Received: 2 February 2017 | Accepted: 13 March 2017

DOI: 10.1002/jcp.25911

REVIEW ARTICLE

Probiotics are a good choice in remission of inflammatory

bowel diseases: A meta analysis and systematic review

Mahboube Ganji-Arjenaki | Mahmoud Rafieian-Kopaei

Medical Plants Research Center, Shahrekord

University of Medical Sciences, Shahrekord, Iran
Correspondence
Mahmoud Rafieian-Kopaei, Medical Plants
Research Center, Shahrekord University of
Medical Sciences, Shahrekord, Iran.
Email: rafieian@yahoo.com
Altered gut bacteria and bacterial metabolic pathways are two important factors in initiation and
progression of inflammatory bowel disease (IBD). However, efficacy of probiotics in remission
of patients with IBD has not been characterized. This study was performed on the studies that
specifically assessed the efficacy of probiotics in attaining clinical response on patients with
various types of IBD. The efficacy of variant species of probiotics in different conditions and the
influence of study quality in outcomes of randomized controlled trials (RCTs) were also
assessed. The RCTs were collected by searching in MEDLINE Web of Science and Google
scholar. Then all studies were abstracted in abstraction form and the outcomes were analyzed
with fixed-effect and mixed-effect models for assessment of efficacy of variant species of
probiotics in subgroups of IBDs. Analysis of 9 trials showed that probiotics had not significant
effect on Crohn’s disease (CD) (p = 0.07) but analysis of 3 trials in children with IBD revealed a
significant advantage (p < 0.01). Analysis of 18 trials revealed that probiotics in patients with
Ulcerative colitis (UC) in different conditions have significant effects (p = 0.007). VSL#3
probiotics in patients with UC had significant effect (p < 0.01). Combination of Lactobacillus
probiotic, prebiotics had significant effect (p = 0.03) only in patients with UC. Combination of
Saccharomyces boulardii, Lactobacillus, and VSL#3 probiotics in CD had also a trend for efficiency
(p = 0.057). In children with IBD, the combination of Lactobacillus with VSL#3 probiotics had
significant effect (p < 0.01). Probiotics are beneficial in IBD, especially the combination ones in
UC.

KEYWORDS
Crohn’s disease, IBD, probiotics, ulcerative colitis

1 | INTRODUCTION
Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and
Crohn’s disease (CD), have multifactorial etiologies. Complex inter-
actions between genetics, epigenetics, gut microbiota, and host
immune system have been considered as leading factors for chronic
inflammation. Altered gut bacteria and modified bacterial metabolic
pathways are two important factors in initiation and progression of
IBD. The bacterial alterations in the composition or balance of
the intestinal microbiota or dysbiosis, for example increase in
abundance of Faecali bacterium and decrease in abundance of
Clostridiales, correlate strongly with disease status. However, there
is still no clear microbial pathogenesis linked to the onset of IBD, but
many investigations favor the altered microbiome as primary cause
which leads to inflammatory reactions (Gevers et al., 2014; Haberman
et al., 2015; Hold et al., 2014; Morgan et al., 2012; Orel & Kamhi Trop,
2014; Ruemmele, Pigneur, & Garnier-Lengliné, 2014; Sepehri,
Kotlowski, Bernstein, & Krause, 2007; Serban, 2015; Walker et al.,
2011).
Dysbiosis can lead to an imbalance in metabolites production
that in turn may link to IBD pathogenesis. For example, F.
bacterium produces short-chain fatty acids (SCFAs), in forms of
acetate, propionate, and butyrate. Acetate forms are substrates
for butyrates and butyrates are a major energy source for bowel
epithelial cells. Butyrate-producing bacteria have an important
role in epithelial barrier integrity. Reduction of butyrate-
producing bacteria level is found in fecal samples of patients
with IBD (Li, Butcher, Mack, & Stintzi, 2015; Machiels et al.,
2013; Mahowald et al., 2009; Wong, De Souza, Kendall, Emam, &
Jenkins, 2006).

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2092 | GANJI-ARJENAKI AND RAFIEIAN-KOPAEI

Antibiotics decrease the concentrations of bacteria and alter the
composition of microbiota in the gut lumen, therefore, may influence
on severity of IBD. These also play an important role in maintenance of
remission but most trials have not shown any benefits for the
treatment of IBDs with antibiotics. Antibiotic therapy is only
associated with a moderate improvement in clinical symptoms.
Some of studies have shown that antibiotics cause dysbiosis and
changes in fungal population in intestine, as well as dysregulation in
immune response, resulting in intolerance to treatment, Clostridium
dificile infection and increase in antibiotic resistance (Nitzan, Elias,
Peretz, & Saliba, 2016; Sheehan, Moran, & Shanahan, 2015; Ungaro
et al., 2014).
Since gut dysbiosis has a potential pathogenetic role in IBD,
therapies targeting the microbiota with aim of controlling the
disease is increasing. Probiotics include nonpathogenic live micro-
organisms that would overpopulate the gut with potentially
beneficial microbes. They have positive impact on the balance of
microbes in the gut, improve the absorption of micronutrients such
as calcium and iron from ingested foods, therefore, may have
positive impact on the course of IBD (Bernstein, 2014; Hajela et al.,
2015; Hill et al., 2014; Sazawal et al., 2010). A meta-analysis, done in
2014 showed positive effects of probiotics on UCs, but did not
evaluate the effects of probiotics in remission of CDs, or the efficacy
of types of probiotics on CD and/or UC (Shen, Zuo, & Mao, 2014). In
this study, we tried to find the answers for the following questions:
What is the efficacy of probiotics on IBD status in detail? or how are
the effectiveness of various species of probiotics in types of IBD or
in its different conditions? Hence, we performed this systematic
review and meta-analysis on the studies that had specifically
assessed the efficacy of probiotics in attaining clinical response on
patients with IBD, in each types of UC and CD separately, and
efficacy of variant species of probiotics in UCs and CDs with
different conditions. Also, we considered the influence of study
quality on outcomes of RCTs.

F I G UR E 1 Flow diagram of assessment of studies selected in the systematic review and meta-analysis
TABLE 1 Characteristics of randomized controlled clinical trials for types of IBD
Study Year Country Subjects Therapy Age Sex M/F Definition of end point
Tamaki et al. (2016) 2016 Japan UC BB536 44 ± 14 27/29 63% remission
GANJI-ARJENAKI

Fedorak et al. (2015) 2007 Canada CD after surgery VSL#3 37.6 ± 12.4 62/58 No differences but lower rate of in recurrence
AND

Yoshimatsu et al. 2014 Japan Inactive UC Lactomin + Clostridium butyricum 44.8 ± 13.8 28/18 69.5% remission
(2015) TO-A + Bacillus mesentericus TO-A
Petersen et al. (2014) 2014 Denmark Active UC E. coli Nissle 1917 + ciprofloxacin 39 ± 1 38/62 Not efficient in remission
Bourreille et al. (2013) 2013 France CD S. boulardii 36.5 ± 1 45/122 Any beneficial effect
Oliva et al. (2012) 2011 Italy Children with UC L. reuteri ATCC 55730 6–18 17/23 Improving mucosal inflammation
RAFIEIAN-KOPAEI

Ishikawa et al. (2011) 2010 Japan UC Bifidobacterium breve strain 45 ± 14 24/17 Improve the clinical condition
yakult + galacto-oligosaccharide
Wildt, Nordgaard, 2006 Denmark Left-sided UC Lactobacillus acidophilus 23–68 10/22 Well tolerated
Hansen, Brockmann, La-5 + Bifidobacterium animalis
and Rumessen subsp. lactis BB-12
(2011)
Tursi et al. (2010) 2010 Italy UC VSL#3 46.4 ± 15.4 93/51 Not signifi cance safe
Matthes, Krummenerl, 1999–2002 Germany Active UC E. coli Nissle 1917 18–70 49/39 Significant effect of rectal EcN
Giensch, Wolff, and
Schulze (2010)
Steed et al. (2010) 2006–2008 UK Active CD Synbiotic: B. longum + Synergy 1 18–79 13/11 Effective in improving
Sood et al. (2009) 2005–2007 North India Active UC VSL#3 38.3 ± 13 88/28 Effective in remissions
Fujimori et al. (2009) 2006 Japan UC Probotic, prebiotic, synbiotic 35 ± 17 39/55 Effects on the mucosal
Garcia Vilela et al. 2006–2007 Brazil CD S. boulardii 19–45 None Not significant effects
(2008)
Miele et al. (2009) 2008 Italy Children with UC VSL#3 1.7–16.1 13/16 No clinical adverse events
Van Gossum et al. 2001–2004 Brussels Early postoperative L. johnsonii, LA1 18–65 33/37 Failed to prevent early recurrence
(2007) endoscopic of CD
Zocco et al. (2006) 2001–2004 Italy UC Lactobacillus GG + mesalazine 33 ± 7 104/83 Effective in remission
Furrie et al. (2005) 2004 UK Active UC VSL#3 24–66 8/8 Improving in chronic inflammation
Marteau et al. (2006) 2002–2004 France CD L. johnsonii LA1 27–42 47/51 Not sufficient effect
Bousvaros et al. (2005) 1999–2002 USA Children with CD L. rhamnosus strain GG 5–21 47/28 With a side effect
Kato et al. (2004) 2003 Japan Active UC Bifidobacteria-fermented milk 30–34 10/10 Effective than conventional treatment
Kruis et al. (2004) 2003 Germany UC E. coli Nissle 1917 19–69 92/70 Efficacy in remission
Tursi et al. (2004) 2003 Italy Active UC VSL#3 + balsalazide 19–63 21/9 Good choice in the treatment
Schultz et al. (2004) 2004 USA Active CD Lactobacillus GG Not define Not define Not effective in remission
Ishikawa et al. (2003) 1998 Japan UC Bifidobacteria-fermented milk 39–60 11/10 Successful in remission
Prantera, Scribano, 1998–2000 Italy CD after surgery Lactobacillus GG 22–71 29/16 Neither to prevent recurrence
|

Falasco, Andreoli,
2093

(Continues)
TABLE 1 (Continued)
2094
|

Study Year Country Subjects Therapy Age Sex M/F Definition of end point
and Luzi (2002)
Rembacken, Snelling, 1999 UK UC E. coli (Nissle 1917) 18–80 29/28 Nonpathogenic and effetive
Hawkey, Chalmers,
and Axon (1999)
Concomitant Study No. of Type of Jadad
Dosage and schedule of therapy used Control group medications duration patients Methodology study score
2-3 × 1011 freeze-dried viable BB536 Placebo None 8 weeks 56 Randomized, double-blinded, MRDC 5
placebo-controlled multicenter trial
1 sachet of VSL#3 Placebo None 90–365 120 Randomized, multicenter, double-blind, MRDC 5
days placebo-controlled trial, open-label
2 mg lactomin, 10 mg clostridium, Placebo Pentasa, salazopyrin, 12 months 46 Randomized, single-center, RDC 5
10 mg B. mesentericus TO-A pentasa, salazopyrin double-blind, placebo-controlled
500 mg × 2 daily ciprofloxacin Placebo Azathioprine, 6-mercaptopurin, 12 weeks 100 Randomized single center RDC 5
100 mg × 1 EcN for 4 days corticosteroid double-blinded placebo controlled
1 g/day Placebo Prednisone, azathioprine/ 52 weeks 165 Randomized, placebo-controlled trial RC 2
6-mercaptopurine
50–75 mg⁄kg⁄day mesalazine an enema Placebo Anti-inflammatory drugs 8 weeks 40 Randomised, placebo-controlled RC 2
solution containing 1010 CFU
L. reuteri ATCC 55730
1 g (10 9 CFU/g) probiotic powder Control Salazosulfapyridine, 1 year 41 Randomized, large-scale placebo RC 2
5.5 g galacto-oligosaccharide mesalazine, steroids controlled trial
1.5 × 1011 CFU daily Placebo 5-aminosalicylic acid 52 weeks 32 Randomised-double-blind RDC 5
(ASA) orally and rectally placebo-controlled
3,600 billion CFU/day Placebo Mesalamine, balsalazide, 8 weeks 144 Randomized, double-blind, RDC 5
azathioprine, methotrexate placebo-controlled
Randomly take one 40 ml, 20 ml, Placebo Corticosteroids 8 weeks 88 Randomised, double-blind, MRDC 5
10 ml EcN placebo-controlled, parallel-group,
multicentre, phase-II
2*1011 freeze-dried viable B. longum in Placebo Steroid, 5-aminosalicylic 6 months 24 Randomized, double-blind RDC 5
a gelatin capsule a sachet containing acid, Azathioprine placebo-controlled trial
6 g Synergy 1 twice daily
3.6*1012 CFU for twice daily Placebo Mesalamine, 12 weeks 116 Randomized, multicenter, MRDC 5
immunosuppressants double-blind, placebo-controlled trial
GANJI-ARJENAKI

Probiotic group one capsule (2*109 Aminosalicylates, prednisolone 4 weeks 120 Randomized trial RC 2
AND

colony-forming units) B. longum the

prebiotic group 8.0-g psyllium. The
synbiotic group underwent both
treatments daily
An oral capsule (200 mg lyophilized) Placebo Mesalamine, azathioprine, 3 months 34 Randomized, blinded RC 3
(Continues)
RAFIEIAN-KOPAEI
TABLE 1 (Continued)
Concomitant Study No. of Type of Jadad
Dosage and schedule of therapy used Control group medications duration patients Methodology study score
S. boulardii-17 6 mg sucrose 2.4 mg prednisone, metronidazole,
GANJI-ARJENAKI

magnesium thrid in day thalidomide

AND

Weight-based dose, range: 450–1,800 Placebo Steroid, mesalamine 1 year 29 Randomized, placebo-controlled, double-blind RDC 5
billion bacteria/day
1010 colony-forming units, CFU/day Placebo Smoker 12 weeks 70 Randomized, multicenter, double-blind placebo- MRCD 5
controlled trial
18*109 viable bacteria/day Lactobacillus Not define Smoker 12 months 187 Randomized, single centre, prospective, RC 2
RAFIEIAN-KOPAEI

GG mg/day mesalazine 2,400 open-label trial

26*1011 freeze dried in a gelatin capsule Placebo Steroids, immunosupressants, 1 month 18 Randomised, double blinded controlled trial RDC 5
B. longum 6 g fructo-oligosaccharide/ 5-ASA
inulin mix twice daily
Two packets (26*109 cfu) lyophilised Placebo Steroid 6 months 98 Randomised, double blind, placebo controlled RDC 5
LA1 per day
1 capsule (1010 bacteria and 295 mg Placebo Aminosalicylates, 9.8 months 75 Randomized, placebo-controlled trial RC 2
inulin) twice per day 6-mercaptopurine,
azathioprine, corticosteroids
100 ml/day Placebo 5-ASA or SASP 12 weeks 20 Randomized placebo-controlled trial RC 2
200 mg once daily Control Oral salicylates 12 months 162 double blind, double dummy trial DC 2
2.25 g balsalazide 3 g VSL#3 daily Control None 8 weeks 30 Randomized multicenter, trial MRC 2
2 × 109 CFU/day Placebo Corticosteroids 6 months 11 Randomized, double-blind, placebo-controlled trial RDC 5
100 ml/day Control Prednisolone, 1 year 21 Randomized controlled trial RC 2
salazosulfapyridine
6 billion cfu twice daily Placebo None 1 year 45 Randomised, double blind, placebo controlled trial RDC 5
Two capsules (2 · 5*1010 viable bacteria Control Aminosalicylates, azathioprine, 1 year 57 Randomised, single-centre, doubledummy RC 2
per capsule) E. coli twice daily prednisolone
|
2095
2096 | GANJI-ARJENAKI AND RAFIEIAN-KOPAEI

2 | M ATERIA LS AN D METH ODS Data were collected based on studies information such as author
name, country, sample size, age of patients, type of medication used, and

2.1 | Data sources outcome. In some RCT studies the years of study were not mentioned. In
these cases the years of publications were recorded. To assess quality of
The MEDLINE (1997 to June 2016) and Google scholar (1999 to June clinical trials, we used the Jadad score (Jadad et al., 1996).
2016) were searched for studies assessing the efficacy of probiotics in
the treatment of patients with IBD.
2.4 | Outcome estimation
2.2 | Search strategy and study selection The primary outcomes of the studies were formed base on the percent
of clinical remission, differences in recurrence and in colonic
We only considered randomized controlled trials (RCTs) in patients
microflora, improving mucosal inflammation and clinical conditions,
with IBD (CD and UC) in different conditions. There were no
reduction of Ulcerative Colitis Disease Activity Index (UCDAI) scores,
restrictions regarding age, sex, and duration of study. The studies
maintaining remission, preventing relapse, differences in biochemical
were identified with the terms “Crohn’s disease,” “inflammatory bowel
elements, comparable with efficacy of mesalazine as a drug of choice in
disease,” “colitis,” “probiotic,” “synbiotic,” “IBD,” “CD,” or “UC.” The
treatment of IBD.
search strategy is described in Figure 1.

2.3 | Data extraction 2.5 | Probiotic intervention

All studies were abstracted in abstract form by two authors MGA and In these RCTs the aim was assessment of efficacy of probiotics on
MRK. types of IBD in difference conditions, from mild to severe UC and CD,

TABLE 2 Outcomes of randomized controlled trials evaluating the effects of probiotics on IBDs
Treat by probiotic Control group

Study Subject Remission Sample size Remission Sample size p value

Rembacken et al. (1999) UC 39 57 44 59 0.005
Prantera et al. (2002) CD after surgery 16 23 19 22 0.2
Ishikawa et al. (2003) UC 3 11 9 10 0.01
Schultz et al. (2004) Active CD 2 5 2 6 0.5
Tursi et al. (2004) Active UC 24 30 37 60 0.02
Kruis et al. (2004) UC 40 162 38 165 0.003
Kato et al. (2004) Active UC 4 10 3 10 0.01
Bousvaros et al. (2005) Children with CD 12 39 6 36 0.2
Marteau et al. (2006) CD 21 48 30 50 0.1
Furrie et al. (2005) Active UC 6 8 2 8 0.01
Zocco et al. (2006) UC 55 65 83 102 0.04
Van Gossum et al. (2007) CD after surgery 1 34 2 36 0.7
Miele et al. (2009) Children with UC 13 14 4 15 0.001
Garcia Vilela et al. (2008) CD 5 15 0 19 0.001
Fujimori et al. (2009) UC 29 40 54 80 0.03
Sood et al. (2009) Active UC 25 77 7 70 0.001
Steed et al. (2010) Active CD 8 13 5 11 0.01
Matthes et al. (2010) Active UC 45 70 10 20 0.04
Tursi et al. (2010) UC under ASA treat 8 71 9 73 0.06
Wildt et al. (2011) Left-side UC 5 20 1 12 0.3
Ishikawa et al. (2011) Mild to moderate UC 20 21 1 20
Oliva et al. (2012) Childern with UC 16 20 15 20 0.01
Bourreille et al. (2013) CD treat with steroids 46 84 39 81 0.5
Petersen et al. (2014) Active UC 16 25 46 75 0.02
Yoshimatsu et al. (2015) Inactive UC 10 23 7 23 0.3
Fedorak et al. (2015) CD after surgery 32 59 39 60 0.8
Tamaki et al. (2016) Mild to moderate UC 15 28 11 28 0.03
GANJI-ARJENAKI AND RAFIEIAN-KOPAEI | 2097

F I G UR E 2 Randomized controlled trials of probiotics in remission of IBDs: (a) Forest plot of randomized controlled trials of probiotics in
treatment of CDs. (b) Funnel plot ofstudies included in panel A. Dots represent the results of each study. (c) Random-effects metaregression
analysis of influence of quality of the studies on efficiency of probiotic treatment in CDs. The circles represent each study. The size of the
circle represents the power of the study. The solid line demonstrates the weighted regression line.(d) Forest plot of randomized controlled
trials of probiotics in patients with CD after surgery. (e) Forest plot of randomized controlled trials of probiotics in children with IBD
2098 | GANJI-ARJENAKI AND RAFIEIAN-KOPAEI

in patients aged from 5 to 80 years old. Probiotics only or with Schneider, & Minder, 1997). Data analysis were performed with
prebiotics and synbiotics or with other drugs such as Mesalazine and Comprehensive Meta-Analysis V3 (Biostat, Englewood, NJ).
Sulfasalazine were included.

2.6 | Statistical analysis

Data were prepared, analyzed, and reported according to guidelines of
the Meta-analysis of Observational Studies in Epidemiology group
(Stroup et al., 2000). We tested dichotomous data by evaluating the
rate difference with their 95% confidence intervals. Random-effects
models were pooled with subgroups depending on the disease, study
designs, and species of probiotics and then fixed-effect model and
mixed-effect models were used to combine subgroups in order to yield
the overall effect. We also quantified the percentage of variability that
could be attributed to between-study differences by the presence of
heterogeneity across trials by using the I2 statistic and also performed
the Begg and Egger tests to assess the potential for publications bias of
the efficacy of probiotics in types of IBD and created funnel plots to
visualize possible asymmetry (Begg & Mazumdar, 1994; Egger, Smith,
3 | RE SULTS
3.1 | Studies quality and characteristics
A total of 49 randomized controlled trials were selected and evaluated
in detail. Of these, 21 articles were excluded for various reasons
(Figure 1), The remaining 27 articles for analysis were included, nine
articles for Crohn’s disease and 18 articles for Ulcerative colitis.
Lactobacillus, VSL#3, Escherichia coli, Saccharomyces boulardii, Bifido-
bacterium probiotics, and prebiotics in 9, 6, 4, 1, 2, 3 trials were
respectively used for remission of types of IBD. Quality of the studies
were assessed by the Jadad score (1 < = Jadad score > = 5). The
characteristics and outcomes of the identified studies are summarized
in Tables 1 and 2.

F I G UR E 3 Randomized controlled trials of probiotics in remission of IBDs. (a) Forest plot of randomized controlled trials of probiotics in
treatment of UCs. (b) Funnel plot ofstudies included in panel A. Dots represent the results of each study
GANJI-ARJENAKI AND RAFIEIAN-KOPAEI | 2099

3.2 | Efficacy of probiotics for remission in
inflammatory bowel sisease
The efficacies of probiotics on patients with CD in different conditions
such as CD after surgery or in children or active CD in 9 trials were
evaluated. The results showed that probiotics had not significat effects
on CD (95% CI, 0.7–1.0, p = 0.07, RR = 0.87) (Figure 2a). The
heterogeneity among the studies was median, as shown by an I2
value of 40.14. The funnel plot revealed some asymmetry, and the
Begg and Egger tests showed a non-significant trend toward
publication bias among the included studies (P:0.8 and 0.0.9,
respectively) (Figure 2b). Randome-effects meta-regression demon-
strated that the study quality significantly influenced the outcome of
the studies with better quality displayed superior outcome (Q = 10.37,
95% CI, p = 0.005) (Figure 2c). Assessment of efficacy of probiotics on
patients with CD after surgery showed effectiveness (p = 0.07,
RR = 0.81) (Figure 2d).
MH risk ratio and 95% CI test with 3 trials in evaluation of the
effect of probiotics in children with IBD revealed a significant
2
advantage (p < 0.01, RR = 2.05, I = 30.50) (Figure 2e). Probiotics in
patients with CD and UC who used steroid drugs (2 trials) showed
significant advantage (p < 0.01, I2 = 97.63, RR = 0.5) (data not shown).
Also, it showed significant effect on patients with CD without specific
condition (2 trials) (data not shown) (p = 0.002, RR = 0.58, I2 = 69.86).
Analysis of 18 trials revealed that probiotics in patients with UC in
different conditions had significant effects (p = 0.007, RR = 0.88,
I2 = 88.78) (Figure 3a). The funnel plot revealed asymmetry, and the
Begg and Egger tests showed a non-significant trend toward
publication bias among the included studies (P:0.9 and 0.7, respec-
tively) (Figure 3b).
3.3 | Efficacy of species of probiotics in inflammatory
bowel disease
Test of MH risk ratio showed that VSL#3 probiotic on patients of UC
had significant effect (p < 0.01, RR = 0.47, I2 = 96.98) (Figure 4a).
Combination of Lactobacillus probiotic, prebiotics in patients with UC
had significant effect (p = 0.03, RR = 1.16, I2 = 89.79) (Figure 4b,c).
Mixture of S. boulardii and VSL#3 probiotics in CD was advantage
(p = 0.09, RR = 0.84, I2 = 76.93) (data not shown). Combination of S.
boulardii, Lactobacillus, and VSL#3 probiotics in CD might also be
efficacious (p = 0.057, RR = 0.85, I2 = 45.13) (Figure 5a). In patients

F I G UR E 4 Randomized controlled trials of species of probiotics in remission of IBDs. (a) Forest plot of randomized controlled trials of VSL#3
probiotic in treatment of UCs. (b) Forest plot of randomized controlled trials of compound of Lactobacillus probiotic, prebiotics in UCs. Lac.,
Lactobacillus, pre., prebiotics
2100 | GANJI-ARJENAKI AND RAFIEIAN-KOPAEI

F I G UR E 5 Randomized controlled trials of species of probiotics in remission of IBDs. (a) Forest plot of randomized controlled trials of
compound of S. boulardii, Lactobacillus, and VSL#3 probiotics in treatment of CDs. (b) Forest plot of randomized controlled trials of compound
of Lactobacillus with VSL#3 probiotics in children with IBD. Lac., Lactobacillus, sac., S. boulardii

with Crohn’s disease after surgery, mixed Lactobacillus with VSL#3
probiotics was effective (p = 0.07, RR = 0.81) (data not shown). Mixed
S. boulardii, Lactobacillus, and VSL#3 probiotics in patients with CD
who also used steroid drugs were significantly efficacious with
analysing 2 trials (p < 0.01, RR = 0.50, I2 = 97.63) (data not shown). In
children with IBD (CD and UC), the Lactobacillus with VSL#3 probiotics
2
had significant effect (p < 0.01, RR = 2.05, I = 30.5) (Figure 5b).
4 | DISCUSSION
This meta-analysis and systematic review was undertaken to evaluate
the efficacy of probiotics for remission in IBDs (UCs and CDs) patients
and assessment of efficacy of variant species of probiotics in types of
IBD with different conditions. Analysis of 27 random controlled trials
by random effect model or mixed-effect analysis revealed that
probiotics had well-tolerance in treatment of IBDs. The trials included
in this study were mild to mostly heterogeneous (I2 = 30–97) that we
showed in each of sections. Sources of heterogeneity in these studies
are variations of the study, duration and size, of patient characteristics
such as age, type and activity of disease, geographic location, and type
of intervention. In our study, Jadad score defined the study quality and
in fact, meta-regression analysis showed that it largely influenced
outcomes and there were no statistically significant publication biases
observed in this study.
Probiotics with restoring the microbial balance, modulating
mucosal protection, protecting against pathogens inducing protective
immune responses through immunization, and modifying gut-associ-
ated lymphoid cells are effective in IBD (Fedorak & Madsen, 2004).
In a meta analysis of 8 trials in 2008, data showed that probiotics,
in general, are not more beneficial than placebo and Lactobacillus
probiotics were not effective in maintaining remission in patients with
CD (Rahimi et al., 2008).
But we by analysis of 27 trials demonstrated that the probiotics
in overall are effective in CD and UC. But combination of S. boulardii
and VSL#3 probiotics in CD seems to be more efficient (p = 0.057). In
children with age range 2–21 having IBD (CD and UC) probiotics,
specifically compound of Lactobacillus with VSL#3 have significant
affect (p < 0.01). Paying attention to occurrence of IBD in infants and
very young children, it might be pointed that genetic factors are
basic and important reasons in this event (Chandrakasan, Venka-
teswaran, & Kugathasan, 2017; Kelsen et al., 2015). It has been
previously shown that VSL#3 is effective in UC, however, probiotics
are not effective in CD (Shen et al., 2014). We confirmed that VSL#3
is effective in UC, and the combination of Lactobacillus or/with
S. boulardii and Lactobacillus is efficient on CD after surgery as well
GANJI-ARJENAKI AND RAFIEIAN-KOPAEI
as in patients who use steroid drugs. Efficacy of combined VSL#3
and Lactobacillus on CD after surgery might be significant, if duration
of treatment under study was longer. Also, if the number of RTCs
evaluating the efficacy of probiotics in CD that used steroid drugs
were more (>2), the result of test might be significant. Compound of
Lactobacillus probiotics, prebiotics is significantly effective in
patients with UC.
Lactobacillus GG probiotic is stable in acid and bile, adheres
to human epithelial cells and prevents the connection of
pathogens to intestinal mucus, increases expression of mucins
MUC2 and MUC3 that inhibit adherence of pathogenic bacteria
such as enteropathogenic E. coli (Gupta, Andrew, Kirschner, &
Guandalini, 2000).
VSL#3 is a high-concentrated probiotic that is able to control the
inflammation, decrease the mucosal infection and increase the
remission period by reducing he tissue levels of tumor necrosis
factor-a (TNFa), interferon-g, inducible nitric oxide synthase, and
matrix metalloproteinases 2 and 9 (Manuzak et al., 2016; Mariman,
Tielen, Koning, & Nagelkerken, 2014; Ulisse et al., 2001).
Disruption of the mucus barrier plays an important role in the
exacerbation of inflammatory bowel disease. Prebiotics with modula-
tion of the mucus barrier that is associated with a decreased activity of
the endocannabinoid system and an increased level of Glucagon-like
peptide 2 (GLP-2) in bowel may stimulate synthesis of proteins forming
tight junctions (Sun et al., 2016; Wasilewski, Zielinska, Storr, & Fichna,
2015).
A compound of prebiotics and probiotics, named synbiotics, may
reduce the concentration of undesirable metabolites, harmful
microflora, such as Clostridium perfringens. Combination of prebiotic
Synergy 1 and Bifidobacterium longum led to improvement of
sigmoidoscopy scores and decrease in b-defensin, TNF-a, and IL-1a
in biopsy samples from patients with UC (Arai et al., 2002; Bengmark,
2005; Wasilewski et al., 2015).
S. boulardii decreases the risk of postoperative complications such
as infections and anastomotic leakage and decreases the gene
expression of SOCS3 which is a suggested mechanism (Kotzampassi
et al., 2015).
5 | C ONC LU SI ON S
In this study, we considered 27 randomized controlled trials, nine
articles with CD and 18 with UC, with main subjects of explored of
effective of probiotics in attain to remission in IBDs. We used fixed and
mixed randome- effect models for analyzing the efficacy of probiotics.
Analysis of tests showed that probiotics may in overall have significant
effect on CD especially in CD after surgery, but in children with IBD,
mixed Lactobacillus and VSL#3 probiotics have a significant advantage.
Combination of S. boulardii, Lactobacillus, and VSL#3 probiotics in CD
might also be efficient. In UC, probiotics are significantly efficient.
VSL#3, compound of Lactobacillus probiotics with prebiotics in
patients with UC have significant effect. Test of study quality
performed with Randome-effects meta-regression revealed that
studies with better quality have superior outcome.
| 2101
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How to cite this article: Ganji-Arjenaki M, Rafieian-Kopaei
M. Probiotics are a good choice in remission of
inflammatory bowel diseases: A meta analysis and
systematic review. J Cell Physiol. 2018;233:2091–2103.
https://doi.org/10.1002/jcp.25911