International Journal of Surgery 75 (2020) 116–127

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International Journal of Surgery

journal homepage: www.elsevier.com/locate/ijsu

Original Research

The efficacy and safety of probiotics in patients with irritable bowel T

syndrome: Evidence based on 35 randomized controlled trials
Heng-Li Niu, Ji-Yuan Xiao∗
Clinical Pharmacy Department, Lanzhou University Second Hospital, Lanzhou, 730030, China

ARTICLE INFO ABSTRACT

Keywords: Background & objectives: Irritable bowel syndrome (IBS) is a functional bowel disorder that may involve dis-
Probiotics turbance of the gastrointestinal microbiota. We performed a systematic review and meta-analysis of the efficacy
Irritable bowel syndrome and safety of probiotics in patients with IBS.
Efficacy Methods: We searched the Cochrane Library, PubMed, EMBASE and Web of Science databases up to 1 April,
Safety
2019. Randomized controlled trials (RCTs) involving adults with IBS that compared probiotics to placebo or no
therapy were eligible for the analysis. Dichotomous symptom data were pooled to calculate the relative risk (RR)
with a 95% confidence interval (CI) of remaining symptoms after therapy. Continuous data were pooled using a
standardized mean difference (SMD) with the 95% CI. Two reviewers assessed trial quality and extracted data
independently.
Results: Thirty-five RCTs involving 3,452 patients were included in the analysis. Compared with placebo, pa-
tients using probiotics had a lower incidence of persistence of symptoms (RR 0.79, 95% CI 0.70 to 0.89, P <
0.0001). Also, probiotics exerted a beneficial effect on global symptoms and the abdominal pain score (SMD
−0.25, 95% CI −0.36 to −0.14, P < 0.00001), bloating score (SMD −0.15, 95% CI −0.27 to −0.03,
P = 0.01), and flatulence score (SMD −0.20, 95% CI −0.35 to −0.05, P = 0.01). However, patients treated
with probiotics had a higher incidence of any adverse event (RR 1.21; 95% CI 1.02 to 1.44).
Conclusions: Supplementation with multi-strain probiotics can improve IBS symptoms. Further research is re-
quired if probiotics are to be adopted as a treatment for IBS.

1. Introduction
Probiotics were defined as live microbial feed supplements that
benefit the host by improving the intestinal microbial balance [1].
Some microorganisms are resistant to the physicochemical conditions
of the digestive tract, and the strains most frequently used as probiotics
belong to the genera Bifidobacterium and Lactobacillus.
Irritable bowel syndrome (IBS) is a common functional bowel dis-
order with a prevalence of 5–20% in the general population [2]. IBS is
more common in females and younger individuals [3]. The effect of
socioeconomic status on the risk of IBS is unclear. The cause of IBS is
unknown, but visceral hypersensitivity [4,5], disturbances of the gas-
trointestinal (GI) flora [6,7], and chronic immune activation leading to
low-grade mucosal inflammation have been implicated in its patho-
genesis [8–11].
Effective pharmacological therapies for IBS exist, but the duration of
most treatment trials is < 6 months, and so the long-term efficacy of
these therapies is unclear [12,13]. In addition, some patients do not
respond to, and others become dissatisfied with, conventional therapies
[14]. Improving symptoms by modulating the GI flora may therefore be
an attractive treatment option. The effect of probiotics—live or atte-
nuated microorganisms beneficial to health—on IBS has been in-
vestigated extensively [15]. Some probiotics have anti-inflammatory
activity while others can modulate visceral hypersensitivity [16,17].
To date, few studies have evaluated the efficacy of probiotics for
IBS. Thus, we performed a systematic review and meta-analysis of 46
RCTs to evaluate the efficacy and safety of probiotics in patients with
IBS.
2. Methods and materials
2.1. Inclusion criteria
We included studies if they met the following criteria: (1) patients
diagnosed with IBS based on a physician's opinion or symptom-based
diagnostic criteria, supplemented by the results of investigations to

∗
Corresponding author. Lanzhou University Second Hospital, No.80, Cuiyingmen, Chengguan District, Lanzhou, 730030, China.
E-mail address: zhangchj001@163.com (J.-Y. Xiao).

https://doi.org/10.1016/j.ijsu.2020.01.142
Received 13 November 2019; Received in revised form 11 January 2020; Accepted 27 January 2020
Available online 31 January 2020
1743-9191/ © 2020 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.
H.-L. Niu and J.-Y. Xiao
Fig. 1. Flow diagram of literature search and selection of included studies for the present meta-analysis.
exclude organic disease where necessary; (2) RCTs comparing probio-
tics with placebo; (3) participants aged > 16 years; (4) minimum
duration of therapy and follow-up of 7 days; and (5) changes in IBS
symptoms as the primary outcome.
Studies were excluded if they met any of the following criteria: (1)
healthy adults or non-IBS patients; (2) experimental trials on animals or
non-human studies; (3) studies in children (age ≤ 16 years); (4) non-
RCT studies; (5) studies with a primary outcome other than change in
IBS symptoms; (6) studies analyzing probiotics in conjunction with
other IBS therapies in the same intervention group; (7) abstracts, let-
ters, editorials, expert opinions, reviews, and case reports; and (8)
studies with insufficient data or that did not meet the inclusion criteria.
The work has been reported in line with PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) and
AMSTAR (Assessing the methodological quality of systematic reviews)
Guidelines.
2.2. Search strategy and data extraction
We searched the Cochrane Library, PubMed, EMBASE and Web of
Science databases up to 1 April, 2019, using combinations of the key-
words: “probiotic*“, “irritable bowel syndrome”, “IBS”, and “diarrhea”.
Two assessors independently screened the titles and abstracts of each
study. The full texts of relevant studies were obtained for further eva-
luation. Other related references were searched online; any that met the
inclusion criteria were included in the analysis.
Data for comparison of probiotics and placebo were extracted in-
dependently by two reviewers, and disagreement was resolved by dis-
cussion. Data were extracted as dichotomous outcomes (global IBS
symptoms persistent or unimproved, or abdominal pain persistent or
unimproved), mean symptom scores, or mean number of stools per
week at the end of the study. In addition, the setting (primary, sec-
ondary, or tertiary care); number of centers; country; prebiotic,
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International Journal of Surgery 75 (2020) 116–127
probiotic, or synbiotic used (including strain and species if applicable);
duration of therapy; total number of adverse events reported; primary
outcome measure used to define symptom improvement or cure fol-
lowing therapy; duration of follow-up; proportion of female patients;
and proportion of patients according to predominant stool pattern for
IBS were analyzed.
2.3. Assessment of quality and risk of bias
Two reviewers assessed the quality of each RCT using the validated
five-point Jadad scale [18]. This scale included three items (randomi-
zation, blinding, loss and withdraw) with a total score of 5. Studies with
scores of ≥3 were considered to be of high quality. In addition, the risk
of bias for each study and across all studies was evaluated and is pre-
sented as figures generated using RevMan version 5.2 software [19].
2.4. Data synthesis and statistical analysis
Dichotomous data were measured as the risk ratio (RR) and con-
tinuous variable data by the standard mean difference (SMD).
Heterogeneity between studies was evaluated by the chi-squared-based
Q statistical test [20]. The Ph value and I2 statistic (range 0%–100%)
were calculated to quantify the effect of heterogeneity. A Ph of ≤0.10
was deemed to represent significant heterogeneity [21], and pooled
RRs were estimated using a random-effects model by the DerSimonian
and Laird method [22]. In contrast, if no significant heterogeneity was
observed (Ph > 0.10), a fixed-effects model with the Mantel–Haenszel
method [23] was used. The effects of outcome measures were con-
sidered significant if the pooled RRs with 95% CI did not overlap with 1
or the pooled SMDs with 95% CI did not overlap with 0.
 Table 1
Characteristics of randomized controlled trials of probiotics vs. placebo in irritable bowel syndrome.
Study/first author Year Country Sample size Diagnostic Probiotic used Duration of Criteria used to defi ne symptom Jadad
(female %) criteria therapy improvement following therapy score

Agrawal A 2009 UK 34 (100%) Rome III Fermented milk (125 g) containing B. animalis DN173 010 4 weeks Continuous scale for IBS symptoms 3
H.-L. Niu and J.-Y. Xiao

(1.25 × 1010 cfu/125 g) S. thermophilus (1.2 × 109 cfu./125 g) and L. bulgaricus

(1.2 × 109 cfu/125 g) bid.
Begtrup LM 2013 Denmark 131 (74%) Rome III Four capsules containing L. paracasei ssp paracasei F19, L. acidophilus La5, and B. 6 months Adequate relief of global IBS symptoms 3
lactis Bb12 (1.3 × 1010 cfu/capsule) od. for at least 50% of the time, and
continuous scale for IBS symptoms
Choi CH 2011 Korea 90 (51%) Rome II Two capsules containing Saccharomyces boulardii (2 × 1011 live cells) bid. 4 weeks Continuous scale for IBS symptoms 2
Cui S 2012 China 60 (70%) Rome III Two capsules containing B. longum and L.acidophilus tid. 4 weeks Improvement in abdominal pain 2
frequency
Dapoigny M 2012 France 52 (70%), Rome III Three capsules containing L. casei rhamnosus LCR35 (2 × 108 cf/capsule) od 4 weeks Reduction in IBS symptom severity score 2
of 50% or more
Drouault-Holowacz 2008 France 106 (76%) Rome II One sachet containing B. longum LA 101, L. acidophilus LA 102, L. lactis LA 103, and 4 weeks Satisfactory relief of global IBS 4
S S. thermophilus LA 104 (1 × 1010 cfu/sachet) od symptoms, and continuous scale for IBS
symptoms
Ducrotte P 2012 India 214 (29%) Rome III One capsule containing L. plantarum LP299V 4 weeks Patients rated treatment effi cacy as 3
DSM 9843 (10 billion c.f.u./capsule) o.d. excellent, and continuous scale for IBS
symptoms
Enck P 2014 Germany 298 (56%) Kruis score E. coli DSM17252 (1.5–4.5 × 107 cfu/ml) 0.75 ml drops tid for 1 week, then 1.5 ml 2–8 weeks 50% Improvement in IBS global 4
tid. symptoms
Enck P 2008 Germany 297 (49%) Kruis score Autolysate of cells and cell fragments of Enterococcus faecalis DSM16440 and 3–8 weeks 50% improvement in IBS global 4
Escherichia coli DSM17252 (3.0–9.0 × 107 cfu/1.5 ml) × 0.75 ml tid for 1 week, symptoms
then 1.5 ml tid. for weeks 2 and 3, then 2.25 ml tid.
Farup PG 2012 Norway 16 (69%) Rome II One capsule containing L. plantarum MF1298 (1010 cfu/capsule) od. 3 weeks Satisfactory relief of symptoms and 1
continuous scale for IBS symptoms

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Gade J 1989 Denmark 54 (78%) Manning Paraghurt (Streptococcus faecium) 4 weeks IBS symptoms “significantly improved” 2
Guglielmetti S 2011 Germany 122 (67%) Rome III One capsule containing B. bifidum MIMBb75 (1 × 109 cfu/capsule) od. 4 weeks Improvement in average weekly global 3
IBS symptom score of 1 or more for 50%
of weeks
Guyonnet D 2007 France, 274 (75%) Rome II Fermented milk (125 g) containing B. animalis DN173 010 4 weeks Continuous scale for IBS symptoms 2
(1.25 × 1010 cfu/125 g) S. thermophiles (1.2 × 109 cfu/125 g) and L. bulgaricus
(1.2 × 109 cfu/125 g) bid.
Hong KS 2009 Korea 70 (33%) Rome III One sachet containing B. bifidum BGN4, B. lactis AD011, L. acidophilus AD031, and 8 weeks 50% Improvement in IBS global 4
L. casei IBS041 (20 billion bacteria/sachet) bid. symptoms
Kajander K 2005 Finland 103 (76%) Rome I/II 1 capsule containing L. rhamnosus GG, L. rhamnosus Lc705, Propionibacterium 6 months Relief of IBS symptoms, and continuous 4
freudenreichii, and Bifidobacterium breve Bb99 (8–9 × 109 cfu/capsule) scale for IBS symptoms
Kajander K 2008 Finland 86 (93%) Rome II Milk-based drink (1.2 dl) containing L. rhamnosus GG ATCC 5310, L. rhamnosus 20 weeks Continuous scale for IBS symptoms 3
Lc705 DSM 7061, P. freudenreichii, and B. animalis Bb12 DSM 15954
(1 × 107 cfu/ml) od.
Ki Cha B 2012 Korea 50 (48%) Rome III 1 capsule containing L. acidophilus KCTC11906BP, L. plantarum KCTC11867BP, L. 8 weeks Adequate relief of global IBS symptoms 3
rhamnosus KCTC11868BP, B. breve KCTC11858BP, B. lactis KCTC11903BP, B. for at least 50% of weeks, and
longum KCTC11860BP, and S. thermophiles KCTC11870BP (5 billion bacteria/ continuous scale for IBS symptoms
capsule) bid.
Kim HJ 2005 USA 48 (94%) Rome II One packet containing VSL # 3 (450 billion bacteria/packet) bid. 4–8 weeks Continuous scale for IBS symptoms 3
Kim HJ 2003 USA 25 (72%) Rome II One packet containing VSL # 3 (225 billion bacteria/packet) bid. 8 weeks Satisfactory relief of IBS symptoms for 3
50% of weeks, and continuous scale for
IBS symptoms
Kim YG 2006 Korea 40 (26%) clinical Medilac DS (Bacillus subtilis and S. faecium) 4 weeks Continuous scale for IBS symptoms 2
diagnosis
Kruis W 2012 Germany 120 (77%) Rome II 1 capsule containing E. coli Nissle 1917 (2.5–25 × 109 cfu/capsule) od for 4 days 12 weeks Patients reported very much satisfied or 4
then bid. a little satisfied with treatment
Michail S 2011 USA 24 (67%) Rome III VSL # 3 (900 billion bacteria/day) 8 weeks Continuous scale for IBS symptoms 3
Niedzielin K 2001 Poland, 40 (80%) clinical Fruit drink (200 ml) containing L. plantarum 299 V (5 × 10 7 cfu/ml) bid. 4 weeks Any improvement in IBS symptoms 2
diagnosis
(continued on next page)
International Journal of Surgery 75 (2020) 116–127
 Table 1 (continued)

Study/first author Year Country Sample size Diagnostic Probiotic used Duration of Criteria used to defi ne symptom Jadad
(female %) criteria therapy improvement following therapy score

Niv E 2005 Israel 54 (67%) Rome II One tablet containing L. reuteri ATCC 55730 (1 × 108 cfu./tablet) qid for 2 weeks 6 months Continuous scale for IBS symptoms 2
then bid.
H.-L. Niu and J.-Y. Xiao

Nobaek S 2000 Sweden, 60 (69%) Rome I Rose hip drink (400 ml) containing Lactobacillus plantarum DSM 9843 4 weeks > 1.5 improvement in VAS scale for 2
(5 × 107 cfu) od abdominal pain, and continuous scale
for IBS symptoms
O'Mahony L 2005 Eire, 80 (64%) Rome II Malted drink containing L. salivarius UCC4331 (1 × 1010 live bacteria/drink) or B. 8 weeks Continuous scale for IBS symptoms 3
infantis 35624 (1 × 1010 live bacteria/drink) od.
Ringel-Kulka T 2011 USA 33 Rome III One pill containing L. acidophilus NCFM and B. lactis Bi-07 (1 × 10 11 cfu/pill) bid. 8 weeks 50-point decrease in IBS symptom 4
severity score
Roberts LM 2013 England, 184 (83%) Rome III One pot containing B. lactis I-2494 (previously known as DN173 010) 12 weeks Adequate relief of global IBS symptoms 2
(1.25 × 1010 cfu/pot), S. thermophilus I-1630 (1.2 × 109 cfu/pot), and L.
bulgaricus I-1632 and I-1519 (1.2 × 109 cfu/pot) bid.
Simren M 2010 Sweden 74 (70%) Rome II Fermented milk (200 ml) containing L. paracasei ssp paracasei F19, L. acidophilus 8 weeks Adequate relief of global IBS symptoms 3
La5, and B. lactis Bb12 (5 × 107 cfu/ml) bid. for at least 50% of weeks, and
continuous scale for IBS symptoms
Simren M 2006 Sweden 66 (63%) Rome II Rose hip drink (400 ml) containing L. plantarum DSM 9843 (5 × 107 cfu/ml) od. 6 weeks Continuous scale for IBS symptoms 3
Sinn DH 2008 Korea 40 (65%) Rome III One capsule containing L. acidophilus SDC 2012 and 2013 (2 × 109 cfu/ml) bid. 12 weeks Any improvement in abdominal pain 3
measured on a 10-point Likert scale
Sondergaard B 2011 Denmark and 64 (75%) Rome II Fermented milk (250 ml) containing L. paracasei ssp paracasei F19, L. acidophilus 8 weeks Adequate relief of global IBS symptoms, 4
Sweden, La5, and B. lactis Bb12 (5 × 107 cf/ml) bid. and continuous scale for IBS symptoms
Whorwell PJ 2006 UK 362 (100%) Rome II One capsule containing B. infantis 35624 (1 × 106 live bacteria/capsule, 1 × 108 4 weeks Adequate relief of IBS symptoms, and 4
live bacteria/capsule, or 1 × 1010 live bacteria/capsule) od. continuous scale for IBS symptoms
Williams EA 2009 UK 52 (87%) Rome II One capsule containing L. acidophilus CUL-60 NCIMB 30157 and CUL-21 NCIMB 8 weeks Continuous scale for IBS symptoms 3
30156, B. bifi dum CUL-20 NCIMB 30153, and B. lactis CUL-34 NCIMB 30172
(2.5 × 1010 cfu/capsule) od.

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Zeng J 2008 China 29 (34%) Rome II Fermented milk (200 ml) containing S. thermophilus (1 × 108 cfu/ml), L. bulgaricus 4 weeks Continuous scale for IBS symptoms 2
(1 × 107 cfu/ml), L. acidophilus (1 × 107 cfu/ml), and B. longum (1 × 107 cfu/ml)
bid.

cfu, colony-forming units; IBS, irritable bowel syndrome; od, once daily; VAS, visual analog scale.
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Fig. 2. Forest plot of comparison between probiotics and placebo in term of persistence of symptoms for IBS.

3. Results
3.1. Included studies, study characteristics, and quality assessment
The search strategy generated a total of 3,134 citations, of which 89
published articles appeared to be relevant and were retrieved for fur-
ther assessment. Of these, 54 articles were excluded for various reasons,
leaving 35 eligible articles involving 3,452 participants [24–58]. We
identified 19 RCTs that evaluated combination probiotics in IBS. There
were eight trials of Lactobacillus in IBS, three of Bifidobacterium, two of

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Fig. 3. Forest plot of comparison between probiotics and placebo in term of GSS or APS for IBS.
Escherichia, one of Bifidobacterium or Lactobacillus, one of Sacchar-
omyces, and one of Streptococcus. The search process and a summary of
the studies are provided in Fig. 1. The other characteristics of the stu-
dies are listed in Table 1.
According to our definitions, 23 RCTs had a Jaded score of ≥3 and
~65.7% were of high quality. Additionally, the risk of bias of each RCT
was evaluated across all included studies and for each study in-
dividually (Figs. S1 and S2). The risk-of-bias analysis indicated gen-
erally good methodological quality. All RCTs showed a low risk of bias
regarding random sequence generation (selection bias). A high risk of
bias was mainly observed in performance bias. The risk of detection,
allocation concealment, and other types of bias was unclear.
3.2. Effect of probiotics on persistence of symptoms
Twenty-three RCTs compared probiotics with placebo in term of
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persistence of symptoms of IBS. Overall, 777 (55.8%) of 1,392 patients
assigned to probiotics reported persistent or unimproved IBS symptoms
following therapy, compared with 865 (73.1%) of 1,183 allocated to
placebo. The RR of IBS symptoms persisting after treatment with pro-
biotics vs. placebo was 0.79 (95% CI 0.70 to 0.89, P < 0.0001). As
significant heterogeneity was observed (Ph < 0.00001 and I2 = 72), a
pooled analysis was performed using a random-effects model. We also
conducted a subgroup analysis of the efficacy of probiotics on symp-
toms of IBS.
Combination probiotics were assessed in 12 RCTs involving 1,197
patients and showed a significant effect on symptoms (RR 0.81, 95% CI
0.67 to 0.98, P = 0.03). Lactobacillus was used in six trials (422 pa-
tients), with no clear benefit detected over placebo (RR 0.75, 95% CI
0.54 to 1.04, P = 0.08). Bifidobacterium was evaluated in two RCTs
(484 patients), with no benefit over placebo (RR 0.71, 95% CI 0.44 to
1.16, P = 0.18). Escherichia was assessed in two trials (418 patients)
H.-L. Niu and J.-Y. Xiao
Fig. 4. Forest plot of comparison between probiotics and placebo in term of bloating scores for IBS.
and showed a benefit compared with placebo (RR 0.86, 95% CI 0.79 to
0.93, P = 0.0003). Finally, Streptococcus was used in one trial involving
54 patients and appeared to be superior to placebo (RR 0.72, 95% CI
0.53 to 0.99, P = 0.04) (Fig. 2).
3.3. Effect of probiotics on the GSS and APS
A total of 24 separate trials making 25 comparisons and comprising
2001 patients reported the effect of probiotics on global symptom score
(GSS) or abdominal pain score (APS); probiotics significantly reduced
the GSS or APS (SMD −0.25, 95% CI −0.36 to −0.14, P < 0.00001).
In addition, combination probiotics were assessed in 15 RCTs involving
2,026 patients and exerted a significant effect on the GSS or APS (SMD
−0.24, 95% CI −0.37 to −0.12, P < 0.0001). Lactobacillus was
evaluated in six trials and showed no clear benefit over placebo (SMD
−0.08, 95% CI −0.38 to 0.21, P = 0.59). Bifidobacterium was assessed
in three RCTs and showed no benefit over placebo (SMD −0.46, 95% CI
−0.92 to 0.00, P = 0.05). Saccharomyces was assessed in one trial in-
volving 69 patients and showed no benefit over placebo (SMD −0.12,
95% CI −0.60 to 0.36, P = 0.61) (Fig. 3).
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3.4. Effect of probiotics on individual symptom scores
A total of 17 separate trials making 18 comparisons and involving
1,446 patients reported the effect of probiotics on the bloating score.
Overall, the bloating score was significantly reduced by probiotics
(SMD −0.15, 95% CI −0.27 to −0.03, P = 0.01). However, no clear
benefit was detected for combination probiotics (SMD −0.08, 95% CI
−0.21 to 0.06, P = 0.27), Bifidobacterium (SMD −0.30, 95% CI −0.68
to 0.09, P = 0.13), Lactobacillus (SMD −0.12, 95% CI −0.67 to 0.43,
P = 0.67), or Saccharomyces (SMD −0.37, 95% CI −0.85 to 0.12,
P = 0.14) (Fig. 4). Ten trials reported continuous data for the effect of
probiotics on the flatulence score in 741 patients. The flatulence score
was significantly lower for probiotics compared with placebo (SMD
−0.20, 95% CI −0.35 to −0.05, P = 0.01). In addition, combination
probiotics exhibited a significant effect on flatulence symptom scores in
seven RCTs involving 292 patients (SMD −0.30, 95% CI −0.53 to
−0.07, P < 0.0001) (Fig. 5).
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Fig. 5. Forest plot of comparison between probiotics and placebo in term of flatulence scores for IBS.

Table 2 3.6. Subgroup analysis and publication bias

Subgroup analysis of overall probiotics for persistence of symptoms.
Subgroups Number of Number of Pooled results
We performed a subgroup analysis of probiotics versus placebo re-
studies participants garding persistence of symptoms, GSS, APS, bloating, and flatulence
RR 95% CI P value AEM scores. As shown in Table 2, probiotics had a beneficial effect on per-
sistence of symptoms in the low risk of bias (RR 0.77, 95% CI 0.67 to
Risk of bias
Low 16 2109 0.77 0.67, 0.89 0.0003 REM
0.89, P = 0.0003), Rome III (RR 0.73, 95% CI 0.58 to 0.93, P = 0.01),
High 7 466 0.85 0.69, 1.06 0.14 REM sample size ≤ 100 pts (RR 0.83, 95% CI 0.70 to 0.98, P = 0.03),
Rome criteria sample size > 100 pts (RR 0.76, 95% CI 0.64 to 0.90, P = 0.001),
Rome II 8 870 0.91 0.81, 1.02 0.09 FEM duration of therapy ≤ 4 weeks (RR 0.75, 95% CI 0.61 to 0.93,
Rome III 10 956 0.73 0.58, 0.93 0.01 REM
P = 0.009), and duration of therapy > 4 weeks (RR 0.81, 95% CI 0.70
Sample size
≤100 pts 13 638 0.83 0.70, 0.98 0.03 REM to 0.94, P = 0.006) subgroups. However, no significant effect was
> 100 pts 10 1937 0.76 0.64, 0.90 0.001 REM found in the high-risk-of-bias (RR 0.85, 95% CI 0.69 to 1.06, P = 0.14)
Duration and Rome II (RR 0.91, 95% CI 0.81 to 1.02, P = 0.09) subgroups.
≤4 weeks 10 724 0.75 0.61, 0.93 0.009 REM Regarding the global symptom or abdominal pain scores (Table 3),
> 4 weeks 13 1489 0.81 0.70, 0.94 0.006 REM
significant effect was found in all subgroups with the exception of the
RR, Relative risk; CI, confidence interval; AEM, Analytical effect model; FEM, high-risk-of-bias subgroup. However, for the bloating score, only the
Fixed-effect model; REM, Random-effect model. low-risk-of-bias (SMD −0.19, 95% CI −0.32 to −0.06, P = 0.004) and
sample size ≤ 100 pts (SMD −0.16, 95% CI −0.31 to −0.01,
3.5. Adverse events with probiotics P = 0.04) subgroups showed a significant effect (Table 4). For the
flatulence score, only the sample size ≤100 pts (SMD −0.30, 95% CI
Total adverse events were reported by 24 RCTs, involving 2,407 −0.49 to −0.10, P = 0.003) and duration of therapy > 4 weeks (SMD
patients. Overall, 201 (16.5%) of 1,215 patients assigned to probiotics −0.30, 95% CI −0.58 to −0.02, P = 0.04) subgroups showed a sig-
experienced an adverse event, compared to 164 (13.8%) of 1,192 pa- nificant effect (Table 5). Begg funnel plots were generated to assess
tients assigned to placebo. The RR of experiencing any adverse event publication bias; no clear evidence of publication bias was detected
was significantly higher with probiotics (RR 1.21; 95% CI 1.02–1.44). (Fig. 6).
The number needed to harm with probiotics was 35 (95% CI 16–362).

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Table 3
Subgroup analysis of overall probiotics for global symptom or abdominal pain scores.
Subgroups Number of studies Number of participants Pooled results

RR 95% CI P value AEM

Risk of bias
Low 17 1473 −0.27 −0.4, −0.15 < 0.0001 REM
High 7 504 −0.15 −0.39, 0.09 0.23 REM
Rome criteria
Rome II 15 1335 −0.15 −0.26, −0.04 0.007 FEM
Rome III 6 527 −0.4 −0.68, −0.13 0.004 REM
Sample size
≤100 pts 16 746 −0.18 −0.32, −0.03 0.02 FEM
> 100 pts 8 1231 −0.32 −0.52, −0.12 0.002 REM
Duration
≤4 weeks 11 956 −0.32 −0.49, −0.14 0.0004 REM
> 4 weeks 13 724 −0.16 −0.31, −0.01 0.03 FEM

SMD, standardized mean difference; CI, confidence interval; AEM, Analytical effect model; FEM, Fixed-effect model; REM, Random-effect model.

Table 4
Subgroup analysis of overall probiotics for bloating scores.
Subgroups Number of studies Number of participants Pooled results

RR 95% CI P value AEM

Risk of bias
Low 13 1023 −0.19 −0.32, −0.06 0.004 FEM
High 4 381 0.04 −0.16, 0.24 0.7 FEM
Rome criteria
Rome II 11 1047 −0.07 −0.20, 0.05 0.26 FEM
Rome III 6 404 −0.27 −0.55, 0.01 0.06 REM
Sample size
≤100 pts 14 685 −0.16 −0.31, −0.01 0.04 FEM
> 100 pts 3 719 −0.15 −0.49, 0.18 0.37 REM
Duration
≤4 weeks 7 587 −0.19 −0.47, 0.10 0.20 REM
> 4 weeks 10 817 −0.11 −0.26, 0.04 0.14 REM

SMD, standardized mean difference; CI, confidence interval; AEM, Analytical effect model; FEM, Fixed-effect model; REM, Random-effect model.

Table 5
Subgroup analysis of overall probiotics for flatulence scores.
Subgroups Number of studies Number of participants Pooled results

RR 95% CI P value AEM

Risk of bias
Low 6 559 −0.16 −0.34, 0.02 0.08 FEM
High 4 182 −0.32 −0.68, 0.04 0.08 REM
Rome criteria
Rome II 6 576 −0.15 −0.33, 0.03 0.11 FEM
Rome III 2 79 −0.28 −0.72, 0.17 0.22 FEM
Sample size
≤100 pts 9 411 −0.30 −0.49, −0.10 0.003 FEM
> 100 pts 1 330 −0.04 −0.29, 0.22 0.78 –
Duration
≤4 weeks 6 544 −0.20 −0.42, 0.03 0.09 REM
> 4 weeks 4 197 −0.30 −0.58, −0.02 0.04 FEM

SMD, standardized mean difference; CI, confidence interval; AEM, Analytical effect model; FEM, Fixed-effect model; REM, Random-effect model.

4. Discussion A strength of this systematic review and meta-analysis is the rig-

The results of this systematic review and meta-analysis demonstrate
that probiotics are effective against IBS, in terms of both improvement
in overall symptoms, as a dichotomous measure, and in the global
symptom, abdominal pain, bloating, and flatulence scores. We found
evidence to support the use of combinations of probiotics. There was
also a trend toward a beneficial effect of Bifidobacterium on global IBS
symptoms and pain scores, although the strain or species responsible is
unclear. Adverse events were rare but significantly more frequent in
subjects who received probiotics.
orous methodology. We assessed eligibility and extracted data in-
dependently and in duplicate. We pooled data using a random-effects
model to minimize the likelihood that treatment efficacy would be
overestimated if significant heterogeneity was detected among studies
or between subgroups, or both. We also contacted investigators of po-
tentially eligible studies to obtain dichotomous or continuous data. This
inclusive approach yielded data for > 2,500 IBS patients treated with
probiotics. We also performed subgroup analyses of the treatment effect
according to the probiotic used, risk of bias, Rome criteria, sample size,
and duration of therapy; additionally, we extracted and pooled adverse

124
H.-L. Niu and J.-Y. Xiao
Fig. 6. Begg's funnel plot for detecting publication bias (A. persistence of symptoms; B. global symptom or abdominal painscores; C. bloating scores; D. flatulence
scores).
events data, if reported. Generally, studies with a low risk of bias in-
volving Rome III patients reported greater efficacy. Dale reported that
use of multi-strain supplements for ≥8 weeks yielded greater beneficial
effects on IBS symptoms [59]; this is in agreement with our findings.
Our results are consistent with the findings of several recent meta-
analyses and systematic reviews that probiotics have significant, albeit
limited, effects on gastrointestinal symptoms [60–62]. A review and
meta-analysis by Ford et al. that included RCTs published from 1946 to
2013 concluded that probiotics had a beneficial effect on IBS symptoms,
and the effect was greater for multi-strain probiotics [61]. A more re-
cent review and meta-analysis by Ford et al. of the efficacy of probio-
tics, prebiotics, and antibiotics against IBS showed that particular
combinations of probiotics, or of specific species and strains, exerted
beneficial effects on general IBS symptoms and abdominal pain; how-
ever, it was not possible to identify the most effective combination [60].
Hungin et al. performed a systematic review of the effects of probiotic
supplements on lower gastrointestinal problems in IBS and reported
marked differences among probiotic types and strains [62].
There are limitations to this systematic review and meta-analysis
that arise from the nature of the studies available for synthesis. The risk
of bias of many of the trials was unclear, and there was evidence of
heterogeneity between RCTs, although there was no evidence of pub-
lication bias. However, when only studies with a low risk of bias were
analyzed, the beneficial effect persisted. In addition, the small size of
some of the subgroups may have resulted in insufficient power to detect
meaningful differences. Furthermore, a wide variety of multi-strain
125
International Journal of Surgery 75 (2020) 116–127
probiotic supplements were used in the included studies. The two most
common bacterial families administered as probiotics in the included
studies were Lactobacillaceae and Bifidobacteriaceae (genera
Lactobacillus and Bifidobacterium). Indeed, all of the eight studies that
involved a multi-strain probiotic supplement had one or both of these
two bacterial families. The Lactobacillus count has been reported to be
both increased and decreased in the fecal microbiota of IBS patients
compared to healthy controls [63,64]; therefore, more studies are re-
quired. The Bifidobacterium count is reportedly decreased in fecal
samples from IBS patients [65–67], in agreement with our findings and
indicating that this genus is linked to significant improvement of
symptoms of IBS. The most efficacious strains and combinations thereof
warrant further investigation. Finally, individual strains of a probiotic
may have different effects, and pooling of the results of a given species
may obscure the beneficial effects of individual strains. Therefore, in-
vestigation of probiotic efficacy at the strain level is needed.
The duration of therapy varied among the 35 studies from 3 to 20
weeks; the majority used 4 weeks. However, there was no significant
difference between the < 4 weeks and > 4 weeks groups. Future stu-
dies are needed to determine whether the effect of probiotic supple-
mentation on IBS symptoms is delayed.
In conclusion, supplementation with a multi-strain probiotic has
greater potential to improve IBS symptoms than a single strain. Our
findings suggest that further long-duration RCTs of the effect of multi-
strain probiotic supplementation on IBS symptoms are needed.
Standardized symptom questionnaires should be implemented to
H.-L. Niu and J.-Y. Xiao International Journal of Surgery 75 (2020) 116–127

identify the most efficacious strains and the IBS subtypes that will de-
rive the greatest benefit from probiotics.
Ethical Approval
Ethical Approval is not applicable.
Sources of funding
There is no funding for this work.
Author contribution
The authors on this paper all participated in study design. All au-
thors have read and approved this version of the article, and due care
has been taken to ensure the integrity of the work. The material of this
article is original research and no part of this paper has been previously
published. The material has also not been submitted for publication
elsewhere while under consideration. No conflict of interest exits in the
submission of this manuscript. HL N and YH M mainly contributed to
the study design, data analysis and quality assessment. CJ Z and YH M
mainly contributed to the literature search. HL N contributed to the
manuscript writing. All authors have the appropriate permissions and
rights to the reported data.
Trail registry number
Research registry.
UNI: reviewregistry762.
Hyper link: https://www.researchregistry.com/register-now/
register-your-systematic-review#registryofsystematicreviewsmeta-
analyses/registerofsystematicreviewsmeta-analyses2/
Guarantor
Heng-Li Niu, Ji-Yuan Xiao.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Data statement
The material of this article is original research. All data in this
manuscript is available and transparent for readers.
Declaration of competing interest
The authors declare no relevant conflict of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.ijsu.2020.01.142.
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