Eur J Clin Pharmacol (2017) 73:1199–1208
DOI 10.1007/s00228-017-2291-6
REVIEW
Efficacy and safety of probiotic-supplemented triple therapy
for eradication of Helicobacter pylori in children: a systematic
review and network meta-analysis
Jue-Rong Feng 1,2 & Fan Wang 1,2 & Xiao Qiu 1,2 & Lynne V. McFarland 3 &
Peng-Fei Chen 1,2,4 & Rui Zhou 1,2 & Jing Liu 1,2 & Qiu Zhao 1,2 & Jin Li 1,2
Received: 8 March 2017 / Accepted: 14 June 2017 / Published online: 5 July 2017
# Springer-Verlag GmbH Germany 2017
Abstract
Aim The aim of this study was to identify the best probiotic
supplementation in triple therapy for pediatric population with
Helicobacter pylori infection.
Methods Eligible trials were identified by comprehensive
searches. Relative risks with 95% confidence intervals and
relative ranks with P scores were assessed.
Results Twenty-nine trials (3122 participants) involving 17
probiotic regimens were identified. Compared with placebo,
probiotic-supplemented triple therapy significantly increased
H. pylori eradication rates (relative ratio (RR) 1.19, 95% CI
1.13–1.25) and reduced the incidence of total side effects (RR
0.49, 95% CI 0.38–0.65). Furthermore, to supplemented triple
therapy, Lactobacillus casei was identified the best for
H. pylori eradication rates (P score = 0.84), and multi-strain
Jue-Rong Feng and Fan Wang contributed equally to the study.
Electronic supplementary material The online version of this article
(doi:10.1007/s00228-017-2291-6) contains supplementary material,
which is available to authorized users.
* Qiu Zhao
Zhaoqiu@medmail.com.cn
* Jin Li
lili234510@126.com
1
Department of Gastroenterology, Zhongnan Hospital of Wuhan
University, No. 169, Donghu Road, Wuchang District,
Wuhan, Hubei Province 430071, China
2
Hubei Clinical Center and Key Laboratory of Intestinal and
Colorectal Diseases, No. 169, Donghu Road, Wuchang District,
Wuhan, Hubei Province 430071, China
3
Department of Medicinal Chemistry, School of Pharmacy, University
of Washington, Seattle, WA 98115, USA
4
Department of Gastroenterology, The Central Hospital of Enshi
Autonomous Prefecture, Enshi, China
of Lactobacillus acidophilus and Lactobacillus rhamnosus for
total side effects (P score = 0.93). As for the subtypes of side
effects, multi-strain of Bifidobacterium infantis,
Bifidobacterium longum, L. acidophilus, L. casei,
L a ct ob a c i l l us p l an t a r um , L ac t ob a ci l l us re u t e ri ,
L. rhamnosus, Lactobacillus salivarius, Lactobacillus
sporogenes, and Streptococcus thermophilus was the best to
reduce the incidence of diarrhea; multi-strain of Bacillus
mesentericus, Clostridium butyricum, and Streptococcus
faecalis for loss of appetite; multi-strain of B. longum,
Lactobacillus bulgaricus, and S. thermophilus for constipa-
tion; multi-strain of Bifidobacterium bifidum, B. infantis,
L. acidophilus, L. bulgaricus, L. casei, L. reuteri, and
Streptococcus for taste disturbance; Saccharomyces boulardii
for bloating; and multi-strain of Bifidobacterium breve,
B. infantis, L. acidophilus, L. bulgaricus, L. casei,
L. rhamnosus, and S. thermophilus for nausea/vomiting.
Conclusions Probiotics are recommended to supplement tri-
ple therapy in pediatrics, and the effectiveness of triple therapy
is associated with specific probiotic supplementation.
Keywords Helicobacter pylori . Probiotics . Children .
Safety . Efficacy . Network meta-analysis
Introduction
High prevalence of Helicobacter pylori infection has been an
important public health problem in both developing and de-
veloped countries [1, 2], because H. pylori infection not only
is associated with chronic gastritis and peptic ulcers but also
has been classified as carcinogen by the World Health
Organization [3]. Children with no symptoms and with gas-
trointestinal symptoms have been reported to have a seroprev-
alence rate of 15.7 and 40%, respectively [4]. H. pylori
1200
eradication in childhood will not only result in symptom relief
but will also prevent long-term complications such as cancer
and mucosa-associated lymphoid tissue (MALT) lymphoma
[5]. Gastric MALT lymphoma can be successfully prevented
if H. pylori is eradicated earlier in their lifetime. Triple therapy
with a proton pump inhibitor (PPI) + two antibiotics as a first-
line therapy for the eradication of H. pylori in children has
been recommended in Europe and North American [6], but
eradication failure resulting from bacterial resistance and side
effects associated with antibiotics has restricted triple therapy
in children [7, 8].
Previous meta-analyses on probiotic-supplemented triple
therapy have been published for H. pylori infection in children
and confirmed to strengthen H. pylori eradication rate and
safety of triple therapy [9–12]. However, not all probiotics
including multi-strain and single-strain types could signifi-
cantly improve H. pylori eradication rates and reduce the in-
cidence of side effects [11, 13, 14]. The efficacy and safety of
triple therapy appeared to be different due to the supplemen-
tation of different probiotics [15]. The evidence of direct com-
parisons among probiotic strains was lacking in pediatrics.
Probiotics recommended for adults do not yet appear to be
suitable for children [16]. Therefore, the network meta-
analysis aimed to identify which probiotic strain or probiotic
regimen is more effective as supplementation in H. pylori tri-
ple therapy for pediatric population.
Methods
Literature research
PubMed, Cochrane library, Embase, and four Chinese data-
bases [China National Knowledge Infrastructure (CNKI), da-
tabase of Wanfang, VIP database, and the Chinese Biomedical
Database (CBM)] were searched for relevant studies from
inception to April 2017 through a comprehensive search strat-
egy based on a combination of the following terms:
(Helicobacter pylori OR H. pylori OR HP), and (probiotics),
and (pediatrics OR children), and (randomized controlled trial
OR RCT OR clinical trial) and (triple therapy). There were no
language restrictions for searching articles. Besides, manual
search of references including reviews and meta-analyses pub-
lished to date was performed as well.
Study selection and exclusion
All studies were reviewed independently by two reviewers
(Jue-Rong Feng and Fan Wang). Studies were included if they
satisfied the following criteria: (i) clinical trials that compared
different probiotics supplemented in H. pylori triple therapy,
(ii) patients included were pediatric population, (iii) patients
were diagnosed as H. pylori infection and randomized into
Eur J Clin Pharmacol (2017) 73:1199–1208
probiotic group and control group, and (iv) apart from
probiotics, both probiotic group and control group shared
the same regimen for H. pylori eradication. Studies were ex-
cluded by the following exclusion criteria: (i) studies without
full texts or reviews, (ii) H. pylori triple therapy included
cimetidine instead of PPI, and (iii) the outcomes of studies
without H. pylori eradication rates and/or side effects.
Data extraction and quality assessment
Data were extracted by two authors (Jue-Rong Feng and Fan
Wang), using standardized data abstraction sheets previously
prepared. All differences were resolved by discussions with
two other researchers. Data extracted were as follows: authors,
year of publication, region, study design, patient characteris-
tics, number of patients, diagnostic methods of detecting
H. pylori infection prior to enrolling and after completing
study, probiotic regimen (including duration, administration
time, and dose), eradication regimen, the number of patients
in different groups, eradication rate, and the incidence of side
effects (including diarrhea, nausea or vomiting, taste distur-
bance, loss of appetite, bloating, headache, constipation, and
abdominal pain). In an open study, it was also regarded as
using placebo. The quality of included studies was assessed
using the Jadad scale [17] according to three items of whether
described as randomized (two points), double-blinded (two
points), and withdrawals and dropouts (one point). Each affir-
mative answer was given a relevant point. Conversely, points
could be deducted (one point in each case) if the study was
described as randomized or double-blinded, but the methods
were not fully described.
Data synthesis and analysis
We conducted the network meta-analysis using the netmeta R
package with a frequentist framework described by Rucker [18]
and Schwarzer et al. [19], which can combine direct and indi-
rect comparisons for all relative treatment effects. Traditional
pairwise meta-analysis was used to analyze direct comparisons
by Stata 11.0 software (Stata Corporation, College Station, TX,
USA). All analyses of network meta-analysis and traditional
pairwise meta-analysis were based on the random effects mod-
el. We calculated the summary effect sizes as relative ratios
(RRs) with 95% confidence intervals (CIs) and relative ranks
using P scores with a higher value indicating greater effective-
ness [20]. Eradication rates of H. pylori were analyzed by
intention-to-treat (ITT) and per-protocol (PP) analysis, respec-
tively, and incidence of side effects was analyzed by an ITT
analysis. Funnel plot and Egger’s and Begg’s tests were con-
ducted to evaluate the publication bias [21, 22]. The heteroge-
neity between studies was examined by Q test and I2 statistic.
For those with I2 >50%, sensitivity analysis was performed by
excluding one individual study each time to assess the influence
Eur J Clin Pharmacol (2017) 73:1199–1208
Fig. 1 Identification process for eligible studies
of each individual study on the pooled RRs. The corresponding
RRs did not alter remarkably, suggesting that the findings of
this meta-analysis are credible. Given that each direct compar-
ison included a limited number of trials, we could not formally
assess statistical heterogeneity and publication bias. Reporting
the results of the traditional and network meta-analysis was
according to Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) statements [23, 24].
Results
Search results, study characteristics, and quality
assessment
Figure 1 summarizes the search and selection of studies.
Twenty-nine studies (3122 pediatric patients) were identi-
fied [3, 5, 25–51], which involved 17 probiotic regimens,
such as (1) Bacillus cereus, Bifidobacterium infantis,
Enterococcus faecalis, and Lactobacillus acidophilus; (2)
Bacillus mesentericus, Clostridium butyricum, and
Streptococcus faecalis; (3) Bifidobacterium animalis and
Lactobacillus casei; (4) B. animalis, L. acidophilus, and
1201
L. casei; (5) Bifidobacterium breve, B. infantis,
L. acidophilus, Lactobacillus bulgaricus, L. casei,
L a c t o b a c i l l u s rh a m no s u s , a n d S t re p t o co c c u s
thermophilus; (6) B. infantis and C. butyricum; (7)
B. infantis, Bifidobacterium longum, L. acidophilus,
L. casei, Lactobacillus plantarum, Lactobacillus reuteri,
L. rhamnosus, Lactobacillus salivarius, Lactobacillus
sporogenes, and S. thermophilus; (8) B. longum,
E. faecalis, and L. acidophilus; (9) B. longum,
L. bulgaricus, and S. thermophilus; (10) L. acidophilus;
(11) L. acidophilus and Bifidobacterium bifidum; (12)
L. casei; (13) Lactobacillus delbrueckii, L. acidophilus,
and Lactococcus lactis; (14) L. rhamnosus; (15)
Saccharomyces boulardii; (16) B. bifidum, B. infantis,
L. acidophilus, L. bulgaricus, L. casei, L. reuteri, and
Streptococcus; and (17) L. acidophilus and
L. rhamnosus. At enrollment, all pediatric patients who
suffered from upper gastrointestinal syndromes or peptic
ulcers or chronic gastritis were diagnosed as H. pylori
infection by urea breath test (UBT), histology, rapid ure-
ase test (RUT), culture, or H. pylori stool antigen (HpSA).
The eradication of H. pylori was confirmed by rechecking
at least 4 weeks after completing the triple therapy. Side
1202
Fig. 2 Forest plot of traditional meta-analysis for Helicobacter pylori eradication of probiotic regimen-supplemented triple therapy compared with
placebo
effects were generally observed during therapy. The dura-
tion of probiotic administration ranged from 7 days to
3 months, and the administration time of most trials was
during the therapy. In quality assessment, overall, the
range of mean quality scores ranged from 2 to 5. The
general characteristics of the included studies are listed
in Table S1.
Eur J Clin Pharmacol (2017) 73:1199–1208
Traditional meta-analysis for efficacy and safety
of probiotic-supplemented triple therapy
There were 16 probiotic regimen-supplemented triple
therapies reporting data of eradication rates (Table S2).
Probiotic-supplemented triple therapy had superiority
over placebo for eradicating H. pylori (ITT analysis: RR
Eur J Clin Pharmacol (2017) 73:1199–1208 1203

1.19, 95% CI 1.13–1.25, I2 = 46.5%; PP analysis: RR
1.19, 95% CI 1.13–1.25, I2 = 45.2%) (Fig. 2). In sub-
group analyses, H. pylori eradication rates of triple thera-
py were improved when supplemented probiotic regimens
except for multi-strain of B. longum, L. bulgaricus, and
S. thermophilus before omitting the study by He [32], as
shown in Table 1.
In the case of safety, there were 4 single-strain and 12
multi-strain probiotic-supplemented triple therapies and 8
types of side effects reported (Table S2; Table 2).
Compared with placebo, probiotic-supplemented triple
therapy reduced incidence of total side effects (RR 0.49,
95% CI 0.38–0.65, I2 = 61.7%) (Fig. 3). After sensitivity
analysis was performed by omitting one trial by Sun [37],
adjusted RR was 0.47 (95% CI 0.37–0.59, I2 = 44.4%). In
subgroup analyses, probiotics could reduce the incidence
of most side effects except for abdominal pain and head-
ache (Table 2). In addition, not all probiotic regimen-
supplemented triple therapies could reduce the incidence
of each type of side effects compared with placebo. For
instance, S. boulardii-supplemented triple therapy could
reduce the incidence of diarrhea (RR 0.50, 95% CI
0.36–0.68, I2 = 0%), while not for abdominal pain (RR
0.65, 95% CI 0.38–1.11, I2 = 39%).
Network meta-analysis for efficacy and safety of probiotic
regimen-supplemented triple therapy
A network involving 17 probiotic regimens and a placebo as
the junction were constructed (Fig. 4). In the case of improv-
ing eradication rates of H. pylori, three probiotic regimen-
supplemented triple therapies were identified, such as
L. casei (P score = 0.84), multi-strain of B. infantis and
C. butyricum (P score = 0.82), and multi-strain of
B. mesentericus, C. butyricum, and S. faecalis (P
score = 0.73).
As for reducing the incidence of total side effects,
multi-strain of L. acidophilus and L. rhamnosus (P
score = 0.93); multi-st rain of B . m e s e n t e r i c u s,
C. butyricum, and S. faecalis (P score = 0.76); and
single-strain of S. boulardii (P score = 0.68) were better
to supplemented triple therapy. Given that probiotic-
supplemented triple therapy failed to reduce the incidence
of abdominal pain and headache in traditional meta-anal-
ysis, these two types of side effects were not taken into
further subgroup of network meta-analysis (Table 2).
T h e r e b y, m u l t i - s t r a i n p r o b i o t i c s of B . i n f a n t i s ,
B. longum, L. acidophilus, L. casei, L. plantarum,
L. reuteri, L. rhamnosus, L. salivarius, L. sporogenes,

Table 1 Traditional meta-

analysis for Helicobacter pylori Probiotics vs. placebo Studies No. of Effect estimate (RR, 95% CI) Heterogeneity
eradication of probiotic regimen- patients
supplemented triple therapy PP analysis ITT analysis P value I2 (%)
compared with placebo (PP/ITT) (PP/ITT)

Total 28a 2860 1.19 (1.13–1.25) 1.19 (1.13–1.25) 0.01/0.00 45.2/46.5

Bifidobacterium 2 264 1.37 (1.16–1.63) 1.41 (1.17–1.70) 0.99/0.71 0/0
infantis and
Clostridium
butyricum
Bifidobacterium 2 266 1.21 (1.07–1.37) 1.21 (1.07–1.37) 0.82/0.82 0/0
longum,
Enterococcus
faecalis, and
Lactobacillus
acidophilus
Bifidobacterium 4 432 1.08 (0.85–1.36) 1.08 (0.85–1.36) 0.00/0.00 84.6/84.6
longum,
Lactobacillus
bulgaricus, and
Streptococcus
thermophilus
3b 272 1.20 (1.07–1.34) 1.20 (1.07–1.34) 1.00/1.00 0/0
Lactobacillus 4 443 1.23 (1.14–1.34) 1.24 (1.14–1.35) 0.99/0.95 0/0
acidophilus
Saccharomyces 5 514 1.16 (1.08–1.26) 1.15 (1.06–1.25) 0.83/0.83 0/0
boulardii

CI confidence interval
a
Indicate the number of all trials including only one trial of probiotics
b
Indicate that sensitivity analysis was performed by omitting the study of He [32]
1204 Eur J Clin Pharmacol (2017) 73:1199–1208

Table 2 Traditional meta-

analysis for the safety of probiotic Comparisons Studies No. of Effect estimate Heterogeneity
regimen-supplemented triple patients (RR, 95% CI)
therapy compared with placebo P I2
value (%)

Side effect 27 2922 – – –

Total side effects 18a 2154 0.49 (0.38–0.65) 0.00 61.7
17b 2058 0.47 (0.37–0.59) 0.03 44.4
Bifidobacterium infantis and Clostridium 2 264 0.76 (0.46–1.27) 0.61 0
butyricum
Bifidobacterium longum, Lactobacillus 3 378 0.46 (0.35–0.59) 0.93 0
bulgaricus, and Streptococcus thermophilus
Lactobacillus acidophilus 3 339 0.49 (0.19–1.27) 0.01 81.2
2b 243 0.33 (0.17–0.62) 0.49 0
Saccharomyces boulardii 3 366 0.37 (0.24–0.60) 0.78 0
Loss of appetite 12a 1289 0.56 (0.35–0.89) 0.24 20.7
Lactobacillus acidophilus 2 243 0.30 (0.05–1.87) 0.48 0
Lactobacillus rhamnosus 2 137 0.88 (0.21–3.60) 0.20 39.5
Diarrhea 20a 2360 0.46 (0.37–0.58) 0.70 0
Bifidobacterium infantis and Clostridium 2 264 0.76 (0.22–2.64) 0.83 0
butyricum
Bifidobacterium longum, Lactobacillus 2 310 0.36 (0.17–0.76) 0.34 0
bulgaricus, and Streptococcus thermophilus
Lactobacillus acidophilus 4 443 0.49 (0.24–1.02) 0.31 17
Saccharomyces boulardii 4 576 0.50 (0.36–0.68) 0.53 0
Nausea/vomiting 20a 2199 0.60 (0.48–0.75) 0.15 25
Bifidobacterium infantis and Clostridium 2 264 0.51 (0.23–1.13) 0.74 0
butyricum
Lactobacillus acidophilus 4 443 0.62 (0.37–1.06) 0.60 0
Lactobacillus rhamnosus 2 137 0.93 (0.59–1.45) 0.50 0
Saccharomyces boulardii 3 382 0.81 (0.64–1.02) 0.60 0
Bloating 9a 885 0.53 (0.34–0.82) 0.83 0
Bifidobacterium infantis and Clostridium 2 264 1.14 (0.16–8.00) 0.89 0
butyricum
Lactobacillus rhamnosus 2 137 1.07 (0.33–3.51) 0.34 0
Constipation 12a 1227 0.46 (0.33–0.64) 0.98 0
Lactobacillus acidophilus 3 279 0.36 (0.13–1.04) 0.88 0
Lactobacillus rhamnosus 2 137 0.68 (0.13–3.50) 0.60 0
Saccharomyces boulardii 2 300 0.40 (0.22–0.72) 0.48 0
Abdominal pain 6a 601 0.65 (0.38–1.11) 0.15 38.9
Saccharomyces boulardii 2c 322 0.62 (0.26–1.46) 0.80 67
Taste disturbance 9a 1010 0.56 (0.37–0.84) 0.69 0
Lactobacillus acidophilus 2 268 0.40 (0.16–1.03) 0.46 0
Headache 3a 510 0.47 (0.16–1.39) 0.62 0

CI confidence interval
a
Indicate the number of all trials including only one trial of probiotics
b
Indicate that sensitivity analysis was performed by omitting the study of Sun [37]
c
Indicate that sensitivity analysis was not performed because of two trials included

and S. thermophilus was identified the best to supplement
triple therapy for reducing the incidence of diarrhea (P
score = 0.88); multi-strain probiotics of B. mesentericus,
C. butyricum, and S. faecalis for loss of appetite (P
score = 0.75); multi-strain probiotics of B. longum,
L. bulgaricus, and S. thermophilus for constipation (P
score = 0.71); multi-strain probiotics of B. bifidum,
B. infantis, L. acidophilus, L. bulgaricus, L. casei,
L. reuteri, and Streptococcus for taste disturbance (P
score = 0.70); S. boulardii for bloating (P score = 0.79);
Eur J Clin Pharmacol (2017) 73:1199–1208
Fig. 3 Forest plot of traditional meta-analysis for total side effects of probiotic regimen-supplemented triple therapy compared with placebo
and multi-strain probiotics of B. breve, B. infantis,
L. acidophilus, L. bulgaricus, L. casei, L. rhamnosus,
and S. thermophilus for nausea/vomiting (P score = 0.78)
(Table S3).
Publication bias
Publication bias was assessed using data of H. pylori eradica-
tion rates of ITT analysis. Visual inspection of the funnel plot
found a slightly asymmetrical distribution (Fig. 5). However,
Egger’s test or Begg’s test showed no significant publication
bias (P = 1.22, P = 0.09, respectively).
1205
Discussion
This is the first network meta-analysis to assess the compara-
tive effectiveness of probiotic-supplemented triple therapy.
Traditional meta-analysis suggested that probiotic-
supplemented triple therapy can improve the H. pylori eradi-
cation and reduce the incidence of side effects including diar-
rhea, nausea/vomiting, taste disturbance, loss of appetite,
bloating, and constipation. Furthermore, network meta-
analysis identified that single-strain probiotics of L. casei
was the most appropriate to supplement triple therapy for im-
proving H. pylori eradication compared with other probiotic
regimens, and multi-strain probiotics of B. mesentericus,
1206
Fig. 4 Network plots of probiotic regimens included in network meta-
analysis. a Network relations of probiotic regimens that supplemented
triple therapy on Helicobacter pylori eradication. b Network relations
of probiotic regimens that supplemented triple therapy on total side
effects of triple therapy. The nodes correspond to and are labeled
according to the probiotic regimens, and the edges show which
probiotic regimens are directly compared. The thickness of the lines is
proportional to the inverse standard error of the direct comparisons. The
two networks include a total of 17 different comparisons (e.g., placebo
versus each of 17 probiotic regimens) from 29 two-armed studies. Multi-
strain probiotic 1: Bacillus cereus, Bifidobacterium infantis,
Enterococcus faecalis, and Lactobacillus acidophilus. Multi-strain probi-
otic 2: Bacillus mesentericus, Clostridium butyricum, and Streptococcus
faecalis. Multi-strain probiotic 3: Bifidobacterium animalis and
Lactobacillus casei. Multi-strain probiotic 4: Bifidobacterium animalis,
Lactobacillus acidophilus, and Lactobacillus casei. Multi-strain probiotic
5: Bifidobacterium breve, Bifidobacterium infantis, Lactobacillus
C. butyricum, and S. faecalis were the most effective in reduc-
ing incidence of total side effects. Moreover, subgroup analy-
ses of side effects suggested that the effectiveness of probiotic
regimens varied from different types of side effects.
In accordance with previously published meta-analyses
[9–14], triple therapy containing probiotics has been proven
to improve the eradication rate of H. pylori; the mechanism
may be the following: competing to bind to surface receptors
of intestinal epithelial cell with H. pylori and inhibiting adhe-
sion of H. pylori to the gastric mucosa [52], altering the
Fig. 5 Begg’s funnel plot for publication in meta-analysis (using the data
based on the ITT analysis for Helicobacter pylori eradication)
Eur J Clin Pharmacol (2017) 73:1199–1208
acidophilus, Lactobacillus bulgaricus, Lactobacillus casei,
Lactobacillus rhamnosus, and Streptococcus thermophilus. Multi-strain
probiotic 6: Bifidobacterium infantis and Clostridium butyricum. Multi-
strain probiotic 7: Bifidobacterium infantis, Bifidobacterium longum,
Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum,
Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius,
Lactobacillus sporogenes, and Streptococcus thermophilus. Multi-strain
probiotic 8: Bifidobacterium longum, Enterococcus faecalis, and
Lactobacillus acidophilus. Multi-strain probiotic 9: Bifidobacterium
longum, Lactobacillus bulgaricus, and Streptococcus thermophilus.
Multi-strain probiotic 10: Lactobacillus acidophilus and
Bifidobacterium bifidum. Multi-strain probiotic 11: Lactobacillus
delbrueckii, Lactobacillus acidophilus, and Lactococcus lactis. Multi-
strain probiotic 12: Bifidobacterium bifidum, Bifidobacterium infantis,
Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus casei,
Lactobacillus reuteri, and Streptococcus. Multi-strain probiotic 13:
Lactobacillus acidophilus and Lactobacillus rhamnosus
expression of inflammatory factor derived from intestinal
lymphoid tissue and intestinal epithelial cells [53], strengthen-
ing the intestinal biological barrier [54], secreting antimicro-
bial substances, and reducing the loads of H. pylori from the
antrum and corpus [55]. In addition, probiotics may enhance
H. pylori eradication indirectly through reducing the incidence
of therapy-associated side effects, which can strengthen pa-
tients’ therapy compliance.
In this study, the duration of probiotic administration varied
from 7 days to 3 months [3, 44, 45] and the administration
time of most trials was during the triple therapy. Thereby,
probiotics should be administrated along with triple therapy,
which could strengthen the effect of triple therapy.
There were several limitations to the meta-analysis. Firstly,
there was the diversity of antibiotics in triple therapy, confir-
mation of H. pylori eradication, and administration time of
probiotics, which could vary the effect size of probiotics be-
tween studies. Secondly, the number of trials on certain pro-
biotic strain or regimen was few so that we cannot make a
further subgroup analysis for the effect of the probiotic-
supplemented triple therapy, such as L. casei and multi-
strain probiotics of L. delbrueckii, L. acidophilus, and
L. lactis (Table S2). In addition, ranking probiotics by network
meta-analysis based on only single trials for eradication and
safety were the lack of robustness. Thirdly, most design of
trials was different among included studies.
Eur J Clin Pharmacol (2017) 73:1199–1208
In conclusion, probiotics are recommended to supplement
triple therapy in pediatrics, and the effectiveness of triple ther-
apy is associated with specific probiotic supplementation.
Author contributions Dr. Jue-Rong Feng and Dr. Fan Wang con-
ceived and designed the search strategy, ran the searches, selected the
studies, extracted the raw data, analyzed the data, and drafted and revised
the manuscript.
Dr. Peng-Fei Chen and Dr. Rui Zhou independently assessed the risk
of bias and checked the extracted data.
Professor Jing Liu and Dr. Xiao Qiu designed the data collection
instruments; supervised the searches, data collection, and analysis; and
critically reviewed the manuscript. Dr. Lynne V. McFarland provided the
additional data and assisted with the manuscript writing.
Professor Qiu Zhao and Professor Jin Li conceptualized and designed
the study, supervised the searches and data analysis, and revised the
manuscript.
All authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
Compliance with ethical standards
Conflict of interest The authors declare that they have no competing
interests.
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