The Probiotic Preparation, VSL#3 Induces Remission in Patients

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:1202–1209
The Probiotic Preparation, VSL#3 Induces Remission in Patients With
Mild-to-Moderately Active Ulcerative Colitis
AJIT SOOD,* VANDANA MIDHA,* GOVIND K. MAKHARIA,‡ VINEET AHUJA,‡ DINESH SINGAL,§ POOJA GOSWAMI,‡ and
RAKESH K. TANDON§
*Department of Gastroenterology and Medicine, Dayanand Medical College and Hospital, Ludhiana, India; ‡Department of Gastroenterology and Human Nutrition, All
India Institute of Medical Sciences, New Delhi, India; and §Pushpawati Singhania Research Institute, Sheikh Sarai-I, New Delhi, India
BACKGROUND & AIMS: Probiotics can maintain ulcerative colitis (UC) in remission effectively, but little is known of
their ability to induce remission. We conducted a multicenter,
randomized, double-blind, placebo-controlled trial of a highpotency probiotic, VSL#3, for the treatment of mild-to-moderately active UC. METHODS: Adult patients with mild-tomoderate UC were assigned randomly to groups that were given
3.6 ⫻ 1012 CFU VSL#3 (n ⫽ 77) or placebo (n ⫽ 70), twice daily
for 12 weeks. The primary end point was a 50% decrease in the
Ulcerative Colitis Disease Activity Index (UCDAI) at 6 weeks. The
secondary end points included remission by 12 weeks and
reduction in total individual UCDAI parameters from baseline
at 12 weeks. Intention-to-treat analysis was performed. RESULTS: At week 6, the percentage of patients with an improvement in UCDAI score that was greater than 50% was significantly higher in the group given VSL#3 (25; 32.5%) than the
group given placebo (7; 10%) (P ⫽ .001). At week 12, there were
33 patients given VSL#3 (42.9%) who achieved remission, compared with 11 patients given placebo (15.7%) (P ⬍ .001). Furthermore, significantly more patients given VSL#3 (40; 51.9%)
achieved a decrease in their UCDAI that was greater than 3
points, compared with those given placebo (13; 18.6%) (P ⬍
.001). The VSL#3 group had significantly greater decreases in
UCDAI scores and individual symptoms at weeks 6 and 12,
compared with the placebo group. CONCLUSIONS: VSL#3
is safe and effective in achieving clinical responses and
remissions in patients with mild-to-moderately active UC.
T
he exact pathogenesis of ulcerative colitis (UC) is not
known. However, an interaction between genetic susceptibility, environmental factors, and immune dysregulation is
implicated in the causation of UC. Intestinal microflora have
been implicated both in the initiation and maintenance of the
inflammatory process in patients with UC.1– 4 Swidsinski et al5
showed that patients with IBD have a greater number of mucosa-associated bacteria, particularly Bacteroides species and
Escherichia coli. In general, larger numbers of Bacteroides species
and Enterobacteriaceae and lower numbers of presumably beneficial bacteria, such as Bifidobacteria and Lactobacilli, have been
reported in patients with UC.3,6 The mainstay of treatment of
UC centers around suppression or modulation of the host’s
immune response and limited attention has been given to the
pathogenic contribution of the intestinal microenvironment.
Current medical management consists of aminosalicylates,
steroids, and immunosuppressants and biologics. A significant
proportion of patients do not tolerate existing treatments because of their adverse effects and about 20% to 30% of patients
fail to respond to the drugs given for induction of remission.7
Consequently, new alternatives for the treatment of UC constantly are being sought.3,6 –9
Probiotics are defined as living microorganisms that, when
consumed in adequate amounts, confer a health benefit to the
host.10 There are many probiotic preparations; the efficacy of
the preparation depends on the bacterial or fungal strains it
contains. Unlike most probiotic products that are composed of
either single microbes or a combination of a few microbes,
VSL#3 is a high-concentration probiotic preparation of 8 live,
freeze-dried bacterial strains, including 4 strains of Lactobacilli (L
paracasei, L plantarum, L acidophilus, and L delbrueckii subspecies
bulgaricus), 3 strains of Bifidobacteria (B longum, B breve, and B
infantis), and Streptococcus thermophilus.11
Probiotics have been used for induction of remission, maintenance of remission of UC, and maintenance of remission of
pouchitis.12–26 Probiotic preparations such as E coli Nissle 1917
and bifidobacterium-fermented milk have been found to be
effective in maintenance of remission of UC.12 In 2 randomized
controlled trials, VSL#3 has been shown to be highly effective in
maintenance of remission of pouchitis.13,14 In a number of
open-label and randomized studies, E coli Nissle 1917, bifidobacterium-fermented milk, and VSL#3 also have shown
efficacy in induction of remission of UC.18 –22 However,
Cochrane review of the 4 available studies did not find a
significant effect of probiotics in the induction of remission of
UC.23 In 2 small recent studies, VSL#3 has been reported to
achieve remission/response in children with mild to moderate
UC.24,25 Although there is growing data on the efficacy of
VSL#3, there is a lack of a large randomized, placebo-controlled
trial in the management of mild-to-moderately active UC.
Hence, the objective of this study was to study the efficacy and
safety of VSL#3 in mild-to-moderately active UC in achieving
clinical response at week 6 and clinical remission at week 12.
Patients and Methods
Design
This was a multicenter, double-blind, placebo-controlled,
randomized trial. The study was conducted at 3 tertiary care
centers in North India between June 2005 and August 2007.
Abbreviations used in this paper: IL, interleukin; UC, ulcerative colitis; UCDAI, Ulcerative Colitis Disease Activity Index.
© 2009 by the AGA Institute
1542-3565/09/$36.00
doi:10.1016/j.cgh.2009.07.016
November 2009
Participants
Adult patients (⬎18 y) who had mild-to-moderately
active UC (Ulcerative Colitis Disease Activity Index [UCDAI]
score, 3–9; with minimum sigmoidoscopic score of 2) extending
for more than 15 cm from the anal verge with at least one
previously documented attack of active disease were included in
this study. None of the participants had enteric infection.
Patients were excluded if they had disease limited to the rectum,
evidence of severe disease (UCDAI, ⬎10), concurrent enteric
infection, use of oral steroids within the past 4 weeks, use of
antibiotics within the past 2 weeks, change in dose of oral
mesalamine within the past 4 weeks, and use of rectal mesalamine or steroids within 7 days before entry into the study.
Patients requiring hospitalization and imminent need for surgery, lactating and pregnant women, and those who received
any investigational medicines within 3 months were excluded.
Patients with significant hepatic, renal, endocrine, respiratory,
neurologic, or cardiovascular diseases also were excluded.
Randomization
Sequence generation. The random numbers were
generated by computerized random number. The randomization list and numbered packing of the intervention was prepared by a person not involved in the study. Randomization
was performed using permuted blocks of 10. There was a
separate randomization list for each study center. Patients were
randomized separately at all 3 study centers.
Randomization-allocation concealment. All the
randomization numbers were concealed in separate envelopes
and marked by patient number on the outer envelope.
Randomization implementation. The randomization was performed by staff not involved with the study. The
intervention was provided at each center. Patients were assigned
the next serial number (corresponding to the randomization
code) of the intervention.
Blinding
The individual sealed envelope method was used to
maintain blinding of the investigators and study participants.
Activity of Ulcerative Colitis
The activity of UC was assessed using the UCDAI. The
UCDAI was calculated by the investigator by adding the individual scores of the 4 parameters: bowel frequency, rectal bleeding, endoscopic score, and physician’s rating of severity26 (Table
1). Rectal bleeding and stool frequency score was assessed by
asking the patient about his/her symptoms over the past 3 days.
The score for these parameters was calculated individually by
taking the average of the scores for the last available 3 days
before the study visit.
Interventions
Eligible patients were assigned randomly, by a block
randomization strategy, in a 1:1 ratio, to receive either VSL#3 or
placebo twice daily for 12 weeks. VSL#3, a probiotic preparation
containing 900 billion viable lyophilized bacteria, was provided
in plastic sealed individual dose sachets. Each VSL#3 sachet
contained 900 billion viable lyophilized bacteria, comprising 4
strains of Lactobacillus (L paracasei, L plantarum, L acidophilus, and
L delbrueckii subspecies bulgaricus), 3 strains of Bifidobacteria (B
VSL#3 INDUCES REMISSION IN UC
1203
Table 1. Ulcerative Colitis Disease Activity Index
Score
Stool frequency
Normal
1–2 stools/d ⬎ normal
3–4 stools/d ⬎ normal
⬎4 stools/d ⬎ normal
Rectal bleeding
None
Streaks of blood
Obvious blood
Mostly blood
Mucosal appearance
Normal
Mild friability
Moderate friability
Exudation, spontaneous bleeding
Physician’s rating of disease activity
Normal
Mild
Moderate
Severe
0
1
2
3
0
1
2
3
0
1
2
3
0
1
2
3
longum, B breve, and B infantis), and 1 strain of Streptococcus
thermophilus. Four sachets of VSL#3 were given daily equating to
a dose of 3600 billion viable lyophilized bacteria. The study
drugs were supplied by VSL Pharmaceuticals, Inc (Gaithersburg, MD). However, they were imported in India by CD
Pharma India Pvt Ltd (Sister company of VSL Pharmaceuticals,
Inc) and distributed to trial sites. Placebo was supplied in
identical sachets containing maize powder. Patients were asked
to take the contents of the sachets morning and evening by
mixing the contents of the sachet in a glass of cold water or
yogurt.
Assessment
At entry to the study (screening visit), each patient’s
demographic characteristics, medical history, and current medications were recorded. At this point, baseline clinical laboratory
tests were conducted. All the laboratory tests were performed at
the local laboratories. Individual disease activity was assessed at
the baseline visit and after 6, 9, and 12 weeks. At each visit, a
detailed physical examination and history was performed. All
the patients underwent sigmoidoscopic examination at the
baseline and then at weeks 6 and 12.
All adverse events were documented, classified, and graded.
Daily disease activity records were written up by the study
participants, who were provided with diary cards to assess and
record their symptoms (stool frequency, bleeding, and abdominal pain) on a daily basis. Participants’ compliance in taking
the study medications (VSL#3 and placebo) was assessed by the
investigators, who counted the used and the unused sachets
that the patients were required to bring with them on postscreening visits (weeks 6, 9, and 12).
If the condition of the patients deteriorated clinically, they
were withdrawn from the study and put on standard medical
treatment. In these cases, assessment of disease activity (including sigmoidoscopy), adverse events, and compliance (sachet
count) were performed. All the patients were given a symptom
diary card. The diary cards were reviewed and symptoms were
1204
SOOD ET AL
assessed on a scale of 0 to 3. The individual scores for the last
available 3 days before the visit were recorded.
Concomitant Medicines
Patients currently taking maintenance oral mesalamine
therapy (stable for 4 weeks before study entry) were continued
on the drug at a stable dose. Patients were off rectal medications at least 7 days before inclusion in the study. Rectally
administered mesalamine or steroids, systemic corticosteroids,
antibiotics, nonsteroidal anti-inflammatory drugs, and antidiarrheal drugs were not allowed during the course of the study.
Patients taking azathioprine or 6-mercaptopurine were maintained on a stable dose for at least 3 months before entry and
throughout the study. All concomitant medications taken during the study period were recorded in the case record form.
Outcome Measures
Primary outcome measure. The primary outcome
measure was improvement in activity of UC. This was defined
as a decrease in the UCDAI by 50% or more from baseline to
week 6.
Secondary outcome measures. Secondary outcome
measures were as follows. First, the proportion of patients
achieving remission (defined by UCDAI score of 0 –2) at week 12
of treatment (clinical and endoscopic remissions were defined
as a score of 0 in the rectal bleeding and stool frequency parts
of the UCDAI together with a score of 0 or 1 in the sigmoidoscopy activity subscore of the UCDAI). Second, improvement
in activity of UC. This was defined as a decrease in the UCDAI
of 3 or more points from baseline to week 12. Third, change in
subjective symptoms (rectal bleeding and stool frequency) score
from baseline to weeks 6 and 12 of treatment. Fourth, mucosal
healing (mucosal appearance score 0) at week 12. Fifth, treatment failure. Lack of improvement at the end of 6 weeks was
considered a treatment failure (failure to decrease UCDAI score
by 3 points or at least 50% of baseline UCDAI score at week 6).
Ethics Committee Approval and Patient
Consent
The protocol was approved by the investigational review board of all 3 respective centers. Written informed consent
was obtained from all the participants. Patients were allowed to
withdraw at any time point during the study, either because of
lack of efficacy or for any other reasons.
Safety Assessments
A safety assessment was performed on the following
protocol: eliciting of a detailed medical history; conduct of a
detailed physical examination at each visit, including vital signs;
and documentation of any adverse events that occurred during
the study period.
Sample Size
The sample size was based on a power of 80% and a
statistical significance (alpha) of 95% (P ⫽ .05). This assumed
that a response to treatment at 12 weeks, such as with oral
mesalamine preparations, was expected to occur in 65% of
patients treated with VSL#3 compared with 40% treated with
placebo (ie, an expected difference of 25%). This assumed that
the probiotic is as effective as oral mesalamine. Hence, 70
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 11
patients were required in each group with an additional 10% for
drop-outs, therefore we planned to have a total of 154 patients
included in the trial.
Statistical Analysis
Data were presented in terms of minimum/maximum,
mean/median, standard deviation/standard error of mean in
place for quantitative variables, and proportion/counts and
percentage in case of categoric variables. Comparisons between
VSL#3 and placebo group for various parameters were performed by using the unpaired t tests. In cases in which the data
did not follow normal distribution, the comparison was performed by using a nonparametric Wilcoxon Mann–Whitney
test. Similarly for comparing various parameters over a period
of time within each group (VSL#3 or placebo), we performed a
paired t test/nonparametric Wilcoxon signed rank-sum test in
cases in which data did not follow normal distribution. The
comparison for different categoric variables between 2 groups
(VSL#3/placebo) was performed by the chi-square test/Fisher
exact test in case of expected cell counts less than 5. The
analysis was subjected further to intention-to-treat analysis.
Analysis was performed for all the primary and secondary end
points. For the purpose of analysis, for patients who dropped
out before the 12-week time point their data were carried
forward from their last assessment to be included in the final
analysis. A P value of .05 or less was considered statistically
significant and a P value of .001 or less was considered highly
statistically significant. The data were analyzed by using SPSS
statistical software version 12.0 (SPSS Inc, Chicago, IL).
Results
Participant Flow
Of 187 patients screened for inclusion in the study, 40
could not be included (18 did not meet inclusion criteria, 12
were excluded, and 10 refused to participate). A total of 147
patients were randomized; 77 received VSL#3 and 70 received
placebo (Supplementary Figure 1). Fifty-five patients in the
VSL#3 group and 29 patients in the placebo group completed
the entire study. Among the 22 patients who withdrew from the
VSL#3 group, 17 had worsening of symptoms and 5 were lost to
follow-up evaluation. In the placebo group, 13 were lost to
follow-up evaluation and 28 patients discontinued therapy (disease worsening in 18 patients, noncompliance in 3 patients, and
other reasons in 7 patients).
Demographic and Clinical Characteristics
The demographic and clinical characteristics such as
age, sex, number of previous relapses, extent of disease, and the
use of steroids or immunosuppressive drugs in both groups
were comparable (Table 2). The median baseline UCDAI in the
VSL#3 and placebo groups were 6 (range, 4 – 8) and 6 (range,
3–9), respectively. Seventy-four (96%) and 62 (88.5%) patients
were receiving mesalamine compounds either alone or in combination with azathioprine in the VSL#3 and placebo groups,
respectively. Although 69 (89.6%) patients were receiving only
mesalamine compound (median dose, 2400 mg) in the VSL#3
group, 27 (67.1%) in the placebo group were on mesalamine
compound (median dose, 2400 mg) alone. A significantly higher
number of patients (15 [21.4%] vs 5 [6.4%]) were receiving a combination of mesalamine and azathioprine in the placebo as com-
November 2009
VSL#3 INDUCES REMISSION IN UC
1205
Table 2. Demographic and Baseline Characteristics of Patients
Characteristics
VSL#3 (n ⫽ 77)
Placebo (n ⫽ 70)
P value
Sex, male:female
Age, y, mean ⫾ SD
Weight, kg, mean ⫾ SD
Height, cm, mean ⫾ SD
Number of previous relapses, mean ⫾ SD
Disease extent, no. of patients (%)
Proctosigmoiditis
Left-sided colitis
Pancolitis
Extraintestinal manifestations, no. of patients (%)
Joints
Skin
Eyes
Hepatic
Joints and skin
Joints, skin, and eyes
None
Concomitant medications, no. of patients (%)
Mesalamine (whether alone or in combination with
immunosuppressants)
Mesalamine compounds alone
Mesalamine ⫹ immunosuppressants
Immunosuppressants alone
No medications
43:3 (56%:4%)
39.8 ⫾ 13
60.3 ⫾ 10.7
164.4 ⫾ 7.9
2.24 ⫾ 1.05
45:25 (64%:36%)
38.3 ⫾ 12.5
58.9 ⫾ 12.4
165.2 ⫾ 8.4
2.3 ⫾ 1
.297
.472
.481
.551
.419
38 (49.3)
21 (27.2)
18 (23.3)
28 (40)
26 (37.1)
16 (22.8)
.438
12 (15.9)
2 (2.6)
2 (2.6)
0 (0)
1 (1.3)
2 (2.6)
57 (75)
16 (22.9)
2 (2.9)
0 (0)
0 (0)
0 (0)
0 (0)
52 (74.2)
.351
74 (96)
62 (88.5)
.3
69 (89.6)
5 (6.4)
1 (1.3)
2 (2.6)
47 (67.1)
15 (21.4)
1 (1.43)
7 (10)
.002
.01
.7
.06
pared with the VSL#3 group (P ⫽ .01). Twenty-two patients in the
VSL#3 group and 24 patients in the placebo group had been
exposed to corticosteroids earlier (P ⫽ NS) (Table 2).
Clinical Response/Remission
Number of patients with a decrease in UCDAI
score of 50% or more from baseline to week 6. A significantly higher number of patients on VSL#3 experienced an
improvement in UCDAI score of at least 50% at week 6 than
those who received placebo (25 [32.5%] in the VSL#3 group
versus 7 [10%] in the placebo group; P ⫽ .001) (Figure 1A). The
median improvement in the UCDAI at 6 weeks in the VSL#3
and placebo groups was 25% (range, 20%–100%) and 0% (range,
75%– 80%), respectively (P ⫽ .001). The absolute risk reduction
in the UCDAI at week 6 in the VSL#3 and placebo groups was
1.87 and 0.34 (P ⬍ .001).
Number of patients with a decrease in UCDAI
score of 3 points or more from baseline to week 12. Similarly, a significantly higher number of patients in the VSL#3
group had a decrease in UCDAI score of 3 or more points from
week 0 to week 12 (40 [51.9%] in VSL#3 vs 13 [18.6%] in
placebo; P ⬍ .001) (Figure 1B). The mean (⫾standard deviation)
decrease in UCDAI from baseline to week 12 also was significantly higher in the VSL#3 group compared with placebo (2.7 ⫾
2.2 vs 0.67 ⫾ 2.08; P ⬍ .001) (Figure 2E).
Number of patients who attained remission (UCDAI
subscore of 0 to 2) at week 12. Thirty-three (42.9%) patients
in the VSL#3 group and 11 (15.7%) patients in the placebo
group experienced remission by the end of 12 weeks (P ⬍ .001)
(Figure 1C).
Decrease in individual symptom score. The improvement in stool frequency score, blood in the stool score,
mucosal appearance, and physician’s global assessment were
significantly higher in the VSL#3 group than in the placebo
group both at week 6 and week 12 (Figure 2).
Mucosal Healing
The mucosal healing rate (mucosal appearance score, 0)
at week 12 was significantly higher in patients in the VSL#3
group as compared with the placebo group (24 [32%] vs 10
[14.7%]; P ⬍ .028) (Figure 1D).
Treatment failure (number of patients who failed
to decrease UCDAI by at least 50% of baseline or by at
least by 3 points from baseline to 6 weeks). A significantly higher number (88.6%) of patients in the placebo arm
were treatment failures as defined as failure to decrease total
UCDAI by at least 50% or by at least 3 points from baseline to
week 6 (88.6% vs 62.3%; P ⫽ .001).
Effect of VSL#3 on patients with proctosigmoiditis and left-sided colitis/pancolitis. We performed a subgroup analysis and compared the primary and secondary outcome measures in the VSL#3 group with only proctosigmoiditis
or left-sided colitis/pancolitis. There was no difference in the
response/remission rate in these 2 groups (Table 3).
Safety and Tolerability
No major adverse event was reported in either of the 2
groups. Fourteen (18.2%) patients on VSL#3 reported abdominal bloating and discomfort for the initial few days and 7 of
these patients also felt an unpleasant taste in their mouth
during study drug administration.
Discussion
This was a multicenter, randomized, double-blind, placebo-controlled trial evaluating the role of the probiotic cock-
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SOOD ET AL
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 11
Figure 1. Bar diagrams showing the
(A) number of patients with a decrease
in UCDAI score from greater than 50%
from baseline at week 6, (B) number
of patients with a decrease in total
UCDAI of at least 3 points at week 12,
(C) number of patients who attained
remission (UCDAI ⬍ 3) at week 12,
and (D) number of patients achieving
mucosal healing (mucosal assessment score of 0 at week 12).
tail VSL#3 for treatment of mild-to-moderately active UC. The
addition of VSL#3 to conventional treatment resulted in significantly higher clinical response and remission rates. Moreover, VSL#3 therapy significantly decreased the frequency of
stools and rectal bleeding, resulting in overall improvement in
participant well-being.
There are a few studies that have shown the effectiveness of
probiotics in the induction of remission in patients with mildto-moderately active UC. Rembacken et al,12 in a study including 116 patients with active UC randomized to E coli Nissle
1917 or mesalamine, after a 1-week course of oral gentamicin to
suppress native flora, reported inductions of remission in 68%
and 75% receiving E coli Nissle 1917 and mesalamine, respectively. Kato et al,20 in another double-blind, placebo-controlled
randomized trial, showed a significant reduction in clinical
activity index at 3 months using Bifidobacterium fermented milk
as compared with placebo. Similarly, in an open-label trial,
Guslandi et al17 showed a remission rate of 68% at week 4 using
Saccharomyces boulardii in patients with active UC who failed to
respond to mesalamine. In an open-label study including patients with mild-to-moderately active UC who failed to respond
to mesalamine or corticosteroids, Bibiloni et al21 reported induction of remission in 63% at 6 weeks using VSL#3. These
results were higher than ours, but the difference perhaps can be
attributed to the study’s inclusion of concomitant medication
use, such as corticosteroids and rectal therapies, both of which
were excluded from our study. The lack of placebo control also
may have contributed to the disparity in the 2 studies. In
addition, another study reported similar results to ours, with a
combination of low-dose balsalazide and VSL#3 resulting in
improvements in treatment of mild-to-moderate UC when compared with balsalazide alone or mesalamine alone.22 However,
these studies had methodologic limitations such as small
size; inadequate power to detect a statistically significant
difference; problems in concealment of allocation, generation of random allocation, and double-blinding procedures;
and use of concomitant therapies. In the recent Cochrane
review, investigators concluded that there was not sufficient
evidence to support the use of probiotics in patients with
active UC.23 Our study builds on this earlier work while
paying particular attention to methodologic standards, and
clearly indicates that there is a promising role for therapeutic
use of VSL#3 in the treatment of mild-to-moderate UC. In
the placebo group, about 20% of the patients were lost to
follow-up evaluation, which is rather high for a randomized
trial. This was a limitation of this study.
Treatment with mesalamine-containing drugs is the gold
standard for treatment of mild-to-moderate UC, but the results
found with this treatment are far from satisfactory. However,
our study results show that the probiotic cocktail VSL#3, in
conjunction with mesalamine, improves symptoms for patients
who have not responded to mesalamine alone. It is possible that
VSL#3 may act in synergy with, or perhaps augment, the antiinflammatory action of mesalamine compounds. Mesalamine
compounds are potent inhibitors of several inflammatory mediators, such as leukotrienes, prostaglandins, and platelet-activating factor, which all play a role in the pathogenesis of
UC.27,28
Probiotics ameliorate inflammation via a number of mechanisms, including alteration of the mucosal immune system,
November 2009
VSL#3 INDUCES REMISSION IN UC
1207
Figure 2. Line diagrams showing the decrease in (A) stool frequency score, (B) rectal bleeding score, (C) mucosal appearance score, (D) physician’s
global assessment score, and (E) UC disease activity score at baseline, week 6, and week 12 in the VSL#3 and placebo groups.
competitive exclusion of proinflammatory pathogens, and production of antimicrobial factors such as bacteriocins and other
metabolites.1,3,11,29,30 One type (eg, VSL#3) might be more effective than another because strain-specific properties might influence the efficacy in different cases and situations.6,11 Although the precise mechanism of action of VSL#3 is not
known, in vivo and in vitro studies have shown that VSL#3
modulates the host-immune response, improves epithelial barrier function, and increases mucus production. After ingestion,
VSL#3 strains are able to survive gastric acidity and bile salt
barrier and to colonize the bowel.13,21,30 VSL#3 has been shown
to modify MUC gene expression and mucus secretion by en-
Table 3. Effect of VSL#3 on Patients With Proctosigmoiditis
and Left-Sided Colitis/Pancolitis
End points
No. of patients with
decrease in UCDAI
score of ⱖ50% from
baseline to week 6
No. of patients with
decrease in UCDAI
score of ⱖ3 points
from baseline to
week 12
No. of patients who
attained remission
(UCDAI 0–2) at
week 12
Mucosal healing at
week 12
Proctosigmoiditis,
n ⫽ 38 (49.3%)
Left-sided colitis
and pancolitis,
P
n ⫽ 39 (50.5%) value
12 (31.6%)
13 (13.3%)
.08
22 (57.9%)
18 (46.2%)
.3
17 (44.7%)
16 (41%)
.7
13 (34.2%)
11 (28.2%)
.5
hancing MUC2, MUC3, and MUC5 gene and protein expression
in intestinal epithelial cells in culture.31 VSL#3 has been shown
to increase anti-inflammatory cytokine interleukin (IL)-10, and
inhibit secretion of proinflammatory cytokines including tumor necrosis factor-␣, interferon-␥, and IL-1␤.1,11,30 Lammers
et al32 showed that bacterial genomic DNA induced a remarkable strain-specific immune response. DNA isolated from feces
before VSL#3 ingestion induced higher levels of IL-1 than IL-10,
whereas DNA from feces after VSL#3 treatment enhanced the
IL-10 secretion but reduced the IL-1 secretion. VSL#3 also has
been shown to inhibit experimentally induced colitis in mice.
Madsen et al30 showed a decrease in the severity of colitis in
IL-10⫺/⫺ mice, as evidenced by decreasing tumor necrosis factor-␣ and interferon-␥ production, and improvement in histologic scores and barrier integrity by VSL#3. In the indocetamide
model of colitis, pretreatment either with Lactobacillus GG or
VSL#3 significantly decreased the severity of colonic damage,
as indicated by decreased myeloperoxidase activity and nitric
oxide synthase activity.33 Rachmilewitz et al34 showed that
VSL#3 significantly decreased colonic disease activity score,
myeloperoxidase activity, and histologic scores in chronic dextran sulfate sodium–induced colitis.
Probiotics have a good safety profile. Cases of infection as a
result of Lactobacilli and Bifidobacteria are extremely rare, occurring at a rate of approximately 0.05% to 0.4% of all cases of
bacteremia. Indeed, when bacteremia with probiotics has been
described, it has been associated with the extremes of age
and/or with concomitant immunosuppression therapy.35 The
main side effects in this study were minor and included alteration in taste and bloating.
In conclusion, VSL#3 led to a 50% decrease in UCDAI at week
6 and clinical remission at week 12 in significantly more patients
with mild-to-moderately active UC than placebo.
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SOOD ET AL
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 11
Supplementary Data
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org.
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Reprint requests
Address requests for reprints to: Rakesh K. Tandon, MD, E–154, Saket,
New Delhi 110 017, India. e-mail: [email protected]; fax: (91)
11-29250548.
Acknowledgments
The authors express their gratitude to Professor Richard Fedorak of
the University of Alberta (Edmonton, Alberta, Canada) for giving useful
advice in finalizing the manuscript, and to CD Pharma (New Delhi) for
providing the research grant as well as the VSL#3 and placebo for the
November 2009
study. The authors sincerely acknowledge the contribution of Mr Aditya
R. Sahu for helping them in the conduct of the study, data analysis,
and manuscript preparation.
The clinical trial is registered with Clinical Trial Registry India, UTRN
no. UTRN 082813953-29052008152129, CTRI no. CTRI/2008/091/
000076, dated June 6, 2008.
VSL#3 INDUCES REMISSION IN UC
1209
Conflicts of interest
The authors disclose no conflicts.
Funding
This study was supported by CD Pharma India Private, Ltd, New
Delhi, India.
November 2009
VSL#3 INDUCES REMISSION IN UC
Supplementary Figure 1. Flow of patients in the VSL#3 and placebo groups.
1209.e1