were estimated as the reference categories being compared with the reference category.
duration and study duration, which could be the consequence meta-analysis investigating the magnitude of placebo response
of a shortage of study funding, so the larger treatment effects in IBS trials, short treatment duration was found to be asso-
could be explained by small-study effects[93]. Second, the lar- ciated with a large placebo effect[97]. Third, the moderator
ger effect of probiotics on IBS might also be attributed to a effect of short treatment duration might reflect the association
powerful placebo – similar to the effect of sham device or between the severity of the IBS symptoms and the effect of the
sham acupuncture reported in previous studies[94–96]. In a assessed intervention. Patients with severer IBS symptoms
3643
might report a smaller treatment effect of probiotics, and the Ethical approval
physicians might be inclined to suggest a longer treatment
duration, especially for those with refractory IBS[98]. This article is a systematic review and meta-analysis; ethical
Regarding that, the diagnostic criteria of refractory IBS are approvals were acquired in the original studies, and additional
difficult to define and the severity of IBS disease is determined approval was not required for this meta-analysis.
by several factors – health-related quality of life, psychosocial
factors, healthcare utilization behaviors, and burden of Consent
illness[99], so it is impossible to test this hypothesis based on
the included trials in this meta-analysis since most of the This article is a systematic review and meta-analysis; consents
included studies did not classify the disease severity owing to were acquired in the original studies, and additional consents
the lack of standard criteria. This informs that there is an were not required for this meta-analysis.
urgent need for a standard scale to estimate the overall severity
of IBS to minimize the heterogeneity caused by the study
population in future meta-analyses on probiotics for IBS.
Sources of funding
Additionally, future RCTs are encouraged to report symptom M.C. received a grant from the National Natural Science
severity of IBS using scales like IBS-SSS in baseline evaluation Foundation of China (No. 82274529) and a grant
to facilitate subgroup or meta-regression analysis for clarifying (no. 2022NSFSC1503) from the Science and Technology
the relationship between severity of IBS and probiotic treat- Department of Sichuan Province. H.Z. received a grant from the
ment duration. Sichuan Youth Science and Technology Innovation Research
Although we did not find an impact of different types of pro- Team (no. 2021JDTD0007).
biotics on the improvement of IBS symptoms, we found that
Bacillus strains led to better improvement in abdominal pain
than other strains and were significantly better than the Author contribution
Saccharomyces strain. This finding was consistent with a recent
All authors had full access to all the data in the study and take
network meta-analysis comparing differential probiotics for the
responsibility for the integrity of the data and the accuracy of the
treatment of IBS[7], which implies that the Bacillus strains might
data analysis. M.C. and H.Z.: conceived and designed the study;
be developed for the treatment of functional abdominal pain and
M.C., L.Y., C.-R.X., X.-Y.W., S.-J.F., and X.-Y.X.: acquired,
warrants further clarification.
analyzed, and interpreted the study data. M.C.: drafted the
Our study had several limitations. First, the certainty of the
manuscript. All authors revised the manuscript.
evidence was low because most of the included trials were clas-
sified as with some concerns or a high risk of bias. Many trials had
some concerns in the randomization process (mainly the problem Conflicts of interest disclosure
of the transparency of allocation concealment) and the mea-
surement of the outcomes. Second, the large heterogeneity in the The authors declare that they have no conflicts of interest.
meta-analysis was also a concern. The heterogeneity might be
caused by the difference in the study population and the inter-
Research registration unique identifying number
vention protocols. We ran the moderator analysis and confirmed
(UIN)
that the duration of treatment and study, the study regions, and
the types of outcomes might be the source of heterogeneity. Third, Open Science Framework (https://osf.io/rq87j).
although the method of transforming between OR and SMD
enlarged the sample size of the meta-analysis, it made the expla-
nation of the results difficult for clinical practitioners, who might Guarantor
transform it back to the original scale by multiplying the SMD
Hui Zheng.
generated from the meta-analysis by the standard deviation of the
specific scale[14]. Fourth, forty-eight reports were excluded for the
unavailability of full-text copies, which were mainly abstracts of Provenance and peer review
conference presentations and supplementary issues. These
reports, known as grey literature, might be valuable for our meta- Not commissioned, externally peer-reviewed.
analysis and might change the conclusion of our study. Updated
systematic review and meta-analysis might therefore be war-
Data availability statement
ranted while many of them were available with sufficient data for
analysis. Data used for analysis will be available upon reasonable request,
which will be released in the Open Science Framework platform
(https://osf.io/rq87j).
Conclusions
Our meta-analysis suggested a medium short-term effect of pro- Role of the funder/sponsor
biotics on the improvement of global IBS symptoms and abdominal
pain. We found that the treatment duration, study regions, the The sponsors had no role in the design and conduct of the study,
types of outcomes, and the types of probiotics might be major effect and they had no role in the decision process to submit the
moderators, which warrants further investigation. manuscript for publication.
3644
References [24] Kim YG, Moon JT, Lee KM, et al. The effects of probiotics on symptoms
of irritable bowel syndrome. Korean J Gastroenterol 2006;47:413–9.
[1] Oka P, Parr H, Barberio B, et al. Global prevalence of irritable bowel
[25] Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated
syndrome according to Rome III or IV criteria: a systematic review and
probiotic Bifidobacterium infantis 35624 in women with irritable bowel
meta-analysis. Lancet Gastroenterol Hepatol 2020;5:908–17.
syndrome. Am J Gastroenterol 2006;101:1581–90.
[2] Matsumoto S, Hashizume K, Wada N, et al. Relationship between
[26] Guyonnet D, Chassany O, Ducrotte P, et al. Effect of a fermented milk
overactive bladder and irritable bowel syndrome: a large-scale internet
containing Bifidobacterium animalis DN-173 010 on the health-related
survey in Japan using the overactive bladder symptom score and Rome III
quality of life and symptoms in irritable bowel syndrome in adults in
criteria. BJU Int 2013;111:647–52.
primary care: a multicentre, randomized, double-blind, controlled trial.
[3] Pace F, Molteni P, Bollani S, et al. Inflammatory bowel disease versus
Aliment Pharmacol Ther 2007;26:475–86.
irritable bowel syndrome: a hospital-based, case–control study of disease
[27] Drouault-Holowacz S, Bieuvelet S, Burckel A, et al. A double blind ran-
impact on quality of life. Scand J Gastroenterol 2003;38:1031–8.
domized controlled trial of a probiotic combination in 100 patients with
[4] Freedman SB, Schnadower D, Tarr PI. The probiotic conundrum: reg-
irritable bowel syndrome. Gastroenterol Clin Biol 2008;32:147–52.
ulatory confusion, conflicting studies, and safety concerns. JAMA 2020;
[28] Enck P, Zimmermann K, Menke G, et al. A mixture of Escherichia coli
323:823–4.
(DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of
[5] Ford AC, Harris LA, Lacy BE, et al. Systematic review with meta-analysis:
the irritable bowel syndrome – a randomized controlled trial with pri-
the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable
mary care physicians. Neurogastroenterol Motil 2008;20:1103–9.
bowel syndrome. Aliment Pharmacol Ther 2018;48:1044–60.
[29] Kajander K, Myllyluoma E, Rajilić-Stojanović M, et al. Clinical trial:
[6] Shang X, E F-F, Guo K-L, et al. Effectiveness and safety of probiotics for
multispecies probiotic supplementation alleviates the symptoms of irri-
patients with constipation-predominant irritable bowel syndrome: a
table bowel syndrome and stabilizes intestinal microbiota. Aliment
systematic review and meta-analysis of 10 randomized controlled trials.
Pharmacol Ther 2008;27:48–57.
Nutrients 2022;14:2482.
[30] Sinn DH, Song JH, Kim HJ, et al. Therapeutic effect of Lactobacillus
[7] McFarland LV, Karakan T, Karatas A. Strain-specific and outcome-
acidophilus-SDC 2012, 2013 in patients with irritable bowel syndrome.
specific efficacy of probiotics for the treatment of irritable bowel syn-
Dig Dis Sci 2008;53:2714–8.
drome: a systematic review and meta-analysis. EClinicalMedicine 2021;
[31] Zeng J, Li Y-Q, Zuo X-L, et al. Clinical trial: effect of active lactic acid
41:101154.
bacteria on mucosal barrier function in patients with diarrhoea-pre-
[8] Leis R, de Castro M-J, de Lamas C, et al. Effects of prebiotic and probiotic
dominant irritable bowel syndrome. Aliment Pharmacol Ther 2008;28:
supplementation on lactase deficiency and lactose intolerance: a sys-
994–1002.
tematic review of controlled trials. Nutrients 2020;12:1487.
[32] Agrawal A, Houghton LA, Morris J, et al. Clinical trial: the effects of a
[9] Riley RD, Jackson D, Salanti G, et al. Multivariate and network meta-
fermented milk product containing Bifidobacterium lactis DN-173 010
analysis of multiple outcomes and multiple treatments: rationale, con-
on abdominal distension and gastrointestinal transit in irritable bowel
cepts, and examples. BMJ 2017;358:j3932.
syndrome with constipation. Aliment Pharmacol Ther 2009;29:104–14.
[10] Houben M, Van Den Noortgate W, Kuppens P. The relation between
[33] Enck P, Zimmermann K, Menke G, et al. Randomized controlled treat-
short-term emotion dynamics and psychological well-being: a meta-
ment trial of irritable bowel syndrome with a probiotic E.-coli prepara-
analysis. Psychol Bull 2015;141:901–30.
tion (DSM17252) compared to placebo. Z Gastroenterol 2009;47:
[11] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an
209–14.
updated guideline for reporting systematic reviews. Int J Surg 2021;88:105906.
[34] Hong KS, Kang HW, Im JP, et al. Effect of probiotics on symptoms in
[12] Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool
Korean adults with irritable bowel syndrome. Gut Liver 2009;3:101–7.
for systematic reviews that include randomised or non-randomised stu-
[35] Hun L. Bacillus coagulans significantly improved abdominal pain and
dies of healthcare interventions, or both. BMJ 2017;358:j4008.
bloating in patients with IBS. Postgrad Med 2009;121:119–24.
[13] Chinn S. A simple method for converting an odds ratio to effect size for
[36] Williams EA, Stimpson J, Wang D, et al. Clinical trial: a multistrain
use in meta-analysis. Stat Med 2000;19:3127–31.
probiotic preparation significantly reduces symptoms of irritable bowel
[14] Murad MH, Wang Z, Chu H, et al. When continuous outcomes are
syndrome in a double-blind placebo-controlled study. Aliment
measured using different scales: guide for meta-analysis and interpreta-
tion. BMJ 2019;364:k4817.
[37] Simrén M, Öhman L, Olsson J, et al. Clinical trial: the effects of a fer-
[15] Serdar CC, Cihan M, Yücel D, et al. Sample size, power and effect size
mented milk containing three probiotic bacteria in patients with irritable
revisited: simplified and practical approaches in pre-clinical, clinical and
bowel syndrome – a randomized, double-blind, controlled study. Aliment
laboratory studies. Biochem Med (Zagreb) 2021;31:010502.
[16] Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of
[38] Choi CH, Jo SY, Park HJ, et al. A randomized, double-blind, placebo-
Interventions, Version 51 0. The Cochrane Collaboration; 2011.
controlled multicenter trial of Saccharomyces boulardii in irritable bowel
[17] Gade J, Thorn P. Paraghurt for patients with irritable bowel syndrome.
syndrome: effect on quality of life. J Clin Gastroenterol 2011;45:679–83.
A controlled clinical investigation from general practice. Scand J Prim
[39] Guglielmetti S, Mora D, Gschwender M, et al. Randomised clinical trial:
Health Care 1989;7:23–6.
Bifidobacterium bifidum MIMBb75 significantly alleviates irritable
[18] Nobaek S, Johansson ML, Molin G, et al. Alteration of intestinal bowel syndrome and improves quality of life – a double-blind, placebo-
microflora is associated with reduction in abdominal bloating and pain in controlled study. Aliment Pharmacol Ther 2011;33:1123–32.
patients with irritable bowel syndrome. Am J Gastroenterol 2000;95: [40] Michail S, Kenche H. Gut microbiota is not modified by randomized,
1231–8. double-blind, placebo-controlled trial of VSL#3 in diarrhea-predominant
[19] Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, irritable bowel syndrome. Probiotics Antimicrob Proteins 2011;3:1–7.
randomized study on the efficacy of Lactobacillus plantarum 299V in [41] Ringel-Kulka T, Palsson OS, Maier D, et al. Probiotic bacteria
patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07
2001;13:1143–7. versus placebo for the symptoms of bloating in patients with func-
[20] Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a tional bowel disorders: a double-blind study. J Clin Gastroenterol
probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant 2011;45:518–25.
irritable bowel syndrome. Aliment Pharmacol Ther 2003;17:895–904. [42] Sondergaard B, Olsson J, Ohlson K, et al. Effects of probiotic fermented
[21] Kajander K, Hatakka K, Poussa T, et al. A probiotic mixture alleviates milk on symptoms and intestinal flora in patients with irritable bowel
symptoms in irritable bowel syndrome patients: a controlled 6-month syndrome: a randomized, placebo-controlled trial. Scand J Gastroenterol
intervention. Aliment Pharmacol Ther 2005;22:387–94. 2011;46:663–72.
[22] Kim HJ, Vazquez Roque MI, Camilleri M, et al. A randomized controlled [43] Cha BK, Jung SM, Choi CH, et al. The effect of a multispecies probiotic
trial of a probiotic combination VSL# 3 and placebo in irritable bowel mixture on the symptoms and fecal microbiota in diarrhea-dominant
syndrome with bloating. Neurogastroenterol Motil 2005;17:687–96. irritable bowel syndrome: a randomized, double-blind, placebo-con-
[23] Niv E, Naftali T, Hallak R, et al. The efficacy of Lactobacillus reuteri trolled trial. J Clin Gastroenterol 2012;46:220–7.
ATCC 55730 in the treatment of patients with irritable bowel syndrome – [44] Cui S, Hu Y. Multistrain probiotic preparation significantly reduces
a double blind, placebo-controlled, randomized study. Clin Nutr 2005; symptoms of irritable bowel syndrome in a double-blind placebo-con-
24:925–31. trolled study. Int J Clin Exp Med 2012;5:238–44.
3645
[45] Dapoigny M, Piche T, Ducrotte P, et al. Efficacy and safety profile of [67] Spiller R, Pélerin F, Cayzeele Decherf A, et al. Randomized double blind
LCR35 complete freeze-dried culture in irritable bowel syndrome: a placebo-controlled trial of Saccharomyces cerevisiae CNCM I-3856 in
randomized, double-blind study. World J Gastroenterol 2012;18: irritable bowel syndrome: improvement in abdominal pain and bloating
2067–75. in those with predominant constipation. United Eur Gastroenterol J
[46] Ducrotté P, Sawant P, Jayanthi V. Clinical trial: Lactobacillus plantarum 2016;4:353–62.
299v (DSM 9843) improves symptoms of irritable bowel syndrome. [68] Thijssen AY, Clemens CHM, Vankerckhoven V, et al. Efficacy of
World J Gastroenterol 2012;18:4012–8. Lactobacillus casei Shirota for patients with irritable bowel syndrome.
[47] Farup PG, Jacobsen M, Ligaarden SC, et al. Probiotics, symptoms, and Eur J Gastroenterol Hepatol 2016;28:8–14.
gut microbiota: What are the relations? A randomized controlled trial in [69] Hod K, Sperber AD, Ron Y, et al. A double-blind, placebo-controlled
subjects with irritable bowel syndrome. Gastroenterol Res Pract 2012; study to assess the effect of a probiotic mixture on symptoms and
2012:214102. inflammatory markers in women with diarrhea-predominant IBS.
[48] Kruis W, Chrubasik S, Boehm S, et al. A double-blind placebo-controlled Neurogastroenterol Motil 2017;29:e13037.
trial to study therapeutic effects of probiotic Escherichia coli Nissle 1917 [70] Pinto-Sanchez MI, Hall GB, Ghajar K, et al. Probiotic Bifidobacterium
in subgroups of patients with irritable bowel syndrome. Int J Colorectal longum NCC3001 reduces depression scores and alters brain activity: a
Dis 2012;27:467–74. pilot study in patients with irritable bowel syndrome. Gastroenterology
[49] Murakami K, Habukawa C, Nobuta Y, et al. The effect of Lactobacillus 2017;153:448–459.e8.
brevis KB290 against irritable bowel syndrome: a placebo-controlled [71] Staudacher HM, Lomer MCE, Farquharson FM, et al. A diet low in
double-blind crossover trial. Biopsychosoc Med 2012;6:16. FODMAPs reduces symptoms in patients with irritable bowel syndrome
[50] Begtrup LM, De Muckadell OBS, Kjeldsen J, et al. Long-term treatment and a probiotic restores bifidobacterium species: a randomized controlled
with probiotics in primary care patients with irritable bowel syndrome – a trial. Gastroenterology 2017;153:936–47.
randomised, double-blind, placebo controlled trial. Scand J [72] Shin SP, Choi YM, Kim WH, et al. A double blind, placebo-controlled,
Gastroenterol 2013;48:1127–35. randomized clinical trial that breast milk derived-Lactobacillus gasseri
[51] Charbonneau D, Gibb RD, Quigley EMM. Fecal excretion of BNR17 mitigated diarrhea-dominant irritable bowel syndrome. J Clin
Bifidobacterium infantis 35624 and changes in fecal microbiota after Biochem Nutr 2018;62:179–86.
eight weeks of oral supplementation with encapsulated probiotic. Gut [73] Catinean A, Neag AM, Nita A, et al. Bacillus spp. spores – a promising
Microbes 2013;4:201–11. treatment option for patients with irritable bowel syndrome. Nutrients
[52] Ko S-J, Han G, Kim S-K, et al. Effect of Korean herbal medicine combined 2019;11:1968.
with a probiotic mixture on diarrhea-dominant irritable bowel syndrome: [74] Madempudi RS, Ahire JJ, Neelamraju J, et al. Randomized clinical trial:
a double-blind, randomized, placebo-controlled trial. Evid Based the effect of probiotic Bacillus coagulans Unique IS2 vs. placebo on the
Complement Alternat Med 2013;2013:824605. symptoms management of irritable bowel syndrome in adults. Sci Rep
[53] Roberts LM, McCahon D, Holder R, et al. A randomised controlled trial 2019;9:12210.
of a probiotic “functional food” in the management of irritable bowel [75] Oh JH, Jang YS, Kang D, et al. Efficacy and safety of new Lactobacilli
syndrome. BMC Gastroenterol 2013;13:45. probiotics for unconstipated irritable bowel syndrome: a randomized,
[54] Abbas Z, Yakoob J, Jafri W, et al. Cytokine and clinical response to double-blind, placebo-controlled trial. Nutrients 2019;11:2887.
Saccharomyces boulardii therapy in diarrhea-dominant irritable bowel [76] Andresen V, Gschossmann J, Layer P. Heat-inactivated Bifidobacterium
syndrome: a randomized trial. Eur J Gastroenterol Hepatol 2014;26:630–9. bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel
[55] Jafari E, Vahedi H, Merat S, et al. Therapeutic effects, tolerability and syndrome: a multicentre, randomised, double-blind, placebo-controlled
safety of a multi-strain probiotic in Iranian adults with irritable bowel clinical trial. Lancet Gastroenterol Hepatol 2020;5:658–66.
syndrome and bloating. Arch Iran Med 2014;17:466–70. [77] Gayathri R, Aruna T, Malar S, et al. Efficacy of Saccharomyces cerevisiae
[56] Lorenzo-Zúñiga V, Llop E, Suárez C, et al. I.31, a new combination of CNCM I-3856 as an add-on therapy for irritable bowel syndrome. Int J
probiotics, improves irritable bowel syndrome-related quality of life. Colorectal Dis 2020;35:139–45.
World J Gastroenterol 2014:8709–16. [78] Kim J, Cho K, Kim JS, et al. Probiotic treatment induced change of
[57] Ludidi S, Jonkers DM, Koning CJ, et al. Randomized clinical trial on the inflammation related metabolites in IBS-D patients/double-blind,
effect of a multispecies probiotic on visceroperception in hypersensitive randomized, placebo-controlled trial. Food Sci Biotechnol 2020;29:
IBS patients. Neurogastroenterology and Motility 2014;26:705–14. 837–44.
[58] Pedersen N, Andersen NN, Végh Z, et al. Ehealth: low FODMAP diet vs [79] Lewis ED, Antony JM, Crowley DC, et al. Efficacy of Lactobacillus
Lactobacillus rhamnosus GG in irritable bowel syndrome. World J paracasei HA-196 and Bifidobacterium longum R0175 in alleviating
Gastroenterol 2014;20:16215–26. symptoms of irritable bowel syndrome (IBS): a randomized, placebo-
[59] Rogha M, Esfahani MZ, Zargarzadeh AH. The efficacy of a synbiotic controlled study. Nutrients 2020;12:1159.
containing Bacillus coagulans in treatment of irritable bowel syndrome: a [80] Martoni CJ, Srivastava S, Leyer GJ. Lactobacillus acidophilus DDS-1 and
randomized placebo-controlled trial. Gastroenterol Hepatol Bed Bench Bifidobacterium lactis UABla-12 improve abdominal pain severity and
2014;7:156–63. symptomology in irritable bowel syndrome: randomized controlled trial.
[60] Sisson G, Ayis S, Sherwood RA, et al. Randomised clinical trial: a liquid Nutrients 2020;12:363.
multi-strain probiotic vs. placebo in the irritable bowel syndrome – a 12 [81] Sadrin S, Sennoune S, Gout B, et al. A 2-strain mixture of Lactobacillus
week double-blind study. Aliment Pharmacol Ther 2014;40:51–62. acidophilus in the treatment of irritable bowel syndrome: a placebo-
[61] Stevenson C, Blaauw R, Fredericks E, et al. Randomized clinical trial: controlled randomized clinical trial. Dig Liver Dis 2020;52:534–40.
effect of Lactobacillus plantarum 299 v on symptoms of irritable bowel [82] Wilson B, Rossi M, Kanno T, et al. β-galactooligosaccharide in conjunction
syndrome. Nutrition 2014;30:1151–7. with low FODMAP diet improves irritable bowel syndrome symptoms but
[62] Yoon JS, Sohn W, Lee OY, et al. Effect of multispecies probiotics on reduces fecal bifidobacteria. Am J Gastroenterol 2020;115:906–15.
irritable bowel syndrome: a randomized, double-blind, placebo-controlled [83] Barraza-Ortiz DA, Pérez-López N, Medina-López VM, et al.
trial. J Gastroenterol Hepatol 2014;29:52–9. Combination of a probiotic and an antispasmodic increases quality of life
[63] Pineton de Chambrun G, Neut C, Chau A, et al. A randomized clinical and reduces symptoms in patients with irritable bowel syndrome: a pilot
trial of Saccharomyces cerevisiae versus placebo in the irritable bowel study. Dig Dis 2021;39:294–300.
syndrome. Dig Liver Dis 2015;47:119–24. [84] Gupta AK, Maity C. Efficacy and safety of Bacillus coagulans LBSC in
[64] Wong RK, Yang C, Song G-H, et al. Melatonin regulation as a possible irritable bowel syndrome: a prospective, interventional, randomized,
mechanism for probiotic (VSL#3) in irritable bowel syndrome: a rando- double-blind, placebo-controlled clinical study [CONSORT Compliant].
mized double-blinded placebo study. Dig Dis Sci 2015;60:186–94. Medicine (Baltimore) 2021;100:e23641.
[65] Yoon H, Park YS, Lee DH, et al. Effect of administering a multi-species [85] Skrzydło-Radomańska B, Prozorow-Król B, Cichoż-Lach H, et al. The
probiotic mixture on the change in facial microbiota and symptoms of effectiveness and safety of multi-strain probiotic preparation in patients
irritable bowel syndrome: a randomized, double-blind, placebo-controlled with diarrhea-predominant irritable bowel syndrome: a randomized
trial. J Clin Biochem Nutr 2015;57:129–34. controlled study. Nutrients 2021;13:756.
[66] Lyra A, Hillilä M, Huttunen T, et al. Irritable bowel syndrome symptom [86] Mack I, Schwille-Kiuntke J, Mazurak N, et al. A nonviable probiotic in irri-
severity improves equally with probiotic and placebo. World J table bowel syndrome: a randomized, double-blind, placebo-controlled, mul-
Gastroenterol 2016;22:10631–42. ticenter study. Clin Gastroenterol Hepatol 2022;20:1039–47.e9.
3646
[87] Moeen-Ul-Haq AN, Babar MK, Hassan F, et al. Role of Lactobacillus [93] Lin L, Shi L, Chu H, et al. The magnitude of small-study effects in the
plantarum 299v versus Placebo in symptomatic improvement of irritable Cochrane Database of Systematic Reviews: an empirical study of nearly
bowel syndrome patients. J Pak Med Assoc 2022;72:404–8. 30 000 meta-analyses. BMJ Evid Based Med 2020;25:27–32.
[88] Mourey F, Decherf A, Jeanne J-F, et al. Saccharomyces cerevisiae I-3856 [94] Meissner K, Fässler M, Rücker G, et al. Differential effectiveness of pla-
in irritable bowel syndrome with predominant constipation. World J cebo treatments: a systematic review of migraine prophylaxis. JAMA
Gastroenterol 2022;28:2509–22. Intern Med 2013;173:1941–51.
[89] Zhang T, Zhang C, Zhang J, et al. Efficacy of probiotics for irritable [95] Schneider A, Enck P, Streitberger K, et al. Acupuncture treatment in
bowel syndrome: a systematic review and network meta-analysis. Front irritable bowel syndrome. Gut 2006;55:649–54.
Cell Infect Microbiol 2022;12:859967. [96] Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo
[90] Dale HF, Rasmussen SH, Asiller ÖÖ, et al. Probiotics in irritable bowel effect: randomised controlled trial in patients with irritable bowel syn-
syndrome: an up-to-date systematic review. Nutrients 2019;11:2048. drome. BMJ 2008;336:999–1003.
[91] Zhang Y, Li L, Guo C, et al. Effects of probiotic type, dose and treatment [97] Ford AC, Moayyedi P. Meta-analysis: factors affecting placebo response rate
duration on irritable bowel syndrome diagnosed by Rome III criteria: a in the irritable bowel syndrome. Aliment Pharmacol Ther 2010;32:144–58.
meta-analysis. BMC Gastroenterol 2016;16:62. [98] Olden KW, Brown AR. Treatment of the severe refractory irritable bowel
[92] Li B, Liang L, Deng H, et al. Efficacy and safety of probiotics in irritable patient. Curr Treat Options Gastroenterol 2006;9:324–30.
bowel syndrome: a systematic review and meta-analysis. Front [99] Lembo A, Ameen VZ, Drossman DA. Irritable bowel syndrome: toward
Pharmacol 2020;11:332. an understanding of severity. Clin Gastroenterol Hepatol 2005;3:717–25.
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’ Systematic Review and/or Meta-analysis

Probiotics for the management of irritable bowel

Figure 1. The study ﬂowchart. WoS, Web of Science.

weeks) for 8 weeks).

International Journal of Surgery

Chen et al. International Journal of Surgery (2023)

Lactobacillus rhamnosus, and

International Journal of Surgery

Single center BNR17 weeks i.d.; 8 weeks

International Journal of Surgery

Chen et al. International Journal of Surgery (2023)

week 3, and 30 drops 3 ×

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