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Clinics and Research in Hepatology and Gastroenterology (2015) xxx, xxx—xxx

Available online at

ScienceDirect
www.sciencedirect.com

ORIGINAL ARTICLE

Probiotics can improve the clinical

outcomes of hepatic encephalopathy: An
update meta-analysis
Li-Na Zhao a, Tao Yu b, Shao-Yang Lan a, Jiang-Tao Hou a,
Zheng-Zheng Zhang a, Shuang-Shuang Wang a, Feng-Bin Liu a,∗

a
Department of Gastroenterology, the First Affiliated Hospital, Guangzhou University of Chinese Medicine,
Guangzhou, China
b
Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou,
China

Summary
Introduction: Although the efficacy of probiotics has been extensively studied in hepatic
encephalopathy (HE), the results remain controversial. The objective of this study is to identify
and update the association between probiotics and HE.
Methods: Up to December 2014, we searched Medline, Embase, Web of Science, Cochrane
CENTRAL, and SinoMed of China for all relevant articles about probiotics and HE. Jadad score
was used to evaluate the quality of studies. Pooled relative risk (RR), publication bias and
heterogeneity were assessed.
Results: Nine studies met the inclusion criteria. Probiotics was associated with improvement of
minimal HE and prophylaxis of overt HE [RR 1.52; 95% confidence intervals (95% CI) 1.00—2.33].
Studies with probiotics showed reduction of ammonia concentration [standard mean difference
(SMD) —0.32, 95% CI —0.54 to —0.11]. Probiotics could reduce physical and psychosocial sickness
impact profile (SIP) score with weight mean difference (WMD) —3.13 (95% CI —4.10 to —2.17)
and WMD —3.50 (95% CI —4.91 to —2.08), respectively. Similar result was obtained with total
SIP score (WMD —4.83; 95% CI —6.24 to —3.43). Reduction of severe adverse events, defined as
minimal HE developing into overt HE, hospitalizations, infections or unrelated emergency room
(ER) visits, was observed in HE with probiotics (RR 0.59; 95% CI 0.39—0.90).

∗ Corresponding author. Department of Gastroenterology, the First Affiliated Hospital, Guangzhou University of Chinese Medicine, 16 Ji

Chang road, Guangzhou 510405, China. Tel.: +86 20 365 911 09; fax: +86 20 365 911 09.
E-mail address: liufengbin163@163.com (F.-B. Liu).

http://dx.doi.org/10.1016/j.clinre.2015.03.008
2210-7401/© 2015 Published by Elsevier Masson SAS.

Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
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CLINRE-738; No. of Pages 9 ARTICLE IN PRESS
2 L.-N. Zhao et al.
Conclusion: Our pooled results indicated that probiotics was associated with improvement of
minimal HE, prophylaxis of overt HE, and reduction of SIP score and severe adverse events.
Large well-designed randomised controlled trials are needed to confirm these results.
© 2015 Published by Elsevier Masson SAS.
Introduction
Hepatic encephalopathy (HE) is a disorder of mental status
and cognitive function as a result of liver failure and/or por-
tosystemic shunt. HE, including overt HE (OHE) and minimal
HE (MHE), impairs patient’s quality of life and daily function-
ing [1]. Neurocognitive deficits in MHE lead to impairment
of ability to work, driving skills and progression to OHE stage
[2]. Furthermore, OHE is associated with decreased survival
and can predict subsequent OHE episodes and hospitaliza-
tion [3]. Thus, treatment of MHE and prophylaxis of OHE are
big challenges for physicians.
Dysbiosis has been associated with impaired cognition,
endotoxemia, and inflammation, and may play a critical role
in the pathogenesis of HE [4]. Antibiotics, prebiotics, pro-
biotics, and synbiotics, which can have beneficial effect on
gut microbiota modification, have been extensively studied,
but the results remain controversial [5—8]. Probiotics are
live microorganisms which can confer a health benefit on
the host. The studies using probiotics have been conducted
in a small number of patients with short treatment duration
[9—17]. The meta-analysis by McGee et al. in 2011, includ-
ing seven randomised controlled trials (RCTs), demonstrated
that while probiotics appear to reduce plasma ammonia
concentration, probiotics are ineffective in altering clin-
ically relevant outcomes [5]. Another two meta-analyses
(Shukla et al., 2011 and Holte et al., 2012) have concluded
that prebiotics, probiotics, and synbiotics appear to be
associated with improvement in HE [6,7], but because pre-
biotics, probiotics, and synbiotics all appear to be effective
for HE through beneficial effect on gut microbiota modifica-
tion. These meta-analyses studies, which mixed probiotics
with synbiotics or prebiotics together or compared probi-
otics with prebiotics (lactulose), may result in significant
bias on the efficacy of probiotics in HE [18]. In addition, fur-
ther well-designed studies with probiotics alone have been
conducted to show the benefit of probiotics in HE [14—17].
Therefore, in this study, we included studies in which the
difference in interventions is probiotics alone, and added
more recent well-designed studies to identify and update
the association between probiotics and HE.
Methods
Search strategies
Up to December 2014, we searched Medline, Embase, Web
of Science, Cochrane CENTRAL, and SinoMed of China for
all relevant articles about probiotics and HE. Medical sub-
ject heading (MeSH) or keywords used in the research
Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
included ‘‘probiotics’’, or ‘‘synbiotics’’, and ‘‘hepatic
encephalopathy’’, or ‘‘minimal hepatic encephalopathy’’,
or ‘‘subclinical hepatic encephalopathy’’, or ‘‘overt hepatic
encephalopathy’’. Reference lists of all included articles
were scrutinized to disclose additional literature on this
topic. All abstracts, review articles, commentaries, and
book chapters were excluded.
Study selection
Inclusion criteria were:
• studies involved patients with MHE (confirmed by neu-
ropsychological tests) or OHE;
• study had to be a RCT comparing use of probiotics with a
placebo or no intervention;
• the study should have reported clinical outcomes with
regard to improvement of MHE, prophylaxis of OHE, or
other relevant clinical outcomes;
• RCT with Jadad score at least 3.
The exclusion criteria were:
• studies involved patients with MHE, which were not con-
firmed by neuropsychological tests;
• nonrandomised controlled trial or RCT with Jadad score
less than 3;
• the interventions include other drugs and the difference
in interventions is not probiotics alone.
Definition of clinical outcomes
The primary outcome evaluated was the improvement of
MHE and prophylaxis of OHE. The secondary outcome was
the effect of treatment on changes in ammonia concentra-
tion, sickness impact profile (SIP), and adverse events. SIP
contains three dimensions: independent categories, physi-
cal, and psychosocial. Physical, psychosocial, and total SIP
score were evaluated respectively. Adverse events were
classified into mild adverse events, severe adverse events,
and mortality. Severe adverse events were defined as MHE
developing into OHE, hospitalizations, infections, or unre-
lated emergency room (ER) visits.
Data extraction and quality assessment
Two authors (LNZ and TY) selected target studies follow-
ing the guidelines laid by the QUOROM statement [19]. All
data were abstracted onto a standard form and crosschecked
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CLINRE-738; No. of Pages 9 ARTICLE IN PRESS
Probiotics and hepatic encephalopathy
by two reviewers independently. Non-English studies that fit
the inclusion criteria were translated. The data extracted
from all the studies were as follows: the last names of first
authors, years of publication, methods to diagnose MHE or
OHE, Child-Turcotte-Pugh (CTP) score in patients, types of
probiotics, time periods of study, and relevant clinical out-
comes. Disagreements were resolved by consensus including
a third author.
The Jadad 5 point scoring system was used to evaluate
the quality of each study. This measure assesses aspects of
methodology in RCTs related to study quality, including 3
items: randomisation (0—2 points), masking (0—2 points),
and dropouts and withdrawals (0—1 point), with a score of at
least 3 considered acceptable and a higher score indicating
better reporting. RCTs with Jadad scores at least 3 were
included.
Statistical analysis
Risk of bias (quality) assessment
The Q and I2 statistics were used to test statistical het-
erogeneity among studies. For the Q statistic, a P value
of less than 0.1 is considered representative of statistically
significant heterogeneity. I2 is the proportion of total varia-
tion contributed by between-study variation. An I2 index of
0—50% is considered to demonstrate low levels of hetero-
geneity, 50%—75% medium, and 75%—100% high. Sensitivity
analysis by reestimating pooled RR with omitting each study
in turn was conducted to investigate the influence of each
individual study on the overall meta-analysis summary esti-
mate. Publication bias and small study effects were assessed
by Begg’s test and Egger’s test, with P < 0.05 considered to
show significant publication bias.
Strategy for data synthesis
Statistical analysis with fixed-effect model meta-analyses
was used if for the Q statistic, a P value is more than 0.1. On
the other hand, random-effects models were used for anal-
yses if a P value is less than 0.1. Review Manager 5 software
(RevMan 2011) and STATA (Version 12.0; STATA Corporation,
College Station, TX, US) was used for all analyses.
Results
Literature search
We reviewed 135 titles and abstracts, and eventually
chose 24 studies for further review. Malaguarnera 2007,
Malaguarnera 2010, Yang 2011, and Shen 2013 were excluded
because the treatment group did not use probiotics alone
[18,20—22]. Pereg 2011 and Lunia 2014 were excluded
because hepatic encephalopathy were not confirmed before
treatment [23,24]. Loguercio 1987 was excluded because
the controlled group is not placebo [25]. Shu 2008 was
excluded because it is not a RCT [26]. Lata 2006, Ye 2006, Liu
2006, Zhang 2007, Qiao 2009, Liu 2009, and Wang 2012 were
excluded because the method of randomisation was not
described and their Jadad scores were less than 3 [27—33].
Finally, 9 full-text articles were identified in this meta-
analysis (Fig. 1) [9—17].
Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
3
Table 1 showed the design and the characteristics of the
trials. One study included patients with cirrhosis who had a
previous history of OHE. All other studies used abnormality
in neuropsychometric tests (outside the mean ± 2 SD) for
the diagnosis and response to treatment of MHE. Six studies
reported CTP score of the patients at the onset of the trial.
The trial durations ranged from 4 to 48 weeks. Nine studies
were published from 2004 to 2014, and the sample sizes
ranged from 25 to 155 [9—17].
Probiotics and HE
Five studies evaluated the efficacy of probiotics in improve-
ment of MHE and one study evaluated the benefit of
probiotics in prophylaxis of OHE. The pooled result showed
that probiotics was associated with improvement of MHE and
prophylaxis of OHE (RR 1.52; 95% CI 1.00—2.33; Fig. 2). A
trend towards improvement of MHE was also shown in five
studies (RR 1.82; 95% CI 0.90—3.70).
Methodological quality and risk of bias
All the studies were of high quality with Jadad score at
least 3. But there was significant heterogeneity across all
studies (I2 = 58%, P = 0.03; Fig. 2). Sensitivity analysis by rees-
timating pooled RR with excluding each study in turn was
conducted. Pooled RRs ranged from 1.33 to 1.84. There was
a statistically significant association between probiotics and
HE when Liu or Sharma study was omitted (Fig. 3). No obvi-
ous publication bias was found by Begg’s test (Fig. 4A) and
Egger’s test (Fig. 4B).
Probiotics and ammonia concentration
Ammonia concentration was evaluated in five studies.
Because the test method for ammonia concentration was
different, standard mean difference (SMD) was used as the
effect size. Probiotics was associated with reduced ammonia
concentration (SMD —0.32, 95% CI —0.54 to —0.11; Fig. 5).
Probiotics and SIP
Two studies with MHE evaluated the change of SIP score.
The pooled result showed that probiotics was associated
with reduced physical and psychosocial SIP score with weight
mean difference (WMD) —3.13 (95% CI —4.10 to —2.17;
Fig. 6) and WMD —3.50 (—4.91 to —2.08; Fig. 6), respec-
tively. Similar result was obtained with total SIP score (RR
—4.83; 95% CI —6.24 to —3.43; Fig. 6).
Probiotics and adverse events
There were no significant differences in mild adverse events
(RR 1.46; 95% CI 0.87 to 2.45; Fig. 7) or all-cause mortality
(RR 0.66; 95% CI 0.35 to 1.26; Fig. 7). Probiotics was asso-
ciated with reduced severe adverse events (RR 0.59; 95% CI
0.39 to 0.90; Fig. 7). Similar results were obtained in studies
with MHE (mild adverse events with RR 0.97 (95% CI 0.31 to
3.00); all-cause mortality with RR 0.54 (95% CI 0.11 to 2.58);
severe adverse events with RR 0.31 (95% CI 0.12 to 0.79)).
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Figure 1 Flowchart of literature search for meta-analysis.

Figure 2 Forest plot (random-effects model) of probiotics and hepatic encephalopathy.

Figure 3 This diagram showed the influence of excluding each study in turn on the primary meta-analysis. The pooled RRs ranged
from 1.33 to 1.84. There was a statistically significant association between probiotics and hepatic encephalopathy when Liu or
Sharma study was omitted.

Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
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CLINRE-738; No. of Pages 9 ARTICLE IN PRESS
Probiotics and hepatic encephalopathy 5

Table 1 Characteristics of studies on probiotics for hepatic encephalopathy.

Study OHE/MHE CTP score in patients Agent in treatment Duration of Jadad

diagnosis (number of patients) group trial (in weeks) score
Treatment Control

Liu 2004 At least one A3, B/C 17 A3, B/C 17 Pediacoccus 4 3

abnormal test of pentoseceus,
NCT or BAEP Leuconostoc
mesenteroides,
Lactobacillus paracasei
subspecies paracasei and
L. plantarum
Bajaj 2008 At least one A15, B2 A7, B1 S. hermophilus, 8 3
abnormal test of L. bulgaricus,
NCT, DST, or BDT L. acidophilus,
Bifidobacteria, and
L. casei
Sharma 2008 Abnormal test of 2 A14, B11, A12, B14, C9 Streptococcus faecalis, 4 3
NCT, 2 FCT, or C10 Clostridium butyricum,
P300 ERP Bacillus mesentricus,
lactic acid Bacillus
Mittal et al., 2011 At least two NR NR NR 12 3
[12] abnormal test of
NCT, BDT, or
picture connection
test
Saji et al., 2011 NCT-A and evoked NR NR L. acidophilus, 4 5
[13] responses L. rhamnosus, B. longum
(auditory and and Sacharomyces
visual) boulardi
Agrawal et al., Consecutive NR NR Four strains of 48 3
2012 [14] patients with Lactobacillus (L. casei,
cirrhosis who had L. plantarum,
no OHE but a L. acidophilus, and
previous history of L. delbrueckii subsp.
HE bulgaricus), three strains
of Bifi dobacterium
(B. longum, B. breve,
and B. infantis), and one
strain of
S. salivariussubsp.
thermophilus (referred
to hereaft er as
S. thermophiles)
Bajaj et al., 2014 At least one NR NR Lactobacillus GG 8 3
[16] abnormal test of 2
NCT, DST, or BDT
Sharma et al., At least two A6, B21, C5 A10, B8, C12 L. acidophilus, 8 3
2014 [17] abnormal tests of L. rhamnosus,
NCT-A, FCT-A, or L. plantarum, L. casei,
DST and/or CFF B. longum, B. infantis,
was < 39 Hz B. breve, S. boulardi,
and S. thermophilus
Zhao et al., 2013 Abnormal NCT A18, B12, A15, B14, NR 4 3
[15] C10 C11
OHE: overt hepatic encephalopathy; MHE: minimal hepatic encephalopathy; NCT: number connection test; BAEP: brainstem auditory
evoked potential; DST: digit symbol test; BDT: block design test; FCT: figure connection tests; ERP: auditory event-related potential;
CFF: critical flicker frequency; CTP: Child-Turcotte-Pugh; NR: not reported.

Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
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CLINRE-738; No. of Pages 9 ARTICLE IN PRESS
6 L.-N. Zhao et al.

Figure 4 Begg’s test and Egger’s test. Begg’s test and Egger’s test identified no publication bias (Begg’s test: Kendall’s tau = 7,
P = 0.19; Egger’s test: bias = 1.44, P = 0.19).

Figure 5 Forest plot of probiotics and ammonia concentration in hepatic encephalopathy.

Figure 6 Forest plots of probiotics and sickness impact profile in hepatic encephalopathy.

Discussion encephalopathy when Liu or Sharma study were omitted

The results of our meta-analysis provided supportive evi-
dence for the efficacy of probiotics in the improvement of
MHE and prophylaxis of OHE. However, there was significant
heterogeneity across all studies (I2 = 58%, P = 0.03; Fig. 2).
Therefore, sensitivity analysis by reestimating pooled RR
with omitting each study in turn was conducted to investi-
gate the influence of each individual study on the overall
meta-analysis summary estimate. There was a statisti-
cally significant association between probiotics and hepatic
[9,11]. One possible reason is that the result of Liu study
was observed in comparison of synbiotics (probiotics and
fermentable fiber) with fermentable fiber and Sharma study
was about comparison of probiotics and lactulose with lactu-
lose. Although the difference in interventions is probiotics
alone, fermentable fiber and lactulose, as prebiotics, can
modify gut flora and may confer benefit effect for HE.
Furthermore, it is reported that lactulose, probiotics, or
combinations of both are equally effective in the treatment
of MHE [11]. In addition, when we excluded the two studies,

Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
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Probiotics and hepatic encephalopathy 7

Figure 7 Forest plots of probiotics and adverse events in hepatic encephalopathy. Severe adverse events were defined as minimal
hepatic encephalopathy developing into overt hepatic encephalopathy, hospitalizations, infections or unrelated emergency room
visits.

there was no significant heterogeneity in MHE studies (RR
3.56, 95% CI 1.76 to 7.19; I2 = 0). Thus, prebiotics, like fer-
mentable fiber and lactulose, may confer significant bias in
the results. However, further studies are required to confirm
these results.
Compared with previous meta-analyses, only studies with
high quality were included in our study, because their results
are less susceptible to bias and more reliable in principle.
Furthermore, all the excluded studies with low Jadad score
obtained positive results for probiotics and HE [27—33].
Lata 2006 showed that the treated group displayed a trend
towards significant reduction of endotoxemia levels and
improvement of liver function assessed with CTP score [27].
Ye RH 2006, Liu JS 2006, Zhang SQ 2007, Qiao XL 2009, Liu
WZ 2009, and Wang XJ 2012 all showed that probiotics were
associated with reduction of endotoxemia levels, ammonia
levels, and improvement of MHE [28—33]. Apart from that,
we also excluded studies in which the difference in inter-
ventions was not probiotics alone because synbiotics and
lactulose can also be effective treatment for HE through
beneficial effect on gut microbiota modification and confer
bias on the efficacy of probiotics in HE [18,20—22]. The
meta-analysis by Shukla, including five RCT studies with lac-
tulose and two studies each of probiotics and synbiotics,
demonstrated that the use of prebiotics, probiotics and syn-
biotics was associated with significant improvement in MHE,
and lactulose appears to have the most beneficial effect,
followed closely by probiotics and synbiotics [6]. Therefore,
selected studies, which were less susceptible to bias, further
enhanced the reliability of our study.
Probiotics presumably work by modulation of gut micro-
biota in cirrhosis to exert a favourable effect on HE. The
gut flora plays a critical role in the pathogenesis of the
systemic inflammation, endotoxemia, and ammonia produc-
tion [4]. Liu and Bajaj study provided data about reduction
of endotoxemia, but the results were controversial [9,16].
TNF-␣ reduction was also observed in patients with pro-
biotics in Bajaj study [16]. Our results provided evidence
that probiotics was associated with reduction of ammonia
concentration. As a result, probiotics may be associated
with reduction of ammonia concentration, endotoxemia,
and inflammatory factors, resulting in the improvement of
MHE and prophylaxis of OHE.
HE has heavy negative influence on patients’ daily life.
Neurocognitive deficits in MHE result in impairment of
health-related quality of life, impaired daily functioning,
ability to work, and driving skills and progression to OHE
stage [3]. Wein et al. showed that MHE impairs fitness to

Please cite this article in press as: Zhao L-N, et al. Probiotics can improve the clinical outcomes of hepatic encephalopathy:
An update meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.008
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CLINRE-738; No. of Pages 9 ARTICLE IN PRESS
8 L.-N. Zhao et al.
drive [34]. Similar observations by Bajaj et al. confirm that
MHE is associated with motor vehicle crashes [35]. Up to 60%
of blue-collar workers and 23% of white-collar workers with
MHE may be unfit for working [36]. Furthermore, OHE is asso-
ciated with decreased survival and can predict subsequent
OHE episodes and hospitalization [4]. Cordoba et al. anal-
ysed characteristics of 1348 consecutive cirrhotic patients
and demonstrated that HE is independently associated with
HE recurrence and reduction of survival probabilities [37].
Therefore, the treatment of MHE and prevention of OHE
have become challenging clinical problems. The pooled
results of our analysis suggested that probiotics was associ-
ated with reduced physical SIP score, psychosocial SIP score,
and total SIP score (Fig. 6). Furthermore, probiotics was
associated with reduction of severe adverse events (defined
as MHE developing into OHE, hospitalizations, infections or
unrelated ER visits). Thus, probiotics appear to improve the
quality of patients’ daily life and reduced severe adverse
events.
There were several limitations in our study. Firstly, stud-
ies with low Jadad score were excluded. Though it enhanced
the reliability of selected studies, some studies with low
Jadad score, which may not be subjected to bias, were
excluded and resulted in publication bias. Secondly, some
subgroup analyses remain too small to have sufficient sta-
tistical power. For example, only two studies with total
95 numbers provided data about probiotics on physical SIP,
psychosocial SIP, and total SIP score. Thirdly, there was
significant heterogeneity among all the studies. We inves-
tigated the influence of each individual study on the overall
estimate and found out that Liu or Sharma study may confer
bias to the pooled results. Therefore, further studies with
well-designed RCT studies are required to confirm these
results.
In summary, our pooled results indicated that probiotics
was associated with improvement of MHE, prophylaxis of
OHE, and reduction of SIP score and severe adverse events.
Large well-designed RCT studies are needed to confirm these
results.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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