Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Probiotics and prebiotics in ulcerative colitis

Lauranne A.A.P. Derikx, MD a,
Levinus A. Dieleman, MD, PhD b, 1,
Frank Hoentjen, MD, PhD a, 1, *
a
Inammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, Radboud University
Medical Centre, Nijmegen, The Netherlands
b
Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada

a b s t r a c t
Keywords:
Ulcerative colitis
Microbiota
Probiotics
Prebiotics

The intestinal microbiota is one of the key players in the etiology of

ulcerative colitis. Manipulation of this microora with probiotics
and prebiotics is an attractive strategy in the management of
ulcerative colitis. Several intervention studies for both the induction and maintenance of remission in ulcerative colitis patients
have been performed. Most of these studies evaluated VSL#3 or E.
Coli Nissle 1917 and in general there is evidence for efcacy of
these agents for induction and maintenance of remission. However, studies are frequently underpowered, lack a control group,
and are very heterogeneous investigating different probiotic
strains in different study populations. The absence of wellpowered robust randomized placebo-controlled trials impedes
the widespread use of probiotics and prebiotics in ulcerative
colitis. However, given the promising results that are currently
available, probiotics and prebiotics may nd their way to the
treatment algorithm for ulcerative colitis in the near future.
2016 Elsevier Ltd. All rights reserved.

* Corresponding author. Inammatory Bowel Disease Centre, Department of Gastroenterology and Hepatology, Radboud
University Medical Centre, PO Box 9101, Code 455 6500 HB, Nijmegen, The Netherlands. Tel.: 31 248187467; fax: 31
243635129.
E-mail addresses: Lauranne.Derikx@radboudumc.nl (L.A.A.P. Derikx), Frank.Hoentjen@radboudumc.nl (F. Hoentjen).
1
Both authors share senior authorship.
http://dx.doi.org/10.1016/j.bpg.2016.02.005
1521-6918/ 2016 Elsevier Ltd. All rights reserved.

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L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Introduction
Inammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a
chronic relapsing inammatory disorder of the gastrointestinal tract with variable prevalences
between 37.5 and 248.6 per 100.000 in North America and 4.9e505 per 100.000 in Europe [1]. Clinical
features involve (hemorrhagic) diarrhea, abdominal pain, weight loss and/or fatigue and some patients
develop IBD-related extra-intestinal manifestations such as primary sclerosing cholangitis, skin lesions
or joint problems. Current strategies for the treatment of IBD involve rst induction of remission,
followed by maintaining remission. UC patients with disease activity are usually treated with topical or
systemic 5-aminosalicylic acids (5-ASA) or corticosteroids. Subsequently, 5-ASA is the rst choice for
maintenance therapy followed by immunomodulators, including azathiopurine and 6-mercaptopurine
in case of persistent disease activity or adverse events to 5-ASA. In case of severe refractory UC,
intravenous corticosteroids, cyclosporine, anti-TNFa agents and lately the anti-integrin vedolizumab
are options to induce remission in order to avoid colectomy.
The therapies outlined above have signicant disadvantages. First, immunosuppressive therapies
and anti-TNFa agents are associated with a higher risk of infectious complications [2]. Second, a third of
patients eventually requires surgical intervention, indicating that current therapeutic options are
insufcient for many patients [3]. Third, the high costs of biological therapies contribute to the
increasing nancial burden of health care and are topic of discussion among health policy makers. This
emphasizes the need for other (non-pharmacological) options, preferably based on pathways that
contribute to chronic mucosal inammation in UC.
Although a multi-factorial etiology in IBD is widely acknowledged, the exact etiology remains
unclear. It is assumed that an exaggerated mucosal immune response to commensal gut bacteria drives
the inammatory process in genetically susceptible individuals [4]. The role for the intestinal microbiota is supported by the nding that intestinal inammation often occurs in anatomical areas with
high bacterial numbers [5,6]. Furthermore, diversion of the fecal stream proximal to the inamed area
decreased disease activity in CD [7e10]. In addition, a meta-analysis showed better induction of
remission rates in antibiotic versus placebo treated CD patients [11]. After the identication of the rst
CD gene, NOD2, many genetic IBD loci have been identied [12]. Many of these loci are associated with
the innate immunity responsible for the primary defensive system against enteric bacteria, further
underscoring the interaction between the gut microbiota and mucosal inammation.
Given the overwhelming evidence for the involvement of the intestinal microbiota in the pathogenesis of IBD, the strategy of manipulation of the microbial composition has been a topic of research
in recent decades. Indeed, promising results were shown for fecal microbiota transplantation to induce
remission in UC [13]. Similarly, pre- and probiotics that also act on the microbial composition, could be
of benet in IBD. This review aims to give an overview of the rationale and role of pre- and probiotics
in UC.
The intestinal microbiota in inammatory bowel disease
Microbiota in general
The gut microbiota refers to all microorganisms colonizing the gut, not only including bacteria but
also other microbes such as fungi and viruses. Collectively, this complex ecosystem contains 101314
bacteria including more than 35.000 bacterial species with an increasing density and diversity from
stomach to colon [14]. The microbiota develops soon after birth, when the sterile gastrointestinal tract
is colonized by successive waves of microorganisms. The individual gut microbiota is relatively stable
over time and differs between subjects. It is mainly dominated by the bacterial phyla Firmicutes and
Bacteroidetes and contains a core microbiome with shared functionality [15e18]. In general, three
robust clusters (enterotypes) with balanced community compositions can be identied around which
individual gut microbiota congregate. These enterotypes are driven by enrichment of the genera
Bacteroides (enterotype 1), Prevotella (enterotype 2), and Ruminococcus (enterotype 3) [19].
The microbiota contains several critical functions that contribute to the overall health of the host.
These functions include nutrient and mineral absorption, synthesis of vitamins and amino acids,

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

57

production of short-chain fatty acids (SCFA), maintenance of structural integrity of the gut mucosal
barrier, immunomodulation and protection against pathogens [14]. The produced SCFA have antiinammatory properties, are important energy sources for epithelial cells, and may enhance epithelial barrier integrity [20]. To maintain homeostasis, both pathogenic and nonpathogenic organisms
co-habit the enterocyt in a symbiotic relationship. Changes in the microbial composition may result in
dysbiosis with subsequently impaired functionality of the microbiota which can result in disease.
Microbiota in IBD
The intestinal microbiota in IBD patients has a different composition compared to healthy
individuals. Less microbial diversity is found in IBD, especially in regions of active inammation,
although total bacterial numbers are increased [18]. In general, fewer Firmicutes and Bacteroidetes are
found as well as a reduced diversity within these phyla [16]. A decrease in the phylum Firmicutes can
mainly be attributed to a decreased bacterial load in different Clostridium classes, including for example
the species Faecalibacterium prausnitzii. [18,21] By contrast, within the phylum Proteobacteria, an
increased number of Enterobacteriaceae is found. As such, Escherichia coli, one of the species within
Enterobacteriaceae, comprise an increased proportion of the fecal and mucosa-associated microbiota in
CD patients. In these patients, Escherichia coli is more frequently present within granulomas and
adjacent to stulae and ulcers [18,21]. Conicting results are reported regarding differences in microbial compositions between CD and UC patients. Some studies reported similar microbial changes,
whereas others found disease specic alterations [21].
Both Clostridia and Bacteroides produce SCFA such as butyrate that has anti-inammatory capacities
and is also the preferred energy source for colonic epithelial cells. The decreased bacterial load of these
species in UC can result in lower fecal concentrations of butyrate and SCFA. Dysbiosis, and thus
decreased SCFA and butyrate concentrations may result in epithelial nutrient deciency and altered
immune responses. In addition, an increased mucosal permeability can lead to an overwhelming
exposure of bacterial ligands and antigens that activate pathogenic immune responses. Activation of
central signaling cascades involving both the innate and adaptive immune system may induce chronic
intestinal inammation through secretion of chemokines and pro-inammatory cytokines. Especially
IBD patients show an exaggerated immune response due to an increased mucosal inltration of CD4
lymphocytes, defective microbial killing and abnormalities in immunoregulatory pathways [18,21].
Probiotics
Probiotics are dened as live microorganisms that confer a health benet to the host when ingested
in adequate amounts [20]. They function via several potential mechanisms including altering the
microbial composition, enhancement of local immune responses, and improvement of the gut barrier
function [22]. Probiotics can alter the intestinal microbial balance by blocking adhesion sites, by
competition for nutrients and by antimicrobial effects [18,22,23]. They directly act by increasing the
production of butyrate and SCFA, which lowers the colonic pH and inhibits the growth of pathogenic
bacteria. Butyrate also provides nutrients to the epithelium and positively affects the intestinal barrier
function by increasing mucin secretion and enhancement of tight-junctions [18]. Down-regulation of
immunoregulatory pathways, such as the NFkB signaling cascade, makes butyrate act as an antiinammatory agent [23]. Furthermore, probiotics in general can affect the immune system via
several mechanisms including changes in cytokine production, induction of regulatory T cells and
increased microbial killing. They could impact on intestinal cell survival and growth and inhibit cell
apoptosis [24]. All of these different mechanisms may counteract the abnormal mucosal immune
response that leads to chronic inammation in IBD.
Although it unknown whether the altered microbiota in IBD is a cause or consequence of
inammation, several probiotics have been studied in order to manipulate the intestinal microora. The administrated microorganisms need to be genetically stable, of human origin, and able
to survive passage through the gastrointestinal tract [18]. Both single species, such as Lactobacillus
and Bidobacterium species, and multispecies products, such as VSL#3 have been studied. These

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L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

different probiotic strains may achieve therapeutic effects via different strain-specic mechanisms
of action [23].
Probiotics in ulcerative colitis
In recent decades several intervention studies were performed in UC comparing probiotic therapy
with placebo or standard care. Studies can be classied into the following two groups: those that
investigated induction of remission in active UC, and those that investigated maintenance of
remission. Several relatively small studies are available. However, these studies greatly differ in
design, for example in regards to the presence and choice of concomitant therapies in the control
groups. In the available studies, different probiotic strains were compared, in different dosages, with
different primary outcomes. The variety within study designs limits the possibility to uniformly
compare and pool the available data and prevented us from drawing rm conclusions with respect to
probiotic use in UC.

Induction of remission in active ulcerative colitis

An overview of the available studies that investigated induction of remission in UC and evaluated
clinical outcomes is given in Table 1. Case reports, abstracts and studies including less than ten patients
in total were not considered for the purpose of this overview and we focused on studies in humans.
Most studies were performed with E Coli Nissle 1917 or VSL#3 [25].
E. coli Nissle 1917
E. coli Nissle 1917, a non-pathogenic strain of Escherichia coli, prevents and antagonizes colonization
of pathogenic bacteria. It reduces colonic mucosal damage and decreases epithelial permeability,
which may improve colonic healing [26]. Three studies investigated the benecial effect of E. coli Nissle
1917 in active UC [27,28].
The rst randomized controlled study compared E. coli Nissle 1917 (10  1010 bacteria) with oral
mesalamine (3  800 mg/d) in 116 patients receiving standard medical therapy and a 1-week course
of gentamycine [28]. No statistical differences in remission rates and time to remission were found
and the authors therefore concluded non-inferiority of E. coli Nissle 1917 compared to mesalamine. A
control group without mesalamine was not included in this study. Another dose-nding phase II trial
(n 90) administered the same probiotic rectally and compared its effect with placebo [27]. A higher
dose-dependent remission rate was found in the per protocol analysis for E. coli Nissle 1917, although
not conrmed in the intention to treat analysis. The latter could be explained by the high number of
drop outs due to protocol violation or lack of efcacy. In contrast, the third study including 100
patients that compared E. coli Nissle 1917 (5e50  109 colony-forming unit, CFU/d), Ciprooxacin
(2  500 mg/d) and placebo, showed the highest remission rates in the placebo group (p < 0.05,
Table 1) [29].

VSL#3
VSL#3 consists of eight bacterial strains, including Lactobacillus acidophilus, Lactobacillus bulgaricus,
Lactobacillus casei, Lactobacillus plantarum, Streptococcus thermophiles, Bidobacterium breve, Bidobacterium infantus and Bidobacterium longum. It down-regulates the host immune response, improves
epithelial barrier function, and increases mucus production [30,31]. In total eight VSL#3 studies have
been performed in patients with active UC, comprising six studies with adult patients and two pediatric studies [30e37]. Five studies included randomized controlled trials (RCT), whereas three were
performed in uncontrolled settings.
Tursi et al. compared VSL#3 (9  1011 CFU/d) in combination with lower dose balsalazide (5-ASA,
2.25 g/d) to balsalazide (4.5 g/d) or mesalamine (2.4 g/d) alone in 90 adults with mild to moderate UC
[36]. The probiotic combination was found to be superior with signicant higher remission rates and
faster achievement of remission. Furthermore, four RCTs compared VSL#3 (3.6  1012 CFU/d, weight-

Table 1
Overview of probiotic intervention studies in ulcerative colitis aiming the induction of remission.
Control group
(daily dose)

RCT, 1 y (12 wk
to achieve
remission; noninferiority)
RCT, 8 wk

E. Coli Nissle
1917
(10  1010)

Mesalamine
(3  800 mg)

E. Coli Nissle
1917 (108/ml;
40, 20, or 10 ml
enemas)

RCT, 12 wk

Tursi 2004 [36]

Bibiloni 2005
[32]

Study design
and duration

Concomitant
therapy

Inclusion

Remission rates (according to ITT

analysis)

Intervention

Controls

Intervention

Controls

(n)

(n)

(n)

(%)

(n)

(%)

p-value

Steroids and
gentamycin

57

59

39

68.0

44

75.0

0.0508

Placebo

Steroids and/or 5ASA

70

20

29

41.4

35.0

0.4430

A. E. Coli Nissle
1917 (5
e50  109)/
placebo
B. E. Coli Nissle
1917 (5
e50  109)/
Ciprooxacin
(2  500 mg)

C. Placebo/
placebo
D. Placebo/
Ciprooxacin
(2  500 mg)

Topical steroids, 5ASA, AZA and/or 6MP

25
25

25
25

NS
NS

41.0
60.0

NS
NS

80.0
72.0

0.02a

RCT, 8 wk

VSL#3
(9  1011)
balsalazide
(2.25 g)

A. Balsalazide
(4.5 g)
B. Mesalamine
(2.4 g)

None

30

30
30

24

80.0

21
16

70.0
53.3

<0.02

Open label,
uncontrolled,
6 wk

VSL#3
(3.6  1012)

n/a

Stable dose of
steroids, 5-ASA,
AZA, 6-MP, IFX,
and/or
cyclosporine

34

n/a

18

53.0

n/a

n/a

n/a

Other
outcomes
(intervention
versus controls)

Probiotic E. Coli Nissle 1917

Rembacken
1999 [28]

Matthes 2010
[27]

Petersen 2014
[29]

Mean time to
remission 42
d vs 44
d (p 0.0092)
PP: correlation
with dosedependent
efcacy
(p 0.0446)
PP: 54% (A) and
66% (B) vs 89%
(C) and 78% (D);
A vs C p<0.05

Probiotic VSL#3
Mean time to
remission 4 d vs
7.5 d vs 13
d (p<0.01)
PP remission
rates: 24/29
(85.7%) vs 21/
26 (80.8%) vs
16/22 (72.7%)
PP remission
rate: 18/32
(56%)
Response
(decrease in

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Intervention
group
(Probiotic
strain; daily
dose)

Author/Year of
publication

Author/Year of
publication

60

Table 1 (continued )
Study design
and duration

Intervention
group
(Probiotic
strain; daily
dose)

Control group
(daily dose)

Concomitant
therapy

Inclusion

Remission rates (according to ITT

analysis)

Intervention

Controls

Intervention

Controls

(n)

(n)

(n)

(n)

(%)

p-value

(%)

Open label,
uncontrolled,
5 wk

VSL#3
(1.8  1012)

n/a

Stable dose of
steroids, 5-ASA,
AZA and/or 6-MP

15

n/a

NS

NS

n/a

n/a

n/a

Huynh 2009
[30]

Open label,
uncontrolled,
8 wk
(pediatrics)
RCT, 1 y
(pediatrics)

VSL#3 (agebased, 4.5

e22.5  1011)

n/a

Stable dose of
steroids, 5-ASA,
AZA and/or 6-MP

18

n/a

10

56.0

n/a

n/a

n/a

VSL#3 (weightbased, 0.45

e1.8  1012)
VSL#3
(3.6  1012)

Placebo

Steroids and/or 5ASA

14

15

13

92.8

36.4

<0.001

Placebo

5-ASA, AZA and/or

6-MP

77

70

33

42.9

11

15.7

<0.001

Sood 2009 [31]

RCT, 12 wk

Ng 2010 [34]

RCT, 8 wk

VSL#3
(3.6  1012)

Placebo

Stable dose of 5ASA, AZA and/or 6MP

14

14

50.0

36.0

0.445

Tursi 2010 [37]

RCT, 8 wk

VSL#3
(3.6  1012)

Placebo

Stable dose of 5ASA, AZA and/or 6MP

71

73

31

47.7

23

32.4

0.132

UCDAI 3): 8
(24%)
UCDAI decrease
from 5.3 1.89
to 0.7 0.34
(p 0.02)
Combined
remission/
response rate
(11/18, 61%)

Response rate
(>50% UCDAI
decrease): 25/
77 (32.5%) vs 7/
70 (10%),
p 0.001
Response rate
(three points
UCDAI
decrease): 10/
14 (71.4) vs 5/
14 (35.7),
p 0.064
PP remission
rates: p 0.069
Response rate
(>50% UCDAI
decrease): 41/
71 (63.1%) vs
29/73 (40.8%),
PP p 0.010,
ITT p 0.031

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Soo 2008 [35]

Miele 2009 [33]

Other
outcomes
(intervention
versus controls)

Other probiotics
Open label,
uncontrolled,
4 wk

Saccharomyces
boulardii
(750 mg)

n/a

5-ASA

25

n/a

NS

NS

n/a

n/a

n/a

Kato 2004 [42]

RCT, 12 wk

Placebo

5-ASA

10

10

40.0

30.0

NS

Furrie 2005
[41]

RCT, 4 wk

Bidofermented milk
(1  1010;
Bidobacterium
breve,
Bidobacterium
bidum,
Lactobacillus
acidophilus)
Bidobacterium
longum
(2  1011)
inulinoligofructose
(6 g)

Placebo

Steroids, 5-ASA
and/or
immusuppressants

Tsuda 2007
[60]

Open label,
uncontrolled,
4 wk

n/a

5-ASA and/or 6-MP

20

n/a

45.0

n/a

n/a

n/a

Takeda 2009
[61]

Open label,
uncontrolled,
24 wk

BIO-THREE
(Streptococcus
faecalis 18 mg,
Clostridium
butyricum
90 mg, Bacillus
mesentericus
90 mg)
Bidobacterium
longum BB536
(2e3  1011)

n/a

None

14

n/a

10

67.0

n/a

n/a

n/a

2011
D'Inca
[62]

RCT, 8 wk

Lactobacillus
casei (1.6  109
oral or

5-ASA (2.4 g)

None

19

NS

NS

n/a

n/a

n/a

Response rate
(CAI<5): 17/25
(68%)
Signicant
reduction
clinical activity
PP remission
rates: 4/10
(40%) vs 3/9
(33%)
Decreased
clinical activity
in both groups
(p < 0.001 vs
p < 0.05)
5/9 vs 3/9
reduced CAI
Endoscopic
difference
between preand postintervention
not
signicantly
different
(p 0.06)
40% no
response, 5%
worsened

Signicant
decrease mean
CAI at week 8,
12 and 24
(p < 0.05)
No improved
clinical activity
scores in both

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Guslandi 2003
[59]

Author/Year of
publication

62

Table 1 (continued )
Study design
and duration

Intervention
group
(Probiotic
strain; daily
dose)

Control group
(daily dose)

Concomitant
therapy

Inclusion

Remission rates (according to ITT

analysis)

Intervention

Controls

Intervention

Controls

(n)

(n)

(n)

(n)

(%)

p-value

Other
outcomes
(intervention
versus controls)

(%)

Oliva 2011 [63]

RCT, 8 wk
(pediatrics)

Lactobacillus
reuteri ATCC
55370 (1  1011
enema)

Placebo

5-ASA

20

20

31.0

0.0

<0.05b

Li 2012 [40]

8 wk

Bid Triple
Viable (Bacillus
acidopilus,
Bidobacterium
bidum, Fecal
streptococci)
Etiasa (1 g/2 d)

Etiasa (1 g/2d)

None

41

41

NS

NS

NS

NS

NS

the oral
(p 0.114) and
rectal
(p 0.108)
probiotic
groups
Decreased
Mayo scores in
the probiotic
group (p<0.01
vs P<0.05)
Lower Mayo
Clinical Score
after treatment
in the probiotic
group (2.46 vs
3.96; p 0.008)

ITT, intention to treat analysis; PP, per protocol analysis; 5-ASA, 5-aminosalicylic acid; AZA, azathiopurine; 6-MP, 6-mercaptopurine; d, day; wk, week; mo, month; y, year; NS, not stated;
UCDAI, ulcerative colitis disease activity index; CAI, clinical activity index.
a
Comparing patients with E. Coli Nissle 1917 (5e50  109) versus without E. Coli Nissle 1917 (5e50  109).
b
Analyzed according to PP analysis.

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

rectal) 5-ASA
(rectal)

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63

based in pediatrics) versus placebo (Table 1) [31,33,34,37]. Conicting results were found regarding
induction of remission, including two studies (n 147 and n 29) that reported signicantly higher
remission rates in the probiotic group, and two (n 144 and n 28) that found no statistical difference in remission. However, achievement of remission was a secondary outcome in all studies and
power calculations were not based on this outcome measure. For example, both large RCT (n 147
and n 144) had a primary endpoint of decrease in Ulcerative Colitis Disease Activity Index (UCDAI)
by 50% (response) and remission was one of the secondary outcomes dened as an UCDAI score 2
[31,37]. Both RCT showed a signicantly better response rate in the probiotic group, however only one
(n 147) also found a better remission rate in patients treated with VSL#3.
A previous meta-analysis, including RCTs comparing VSL#3 versus controls (placebo or 5-ASA;
n > 30) showed a risk ratio (RR) of 1.69 (95% condence interval; 95% CI 1.17e2.43) indicating
signicant benet of VSL#3 compared to controls for inducing remission [18]. A similar trend was seen
when only RCTs were included that compared VSL#3 versus placebo, although no statistical signicance was reached (RR 1.88, 95% CI 0.96e3.67). Another meta-analysis comparing VSL#3 versus
placebo demonstrated odds ratios of 2.79 and 3.03 to achieve respectively a 50% decrease or 3-point
reduction in UCDAI, favoring VSL#3 [38].
Other probiotics
Several other relatively small studies with different probiotic strains have been performed as
shown in Table 1. Probiotic strains and combinations included Saccharomyces boulardii, Bidobacterium longum, Lactobacillus casei, Lactobacillus reuteri, Bido-fermented milk (Bidobacterium
breve, Bidobacterium bidum, Lactobacillus acidophilus), BIO-THREE (Streptococcus faecalis, Clostridium butyricum, Bacillus mesentericus), Bid Triple Viable (Bacillus acidopilus, Bidobacterium
bidum, Fecal streptococci). Many studies were performed in an uncontrolled setting and most did
not report and/or compared remission rates. In summary, six of these studies reported a signicant
(larger) reduction in clinical activity index, whereas only one found no benecial effect of the
probiotic strain Lactobacillus casei. In addition, some reported lower endoscopic and histological
colonic inammation [39,40].
Overall
A previous meta-analysis analyzed the overall effect of probiotics versus controls for active UC.
Three RCTs were identied including active UC patients who were treated with different probiotics
(VSL#3 (9  1011 CFU/d), Bido-fermented milk (1  1010 CFU/d) or Bidobacterium longum
(2  1011 CFU/d)) [36,41e43]. The pooled relative risk for UC induction of remission was 2.27 (95% CI
1.00e5.14) indicating benet of probiotic use in general [23,43].
Maintenance of remission in ulcerative colitis
Fewer studies investigated probiotic use for maintenance of remission in UC. An overview of these
studies that investigated clinical outcomes is displayed in Table 2, excluding those with less than ten
patients [44]. In most studies, relapse rates and time to relapse were investigated in patients with
inactive UC during a 1-year period of follow-up.
E.coli Nissle 1917
Three studies (n 103, n 116 and n 327) compared E. coli Nissle 1917 (5  1010 CFU/d) versus
mesalamine (3  500 mg/d or 3  400 mg/d) in a non-inferiority RCT study design [28,45,46]. Primary
end point in these studies was the relapse rate, based on an increase of at least three points in Colitis
Activity Index (CAI) according to Rachmilewitz. One evaluated the primary objective after 12 weeks,
whereas the other two investigated relapse rates after one year. None of these studies found signicant
differences in relapse rates between cases and controls with oral 5-ASA, and all authors concluded that
treatment with E. coli Nissle 1917 was equally effective as mesalamine in maintaining remission. In
addition, no differences in adverse effects were observed between treatment groups. A previous meta-

Author/Year of
publication

Study design
and duration

Intervention
group
(Probiotic
strain; daily
dose)

Control group
(daily dose)

Concomitant
therapy

64

Table 2
Overview of probiotic intervention studies in ulcerative colitis aiming maintenance of remission.
Inclusion

Relapse rates
(according to ITT analysis)

Intervention

Controls

Intervention

Controls

(n)

(n)

(n)

(%)

(n)

(%)

p-value

Other
outcomes
(intervention
versus controls)

Kruis 1997 [46]

RCT, 12 wk
(noninferiority)

E. Coli Nissle
1917 (5  1010)

Mesalamine
(3  500 mg)

None

50

53

16.0

11.3

>0.05

Rembacken
1999 [28]

RCT, 1 y (noninferiority)

E. Coli Nissle
1917 (5  1010)

Mesalamine
(3  400 mg)

Steroids and
gentamycin

57

59

26

67.0

32

73.0

>0.05

Kruis 2004 [45]

RCT, 1 y (noninferiority)

E. Coli Nissle
1917 (5  1010)

Mesalamine
(3  500 mg)

None

162

165

73

45.1

61

37.0

>0.05

Open label,
uncontrolled, 1
y
RCT, 1 y
(pediatrics)

VSL#3
(3  1012)

n/a

None

20

n/a

20.0

n/a

n/a

n/a

VSL#3 (weightbased, 0.45

e1.8  1012)

Placebo

Steroids and/or
5-ASA

14

15

21.4

11

73.3

0.014

RCT, 1 y

Bidofermented milk
(1  1010;
Bidobacterium
breve,
Bidobacterium
bidum,

No treatment

5-ASA

11

10

27.0

90.0

0.0174

Mean relapsefree time 106

d vs 103
d (p > 0.05)
PP: 6/32
(18.8%) vs 5/38
(13.2%),
p > 0.05)
Mean relapsefree time 221
d vs 206
d (p 0.0174)
PP: 40/110
(36.4%) vs 38/
112 (33.9%),
p > 0.05

Probiotic VSL#3
Venturi 1999
[48]
Miele 2009 [33]

Other probiotics
Ishikawa 2003
[64]

Relapse after 3,
5 (n 2), and 7
mo

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Probiotic E. Coli Nissle 1917

RCT, 8 wk

Zocco 2004
[49]

Open label,
randomized
trial, 1 y

Wildt 2011
[66]

RCT, 1 y

Lactobacillus
acidophilus (La5)
Bidobacterium
animalis lactis
(BB-12)
(1.5  1011)

Placebo
Mesalamine
(2.4 g)

Placebo

Steroids and/or
5-ASA
None

None

15

15

20.0

14

93.3

<0.01

65
62

60

10
10

15.0
16.0

12

20.0

0.77

20

12

15

75.0

11

92.0

0.37

Relapse rates
after 6 mo not
signicantly
different
(p 0.44)
Increased
remission-free
time in
probiotic
groups
(P < 0.05)
Median time to
relapse: 125.5
d vs 104
d (p 0.683)

ITT, intention to treat analysis; PP, per protocol analysis; 5-ASA, 5-aminosalicylic acid; AZA, azathiopurine; 6-MP, 6-mercaptopurine; d, day; wk, week; mo, month; y, year; NS, not stated.

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Cui 2004 [65]

Lactobacillus
acidophilus)
Bid triple
viable (1.26 g)
A. Lactobacillus
CG (1.8  1010)
B. Lactobacillus
CG (1.8  1010)
Mesalamine
(2.4 g)

65

66

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

analysis that pooled these three studies showed a RR of 1.08 (95% CI 0.86e1.37), which indicated that E.
coli Nissle 1917 was not statistically signicantly inferior to oral mesalamine [18]. However, placebocontrolled trials with E. coli Nissle 1917 are lacking, leaving the question whether or not low-dose
5-ASA or E. coli Nissle 1917 provide benet in this group with stable mild-to-moderate UC [47].
VSL#3
VSL#3 was investigated in a small RCT in a pediatric population including 29 children with newly
diagnosed UC [33]. Fourteen received weight-based VSL#3 and after 1 year three patients (27.0%)
relapsed (>3 points increase in Lichtiger CAI). This relapse rate was signicantly lower compared to the
placebo group (11/15, 73.3%; p 0.014). Furthermore, a small uncontrolled open label study with
VSL#3 was performed including 20 patients with inactive UC who were intolerant for 5-ASA [48]. Four
patients relapsed, however the small uncontrolled setting did not allow meaningful conclusions from
this trial.
Other probiotics
Alternative probiotic therapies for maintenance of UC remission were investigated, including the
following (combinations of) strains: Bido-fermented milk (Bidobacterium breve, Bidobacterium bidum, Lactobacillus acidophilus), Bid triple viable, Lactobacillus CG, and Lactobacillus acidophilus in
combination with Bidobacterium animalis lactis (Table 2). Zocco et al. performed the largest RCT with
Lactobacillus CG (1.8  1010 CFU/d), and included 187 patients [49]. Similar relapse rates and clinical,
endoscopic and histological scores were found between the probiotic and mesalamine (2.4 g/d) group.
However, relapse-free survival was signicantly prolonged in the probiotic intervention group. Another
trial (n 41) investigated endoscopic improvement of Bidobacterium breve (3  109 CFU/d) in combination with galacto-oligosaccharide (5.5 g/d). A signicant better improvement of the endoscopic score
was found after 1 year in those who received this probiotic versus those without additional treatment [50].
Overall
A Cochrane review evaluating overall probiotics for maintenance of remission in UC performed a
pooled analysis to compare relapse rates [51]. Three studies comparing different probiotic strains (E.
coli Nissle 1917 (5  1010 CFU/d) and Lactobacillus CG (1.8  1010 CFU/d)) versus mesalamine
(3  500 mg/d or 2.4 g/d) were included. This resulted in an odds ratio of 1.33 (95% CI 0.94e1.91),
suggesting similar efcacy [45,46,49,51]. However, the lack of placebo-controlled studies impeded
pooled analysis to determine efcacy of probiotics versus placebo for maintenance of remission.

Prebiotics
Prebiotics are non-digestible carbohydrates acting as a nutritive substrate to stimulate the growth
and metabolism of certain bacteria [20]. Whereas probiotics introduce exogenous bacteria in the
colonic microbiota, prebiotics aim to modulate the endogenous luminal microora by selectively
stimulating the growth of health-promoting bacteria already present in the colon. For example,
different non-digestible carbohydrates, such as galacto-oligosaccharides, showed the potential to
increase the number of Bidobacteria and subsequently the production of SCFAs in healthy volunteers
[52]. In theory, the net result of prebiotic administration may be similar to that of probiotic administration. However, the effect of prebiotics can be present for several weeks after administration, while
the effect of probiotics is generally shorter [53].
Limited consensus exists on which compounds constitute prebiotics and which do not [54]. One
of the key qualiers for a prebiotic is that it should selectively change the gut microbiota. In
contrast, dietary bers are often considered prebiotics, although some of them do not induce
selective changes in the microbial composition. It is unclear how selective the prebiotic effect
should be. Several oligosaccharides are therefore generally accepted as prebiotics (like inulin,
fructo-oligosaccharides, galacto-oligosaccharides and lactulose), whereas many others are
considered candidate prebiotics.

Table 3
Overview of prebiotic intervention studies.
Author/Year of
publication

Study design
and duration

Intervention
group (Prebiotic;
daily dose)

Control group
(daily dose)

Concomitant
therapy

Inclusion

Remission/relapse rates (according to ITT

analysis)

Intervention

Controls

Intervention

Controls

(n)

(n)

(n)

(%)

(n)

(%)

p-value

Other outcomes
(intervention
versus controls)

Kanauchi 2003
[67]

Open label RCT,

24 wk

Germinated barley
foodstuff
(20e30 g)

No treatment

Steroids and/or
5-ASA

21

NA

NS

NS

NS

NS

NS

Casellas
2007 [56]

RCT, 2 wk

Oligofructoseenriched inulin
(12 g)

Placebo

Mesalamine
(3 g/d)

10

10

100

77.8

NS

Hafer 2007 [68]

RCT, 4 mo

Lactulose (10 g)

No treatment

5-ASA,
immunosuppressive
drugs and/or
antibiotics

57.1

0.0

0.092

Signicant greater
decrease CAI in
prebiotic group
(p < 0.05)
Both groups
showed a
signicant
reduction in CAI
(p < 0.05),
although not
different between
groups
Signicant
improvement CAI
(from
10.3 2.2 to
4.7 1.8,
p 0.047)

Prebiotics for maintenance of remission

Hallert 1991 [69]

RCT (cross over),

4 mo

Plantago ovate
(14 g)

Placebo

Regular medication

29

29 (cross
over)

NS

NS

NS

NS

MS

ndezFerna
~ ares 1999
Ban

Open label
RCT, 1 y

A. Plantago ovata
seeds (20 g)
B. Plantago ovata
seeds (20 g)
Mesalamine
(3  500 mg)
Germinated barley
foodstuff (20
e30 g)

Mesalamine
(3  500 mg)

None

35
30

37

14
9

40.0
30.0

13

35.1

0.67

No treatment

Conventional
treatment

22

37

NS

NS

NS

NS

NS

[55]

Hanai 2004 [70]

RCT, 1 y

67

ITT, intention to treat analysis; 5-ASA, 5-aminosalicylic acid; d, day; wk, week; mo, month; y, year; NS, not stated; NA, not available.

Signicantly
higher rate of
improvement
(69% vs 24%,
p < 0.001)
Greater reduction
on CAI (1.90 vs
0.99, p < 0.05)
Cox regression
showed adjusted
for confounders no
differences in
remission-free
survival (p 0.41)
Signicantly
better CAI after
treatment
in the intervention
group

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Prebiotics for induction of remission

68

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

Prebiotics in ulcerative colitis

Evidence for prebiotic use in UC is less extensive than that for probiotics. An overview of the
available studies is given in Table 3, including three induction studies and three maintenance studies.
Different prebiotics were investigated in small study populations. The largest RCT (n 102) compared
Plantago ovata seeds (also known as Psyllium; 14 g/d) versus mesalamine (3  500 mg/d) in UC
patients in remission [55]. They found a similar ability of sustained remission (p 0.67), dened as
the absence of both clinical and endoscopic signs of active disease. Subsequently, they concluded that
both agents might be equally effective, although no non-inferiority study design was adopted. Furrie
et al. investigated a synbiotic, the combination of a prebiotic and probiotic [41]. During this pilot
study using synbiotics, nine patients received Bidobacterium longum (2  1011 CFU/d) in combination
with inulin-oligofructose (6 g/d) and nine patients received placebo during 1 month. There was a
trend for reduced endoscopic disease activity with synbiotics and a signicant reduction of mucosal
inammatory cytokines. However, reduction in clinical disease activity was not signicant between
both groups. In another small RCT (n 19) with inulin-oligofructose and concomitant oral 5-ASA in
mildly active UC, Casellas et al. reported a signicant reduction in the objective inammatory stool
marker fecal calprotectin, although a reduction of disease activity could not be found, possibly due to
a limited study duration of 2 weeks [56]. Another study (n 94) compared the prebiotic Psyllium (4 g/
d) versus the probiotic Bidobacterium longum (2  1011 CFU/d) versus the combination (synbiotic)
[57]. A larger increase in quality-of-life (primary end point) was seen in the synbiotic group,
suggesting a synergistic effect of both therapies. In summary, large well-powered RCT using prebiotics or synbiotics in UC are still lacking. Therefore, the evidence for benet from prebiotics on
disease activity in UC is limited at this time.

Summary and discussion

Probiotics and possibly prebiotics could be of benet for the induction and maintenance of
remission in UC since involvement of the microbiota in the pathogenesis of IBD is evident. By several
mechanisms of action that interfere with pathogenic factors of IBD, manipulation of this ecosystem
may reduce mucosal inammation. The relatively low costs and excellent safety prole of probiotics
and prebiotics make these therapies attractive for implementation into current treatment regimens
[18,28,37]. However, the evidence for efcacy of probiotics to induce and maintain remission in UC is
limited to specic probiotics such as VSL#3 and E. coli Nissle 1917 at their published doses. The evidence for prebiotics is still insufcient to recommend its use for UC in daily clinical practice, although
some promising studies are underway.
Most probiotic studies in UC are performed with VSL#3 or with E. Coli Nissle 1917. Both probiotic
strains received grade A recommendations (strong positive studies) for maintenance of UC remission
and grade B recommendations (positive controlled studies with the presence of some negative studies)
for induction of UC remission, according to the third Yale Workshop on probiotics in 2015 [58]. A
pooled analysis showed a trend towards signicant benet of VSL#3 versus placebo for remission
induction (RR 1.88, 95% CI 0.96e3.67) whereas non-inferiority was shown for E. coli Nissle 1917
compared to mesalamine (RR 1.08 95% CI 0.86e1.37) to maintain remission [18]. Although these data
look promising, studies are very heterogeneous with different clinical outcome measures, absent or
different control groups (placebo or 5-ASA), different inclusion criteria (different UC extend and
severity), and a high number of drop-outs. This makes it difcult to compare results and draw rm
conclusions on probiotic use and hampers widespread use. Evidence for efcacy of prebiotics in UC is
insufcient, discouraging its use in daily clinical practice.
In the future, probiotics and prebiotics could become major key players in tailored dietary IBD
therapies. However, more robust, well-powered RCTs are needed that investigate different (novel)
probiotic strains and their administration route and dose. Increasing insights in the microora of IBD
patients may aid in tailored probiotic strain selection. In extension, other treatment strategies that
could manipulate the colonic microora, such as fecal transplantation, and anti-inammatory diets
may also benet IBD treatment and deserve further research.

L.A.A.P. Derikx et al. / Best Practice & Research Clinical Gastroenterology 30 (2016) 55e71

69

Practice points
- Overwhelming evidence supports the involvement of the intestinal microbiota in the pathogenesis of IBD.
- Probiotics (live microorganisms that confer a health benefit to the host) and prebiotics
(nutritive substrates to stimulate the growth and metabolism of specific endogenous intestinal bacteria) affect the intestinal microbiota and can be of benefit in IBD.
- Current probiotic studies in IBD are very heterogeneous including different probiotic strains
and different outcome measures, which makes it very difficult to compare results and draw
firm conclusions on probiotic use.
- VSL#3 may be considered for remission induction of mild-to-moderate UC, as an adjunctive
to current standard therapies such as oral mesalamine.
- E. Coli Nissle 1917 may be considered for maintenance of UC remission as non-inferiority was
shown compared to oral mesalamine.
- Evidence for efficacy of prebiotics in UC is still insufficient, and use of it therefore not yet
accepted in clinical practice.

Research agenda
- More well-powered, placebo-controlled RCTs are needed that investigate specific probiotic
strains including their administration route and dose.
- Specific subgroups of patients within UC need to be identified that could specifically benefit
from probiotic therapy. The profile of endogenous microbiota already present should be
taken into account with cutting-edge technologies.
- Prebiotics in UC should be further investigated as adjunctive to current therapies in large,
placebo-controlled RCTs.
- Other treatment modalities that could manipulate the intestinal microflora, such as fecal
transplantation and dietary therapy, may also benefit the treatment of IBD and deserve further
research.

Funding source
This work was not supported by any company or grants.
Conicts of interest statement
None.
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