ARTIGO ORIGINAL

Prévia do material em texto

ORIGINAL ARTICLE
A pilot study on the effect of a symbiotic mixture in irritable bowel
syndrome: an open-label, partially controlled, 6-month extension
of a previously published trial
C. Bucci • F. Tremolaterra • S. Gallotta •
A. Fortunato • C. Cappello • C. Ciacci •
P. Iovino
Received: 22 May 2013 / Accepted: 25 July 2013
� Springer-Verlag Italia 2013
Abstract
Background In recent years, the efficacy of probiotics has
received considerable attention in the treatment for irritable
bowel syndrome (IBS). In this regard, a symbiotic mixture
(Probinul�) has shown beneficial effects. The aim of this
study was to extend the previously published 4-week ran-
domized, double-blinded, placebo-controlled study of this
symbiotic mixture.
Methods This is an open-label prospective, partially
controlled, 6-month extension period pilot study in which
patients continued to receive the symbiotic mixture (Group
1) or were switched from placebo to symbiotic mixture
(Group 2) using cyclic administration (last 2 weeks/
month). The primary endpoints were the overall satisfac-
tory relief of bloating and flatulence (assessed as propor-
tions of responders). The secondary endpoints were
evaluation of the symptom severity scores (bloating, flat-
ulence, pain and urgency) and bowel function scores (fre-
quency, consistency and incomplete evacuation).
Results Twenty-six IBS patients completed the 6-month
extension period (13 patients in Group 1 and 13 patients in
Group 2). In the per-protocol analysis, the proportions of
responders across time were not significantly different in
the groups but in Group 2, there was an increased per-
centage of responders for flatulence (p = 0.07). In addi-
tion, the score of flatulence was reduced significantly
during the 6-month treatment period in Group 2 (p \ 0.05),
while no other significant differences were detected.
Conclusions Treatment with this symbiotic mixture was
associated with persistence of relief from flatulence or new
reduction in flatulence in the present 6-month long exten-
sion study. These results need to be more comprehensively
assessed in large, long-term, randomized, placebo-con-
trolled studies.
Keywords Symbiotic � Probiotic � Prebiotic �
Irritable bowel syndrome � Bloating � Flatulence �
Functional bowel disorders � Cyclic administration �
Clinical trial
Introduction
Irritable bowel syndrome (IBS) is a common gastrointestinal
disorder characterized by abdominal pain or discomfort and
altered bowel habits [1]. Because the etiology underlying IBS
remains unclear and different pathophysiological mecha-
nisms have been proposed, there is no discrete lesion toward
target therapy. As a result, the management of IBS has tended
to focus on the amelioration of symptoms, rather than disease
modification or cure without reaching a complete resolution of
symptoms [2]. In recent years, the efficacy of using probiotics,
defined as live microorganisms, which, when administered in
adequate amounts, confer a health benefit on the host [3], has
received considerable attention in the prevention and treat-
ment of gastrointestinal diseases [4–6]. Oral probiotic prepa-
rations, aimed at restoring the ‘‘healthy commensal biota
balance,’’ have been met with much enthusiasm by IBS
C. Bucci � S. Gallotta � A. Fortunato � C. Ciacci � P. Iovino (&)
Gastrointestinal Unit, Department of Medicine and Surgery,
University of Salerno, Via S Allende, 84081 Baronissi,
Salerno, Italy
e-mail: piovino@unisa.it
F. Tremolaterra
Centro di Riferimento Oncologico di Basilicata, IRCCS,
Rionero in Vulture, PZ, Italy
C. Cappello
General and Geriatric Surgery Department, Federico II
University of Naples, Via Pansini 5, 80131 Naples, Italy
123
Tech Coloproctol
DOI 10.1007/s10151-013-1055-2
patients, and studies have shown that both lactobacilli and
bifidobacteria preparations modulate gastrointestinal immune
function and improve IBS symptoms [7, 8]. It is plausible that,
by altering the luminal milieu, probiotics can attenuate
symptom generation by reducing both levels of inflammation
and visceral hypersensitivity [5, 8].
It has been shown that the symbiotic mixture (Probi-
nul�, CaDiGroup Srl, Rome, Italy), a combination of
probiotics and prebiotics, reduces the severity of flatulence
in IBS patients, is not associated with adverse events and
has a good side-effect profile, but Probinul has failed to
achieve an improvement in overall satisfactory relief of
abdominal flatulence and bloating [9].
This study presents results from an extension of an
earlier published [9] clinical assessment of a symbiotic
mixture (Probinul) in patients with IBS. Addressed in the
present pilot study are data from a 6-month open-label
extension period taking into account the preceding 4-week
double-blinded, randomized, placebo-controlled study.
Materials and methods
The study protocol was approved by the ethics committee
of Federico II University of Naples and, therefore, was in
accordance with the ethical standards laid down in the
1964.
Declaration of Helsinki: All participants signed a con-
sent form prior to being enrolled in the study.
Inclusion and exclusion criteria
Patients were eligible for participation in the original study
[9] if they were females and males 18–75 years old diag-
nosed with IBS according to the Rome III criteria [10]
(Table 1), together with the exclusion of any other organic
disease. Patients meeting the foregoing criteria were
recruited from an outpatient clinic for gastrointestinal
functional disorders. Table 2 shows the inclusion and
exclusion criteria.
Concomitant medications
The following medications were permitted during the
course of the study, as long as they had been used at a
constant dosage and commenced at least 1 month prior to
the start of the 2-week run-in period of the core study: birth
control pill or depot intramuscular contraceptive prepara-
tion; estrogen–progesterone replacement therapy; L-thy-
roxine; low-dose antidepressants (up to 25 mg/day of
amitriptyline, nortriptyline, or a selective serotonin reup-
take inhibitor), or the following antihypertensives such as
diuretics, angiotensin-converting enzyme inhibitors or
angiotensin II inhibitors. If patients received antibiotics for
acute infections (for example, bacterial throat or urinary
infections), the symptom data for the time of antibiotic
administration and 1 week after completion were excluded
from analysis, and the treatment period prolonged to ensure
availability of the requisite number of months of study
treatment. Moreover, we tracked the intake of all rescue
medications during the trial.
Study design
Figure 1 shows the designs of the parallel-group, double-
blinded, randomized, placebo-controlled study (core study)
Table 1 Diagnostic criteria for irritable bowel syndrome according
to the Rome III criteria
Presence of recurrent abdominal pain or discomfort at least 3 days/
month in the last 3 months associated with 2 or more of the
following
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool
Supplementary signs
a. Abnormal stool frequency (B3 bowel movements per week or
[3 bowel movements per day)
b. Abnormal stool form (lumpy/hard stool or loose/watery stool)
c. Defecation straining
d. Urgency
e. Feeling of incomplete bowel movement
f. Passing mucus
g. Bloating
Table 2 Inclusion and exclusion criteria
Inclusion criteria
a. Male and female, 18–75 years, fulfilling the Rome III criteria
b. Signed consent form
c. Ability to understand and willingness to comply to the study
proceduresExclusion criteria
a. Serious, unstable medical condition, insulin-dependent diabetes
mellitus, major psychiatric diagnosis
b. Previous abdominal surgery except appendectomy, caesarean
section, tubal ligation, laparoscopic cholecystectomy,
hysterectomy or abdominal wall hernia repair
c. Previous history of drug or alcohol abuse 6 months prior to
screening
d. Diagnosis of lactase deficiency or if symptoms resolved with
lactose-free diet
e. Current use of medications that may alter gastrointestinal
motility, or long-term antibiotics or proton pump inhibitors
f. Withdrawal of consent
Tech Coloproctol
123
[9] and the open-label prospective, partially controlled,
6-month extension period. During the core study, a total of
64 patients were randomized to either placebo (n = 32) or
symbiotic (n = 32). Together, the core study and the
6-month extension period constituted a partial crossover
design, in which patients continued to receive the symbiotic
mixture (Group 1) or were switched from placebo to sym-
biotic mixture (Group 2). During the 4-week randomization
period of the core study, patients were instructed to ingest
the investigational powder preparation (a sachet) twice
daily, preferably in the morning and in the evening far from
meals, dissolving it in water. Thereafter, they continued
with one sachet containing the symbiotic mixture twice
daily, 2 weeks a month, for the 6-month extension period.
Patients were clinically evaluated at week 4 (end of core
study) and again at the end of the third (T1 visit) and sixth
(T2 visit) month of the extension period (Fig. 1).
Patients filled in a daily diary to evaluate stool fre-
quency, bowel function and symptoms and record a weekly
response to a question on the overall satisfactory relief of
abdominal bloating and sensation of flatulence during the
core study and, thereafter, only for the last 2 weeks of the
third and sixth month of the extension period before the
follow-up visits (T1 and T2 visits, respectively).
Study treatments
The symbiotic mixture contains lyophilized bacteria (5 9 109
Lactobacillus plantarum, 2 9 109 Lactobacillus casei sub-
rhamnosus and 2 9 109 Lactobacillus gasseri, 1 9 109 Bifi-
dobacterium infantis and 1 9 109 Bifidobacterium longum,
1 9 109 Lactobacillus acidophilus, 1 9 109 Lactobacillus
salivarius and 1 9 109 Lactobacillus sporogenes, 5 9 109
Streptococcus thermophilus) and as prebiotic Inulin (2.2 g VB
beneo Sinergy 1), 1.3 g Tapioca-resistant starch. The study
preparation was provided in a powder form (5 g per sachet)
containing the symbiotic mixture.
Assessment of symptoms and bowel functions
Bowel function was assessed on validated adjectival scales:
stool consistency by the Bristol stool form scale [11–14]
and the sensation of incomplete evacuation by a binomial
answer (yes or no). Bowel symptoms were bloating, flat-
ulence, pain and fecal urgency which were assessed on
100 mm visual analogue scales (VAS). Overall, satisfac-
tory relief of abdominal bloating and sensation of flatu-
lence was assessed by a single statement (yes or no) with
the following questions: ‘‘Have you experienced overall
satisfactory relief of abdominal bloating? Please answer
yes or no’’ and ‘‘Have you experienced a overall satisfac-
tory relief from flatulence? Please answer yes or no.’’
Diet registration
In a diary, patients recorded all the food they had eaten
during 2 weekdays in the core study and in the last 2 weeks
of the third and sixth months of the extension period before
the scheduled visits (T1 and T2). Nutrients were manually
calculated.
Compliance
The patients reported the daily consumption of the study
product in the diary. Compliance was calculated as the
percentage of planned ingestion of the study product and
the minimum requirement for acceptable compliance were
set at [80 %.
Tolerability and safety
Tolerability and safety were assessed by recording all
reported adverse events.
Statistical analysis
Primary endpoints were analyzed according to both the
intention-to-treat principle, i.e., all randomized patients who
met the eligibility criteria were included in the analysis of
their allocated group, and per-protocol analysis, i.e., patients
who reached the minimum requirement of compliance with
the treatment for the primary endpoint. In this study, the
primary endpoint was the overall satisfactory relief from
bloating and flatulence. The primary analysis was a
Fig. 1 Designs of the parallel-
group, double-blinded,
randomized, placebo-controlled
study (core study) [9] and the
open-label prospective, partially
controlled, 6-month extension
period
Tech Coloproctol
123
comparison using Cochran’s Q test of the proportion of the
responders across time (T0, T1, T2) in the extended symbi-
otic treatment group (Group 1) and in patients who switched
from placebo to open-label symbiotic treatment (Group 2).
Responders were defined as individuals who responded yes
to at least 50 % of overall satisfactory relief questions in the
weekly assessment during the last 2 weeks at the end of the
third and sixth months during the extension period.
The secondary endpoints included severity VAS scores
for symptoms and bowel function scores. The daily diary
was used to assess the bowel function scores (frequency,
consistency and the proportion of days with the sense of
incomplete evacuation) and the severity of individual
symptoms (abdominal bloating, flatulence, pain and
urgency). The VAS symptom scores were rounded to the
nearest integer in millimeters. The adjectival scales for
stool consistency (Bristol stool form scale) were recorded
as numerical values.
The data on bowel function scores and VAS scores of
individual symptoms during the last 2 weeks of the third
and sixth months during the extension period were sum-
marized as the mean and standard error in each treatment
group.
Planned data analyses included: (1) repeated-measures
analyses of covariance (ANCOVA) model with the corre-
sponding value of the last week of the study core as the
covariate to assess the trends in more extended symbiotic
treatment in Group 1. Age was also included as a covariate
for analyses of the symptoms; (2) ANCOVA model with
the corresponding value of the last week of the study core
as the covariate to assess open-label symbiotic treatment in
Group 2. Age was also included as a covariate for analyses
of the symptoms. The significance level was set at
p \ 0.05. The SPSS software package for Windows
(release 15.0; SPSS Inc, Chicago, IL, USA) was used for
statistical analysis.
Results
Demographic characteristics
A schematic flow diagram of the patient inclusion and
follow-up process is shown in Fig. 2. Sixty-four patients
completed the 4-week core study as previously described
[9]. Of the 32 IBS patients that initially received the
blinded symbiotic mixture, 22 (Group 1) agreed to partic-
ipate and entered the 6-month extension, 20 underwent the
scheduled third month visit and 13 IBS patients completed
the extended study. Conversely, of the 32 IBS patients that
during the 4-week core study received the placebo (Group
2), 24 agreed to continue, 19 patients underwent the
scheduled third month visit and 13 IBS patients completed
the 6-month extension period. Baseline characteristics of
the patients who agreed to participate are listed in Table 3.
There were no significant differences in terms of baseline
characteristics among Groups 1 and 2. Twenty patients
who initially agreed to participate in the extension study
were lost to follow-up primarily due to refusal to continue
treatment, concomitant new treatments or change ofresi-
dence (Fig. 2).
Primary outcomes
Group 1: (patients who received 4 weeks of blinded sym-
biotic treatment and 6-month open-label symbiotic treat-
ment). Responders for abdominal bloating were 46.9 %
(15/32) at the end of the 4-week core period. In the per-
protocol analysis, there was no difference in the proportion
of responders for abdominal bloating across T0, T1, T2
time points in the patients (n = 13) who completed the
6-month extension period (Cochran’s Q test 2.000,
p = 0.6). The proportion of responders for abdominal
bloating at 3 months and at 6 months of the open-label
extension period in the intention-to-treat analysis and in
per-protocol analysis are shown in Table 4.
Responders for flatulence were 50 % (16/32) at the end
of the 4-week core period. In the per-protocol analysis,
there was no difference in the proportion of responders for
flatulence across T0, T1, T2 time points in the patients
(n = 13) who completed the 6-month extension period
(Cochran’s Q test 3.000, p = 0.3). The proportion of
responders for flatulence at 3 months and at 6 months of
the open -label extension period in the intention to treat and
in per-protocol analysis are shown in Table 4.
Group 2 (patients who switched from placebo to open-
label symbiotic treatment): Responders for abdominal
bloating were 65.6 % (21/32) at the end of the 4-week core
period. In the per-protocol analysis, there was no difference
in the proportion of responders for abdominal bloating
across T0, T1, T2 time points in the patients (n = 13) who
completed the 6-month extension period (Cochran’s Q test
4.667, p = 0.2). The proportion of responders for abdom-
inal bloating at 3 months and at 6 months of the open-label
extension period in the intention-to-treat analysis and in
per-protocol analysis are shown in Table 4.
Responders for flatulence were 62.5 % (20/32) at the
end of the 4-week core period. In the per-protocol analysis,
there was an increased percentage of responders for flatu-
lence across T0, T1, T2 time points in the patients (n = 13)
who completed the 6-month extension period but this just
failed to reach statistical significance (Cochran’s Q test
6.500, p = 0.07). The proportion of responder for flatu-
lence at baseline, 3 months and at 6 months of the open-
label extension period in the intention to treat and in per-
protocol analysis are shown in Table 4.
Tech Coloproctol
123
Secondary outcomes
Group 1: per-protocol analysis showed that symbiotic
treatment was associated with a persistence of relief in the
severity scores of abdominal pain, flatulence and urgency
during the 6-month extension period, while bloating
significantly changed (Fig. 3). There were no statistically
significant differences detected for bowel function such as
stool frequency (repeated-measures ANCOVA, p = 0.3),
Bristol stool scale score (repeated-measures ANCOVA,
p = 0.6) or proportion of days with the sense of incomplete
evacuation (repeated-measures ANCOVA, p = 0.7).
Fig. 2 Schematic flow diagram
of patient inclusion and follow-
up process
Tech Coloproctol
123
Group 2: per-protocol analysis showed that with the
symbiotic mixture, there was a significant reduction in the
flatulence score during the 6-month extension period
(Fig. 2) (repeated-measures ANCOVA, p \ 0.05). There
was no significant difference in the symptoms of abdomi-
nal pain, bloating and urgency (Fig. 3).
During the 6-month extension period, there were no
statistically significant differences detected for bowel
function (repeated-measures ANCOVA, frequency
p = 0.1, consistency p = 0.8) or proportion of days with
the sense of incomplete evacuation (repeated-measures
ANCOVA, p = 0.9).
Diet
Quality and quantity of food intake was unchanged during
the entire study (data not shown).
Compliance
The compliance was [95 % in both groups as analyzed
from the study diaries. One of the participants in Group 2
required antibiotic therapy during the study period for
upper respiratory infection and adhered to protocol
instructions. One patient from each treatment group used a
ketoprofen tablet as predefined rescue medication for
headache during the 6-month extension period.
Tolerability and safety
This symbiotic mixture was well tolerated, and there were
no adverse events noted with the use of this symbiotic
mixture and/or placebo treatment.
Discussion
IBS is a heterogeneous disorder, consisting of a number of
troublesome symptoms that we are still unable to treat
efficaciously. The most troublesome, besides abdominal
pain, are bloating symptoms, including abdominal disten-
sion and gas, which are a frequent reason to seek medical
care [15]. Previous studies conducted with the gas chal-
lenge test have demonstrated that pharmacological colonic
stimulation by prokinetics clearly improves gas-related
symptoms [16, 17], while non-pharmacological agents
provided inconstant results [18, 19]. As it has been recently
demonstrated that the microbiota may be disturbed in
functional gastrointestinal disorders, a new potential
treatment approach is to try to correct dysbiosis using
either the administration of an antibiotic or a preparation of
‘‘beneficial’’ bacteria. Several studies targeting the intesti-
nal microbiota for treatment of functional GI symptoms
showed some interesting positive effects on many gastro-
intestinal symptoms, especially bloating and flatulence
[20–23].
Taken together, these data coming from studies on
probiotics in IBS patients demonstrated that not all probi-
otics are the same, and that effects can differ considerably
Table 3 Baseline characteristics of patients who agreed to continue
the open-label 6-month pilot study
Group 1 Group 2 p
Number of patients 22 24
Female, n (%) 15 (68 %) 13 (54 %) 0.3
Age (mean ± SD), years 35.5 ± 2.7 42.2 ± 2.7 0.09
Predominant bowel habit
Diarrhoea, n (%) 6 (27 %) 12 (50 %)
Constipation, n (%) 9 (40 %) 8 (33 %)
Mixed, n (%) 7 (31 %) 4 (16 %)
Undetermined, n (%) 0 0 0.3
n number, SD standard deviation
Table 4 Proportion of responders for abdominal bloating and flatulence at baseline, 3 and 6 months in the intention-to-treat (ITT) analysis and
in per-protocol (PP) analysis
Group 1 Group 2
T0 T1 T2 T0 T1 T2
ITT proportion of responder for
bloating
9/22 (40.9 %) 14/22 (63.6 %) 12/22§ (54.5 %) 15/24 (62.5 %) 18/24 (75 %) 20/24* (83.3 %)
PP proportion of responder for
bloating
6/13 (46.2 %) 8/13 (61.5 %) 6/13 (46.2 %) 7/13 (53.8 %) 8/13 (61.5 %) 10/13 (76.9 %)
ITT proportion of responder for
flatulence
11/22 (50 %) 13/22 (59.1 %) 9/22# (40.9 %) 13/24 (54.2 %) 18/24 (75 %) 20/24� (83.3 %)
PP proportion of responder for
flatulence
9/13 (69.2 %) 11/13 (84.6 %) 7/13 (53.8 %) 8/13 (61.5 %) 11/13 (84.6 %) 12/13 (92.3 %)
Statistics were calculated by the Cochran’s Q test
* Cochran’s Q test p = 0.03; § Cochran’s Q test p = 0.08; # Cochran’s Q test p = 0.4; � Cochran’s Q test p = 0.007
Tech Coloproctol
123
between one organism and another. Thus, the effect of a
specific probiotic cannot be extrapolated to another probi-
otic strain. For example, if one organism is beneficial, this
does not mean that related organisms will behave similarly
[24, 25].
For this reason, after having established during a
4-week, randomized, double-blind, placebo-controlled
study (core study) that a symbiotic mixture (Probinul) had
a beneficial effect on flatulence [9], we went on to study
prospectively, in the same population, the effect of open-
label Probinul treatment using cyclic administration (last
2 weeks/month) over a 6-month period.
The results of the per-protocol analysis suggest a treat-
ment-associatedsignificant reduction in flatulence severity
in the group of patients who switched from placebo to open-
label symbiotic treatment (Group 2). This result largely
parallels that in the core study. Moreover, in the same group,
there was a reduction that just failed to reach statistical
significance in the overall relief from flatulence, one of the
predefined primary end points and an even more signifi-
cance, was obtained regarding both flatulence and bloating
in an intention-to-treat analysis. The lack of statistical sig-
nificance of the overall relief from flatulence in the per-
protocol analysis may be related to the intrinsic limitations
of the study design which was an extension study with a
small number of patients that leads to a lack of statistical
power (type 2 error). Furthermore, in Group 1, which con-
sisted of patients who continued on symbiotic treatment, no
significant changes were observed in primary endpoints both
in the intention to treat and per-protocol analysis or in sec-
ondary endpoints with the exception of bloating that chan-
ged across time. This suggests that the effect of symbiotic
treatment was maintained over time, continuing efficacy
trends also using cyclic administration. As in the core study,
this symbiotic mixture was well tolerated by the participants
in the study, with no adverse events.
Fig. 3 VAS scores of bloating, flatulence, abdominal pain and
urgency during the 6-month extension period in Group 1 (patients
who continued to receive the symbiotic mixture) and Group 2
(patients who switched from placebo to symbiotic mixture). (Mean
values ± standard error) *repeated-measures ANCOVA, p \ 0.05)
Tech Coloproctol
123
Symbiotic treatment should exert a synergistic benefit
upon the host’s health by means of specific changes in the
composition and/or activity of the gastrointestinal micro-
biota made by the selective, co-administered prebiotic
substrate [26], but the mechanisms of such benefits are
unfortunately still poorly understood. In the literature,
several mechanisms have been suggested to explain the
efficacy of probiotics in IBS, such as the influence of the
environment of the intestinal lumen, the maintenance of
epithelial and mucosal barrier function and the modulation
of the mucosal or systemic immune system including both
innate and adaptive immune systems [27–29], but none
have been shown to be prevalent.
Study limitations
This extension study presents some notable limitations.
First, to avoid asymmetric transfer after symbiotic treat-
ment (e.g., carryover effects not resolvable by washout),
a full crossover design was not chosen [30, 31]. Group 1
data were employed to begin to assess the continuing
effect after the double-blind study via trend analysis
across 6 months of treatment. The extended treatment
period and repeated measures provided for a statistically
powerful look at continuing efficacy trends afforded by
the 4-week core study [31, 32]. This method is subject to
potential challenges/biases [31, 33, 34], and some were
implicitly addressed when it was calculated that the
flatulence, bloating, abdominal pain and urgency trend
across weeks at the transition between blinded and open-
label symbiotic mixture were linear (data not shown)
[31]. Group 2 data were focused on whether the control
group would respond to treatment as in the core study.
Again this assessment could have some biases (e.g.,
potential placebo and expectancy effects [33, 34] that
have been moderated by making symptom assessments
before each physician contact [31, 33]). These assess-
ments were carried out at transition to the open-label
extension (after completion of the core data collection)
and after completion of extension data collection at 3 and
6 months. No bias was found in the statistical compari-
sons of treatment week 2 versus treatment week 1 and of
treatment week 4 versus treatment week 3. In addition,
when interpreting the results of the present extension
study (and those of the core study), one must consider the
potential of this patient-selection bias to affect general-
izability to other IBS patient groups because we included
a heterogeneous IBS population. Moreover, the study
population was not sufficiently large enough for a sub-
group analysis of IBS subtypes. We were, therefore,
unable to show whether some IBS subtypes would actu-
ally benefit more from the consumption of the symbiotic
mixture than the others.
Conclusions
Treatment with this symbiotic mixture (Probinul) was
found to be associated with both 4-week (short-term)
reductions in flatulence during the double-blind core study
and persistence of relief from flatulence, or new reduction
in flatulence, in the present open 6-month (long-term)
extension study. These results need to be more compre-
hensively assessed in large, long-term, randomized, pla-
cebo-controlled studies.
Conflict of interest None.
References
1. Thompson WG, Longstreth GF, Drossman DA, Heaton KW,
Irvine EJ, Muller-Lissner SA (1999) Functional bowel disorders
and functional abdominal pain. Gut 45(Suppl 2):II43–II47
2. Brandt LJ, Chey WD, Foxx-Orenstein AE et al (2009) An evi-
dence-based position statement on the management of irritable
bowel syndrome. Am J Gastroenterol 104(Suppl 1):S1–S35
3. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB
(2004) Dietary modulation of the human colonic microbiota:
updating the concept of prebiotics. Nutr Res Rev 17:259–275
4. Moayyedi P, Ford AC, Talley NJ et al (2010) The efficacy of
probiotics in the treatment of irritable bowel syndrome: a sys-
tematic review. Gut 59:325–332
5. Ritchie ML, Romanuk TN (2012) A meta-analysis of probiotic
efficacy for gastrointestinal diseases. PloS One 7:e34938
6. Simren M, Barbara G, Flint HJ et al (2013) Intestinal microbiota
in functional bowel disorders: a Rome foundation report. Gut
62:159–176
7. O’Mahony L, McCarthy J, Kelly P et al (2005) Lactobacillus and
bifidobacterium in irritable bowel syndrome: symptom responses
and relationship to cytokine profiles. Gastroenterology
128:541–551
8. Ohman L, Simren M (2013) Intestinal microbiota and its role in
irritable bowel syndrome (IBS). Curr Gastroenterol Rep 15:323
9. Cappello C, Tremolaterra F, Pascariello A, Ciacci C, Iovino P
(2013) A randomised clinical trial (RCT) of a symbiotic mixture
in patients with irritable bowel syndrome (IBS): effects on
symptoms, colonic transit and quality of life. Int J Color Dis
28:349–358
10. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Me-
arin F, Spiller RC (2006) Functional bowel disorders. Gastroen-
terology 130:1480–1491
11. Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide
to intestinal transit time. Scand J Gastroenterol 32:920–924
12. Heaton KW, Radvan J, Cripps H, Mountford RA, Braddon FE,
Hughes AO (1992) Defecation frequency and timing, and stool
form in the general population: a prospective study. Gut
33:818–824
13. Heaton KW, O’Donnell LJ (1994) An office guide to whole-gut
transit time. Patients’ recollection of their stool form. J Clin
Gastroenterol 19:28–30
14. Heaton KW, Ghosh S, Braddon FE (1991) How bad are the
symptoms and bowel dysfunction of patients with the irritable
bowel syndrome? A prospective, controlled study with emphasis
on stool form. Gut 32:73–79
15. Ringel Y, Williams RE, Kalilani L, Cook SF (2009) Prevalence,
characteristics, and impact of bloating symptoms in patients with
irritable bowel syndrome. Clin Gastroenterol Hepatol 7:68–72
Tech Coloproctol
123
16. Caldarella MP, Serra J, Azpiroz F, Malagelada JR (2002)
Prokinetic effects in patients with intestinal gas retention. Gas-
troenterology122:1748–1755
17. Coleski R, Owyang C, Hasler WL (2006) Modulation of intes-
tinal gas dynamics in healthy human volunteers by the 5-HT
receptor agonist tegaserod. Am J Gastroenterol 101:1858–1865
18. Villoria A, Serra J, Azpiroz F, Malagelada JR (2006) Physical
activity and intestinal gas clearance in patients with bloating. Am
J Gastroenterol 101:2552–2557
19. Tremolaterra F, Pascariello A, Gallotta S, Ciacci C, Iovino P
(2013) Colonic gas transit in patients with bloating: the effect of
an electromechanical stimulator of the abdominal wall. Tech
Coloproctol 17:405–410
20. Whorwell PJ, Altringer L, Morel J et al (2006) Efficacy of
an encapsulated probiotic Bifidobacterium infantis 35624 in
women with irritable bowel syndrome. Am J Gastroenterol
101:1581–1590
21. Kim HJ, Camilleri M, McKinzie S et al (2003) A randomized
controlled trial of a probiotic, VSL#3, on gut transit and symp-
toms in diarrhoea- predominant irritable bowel syndrome. Ali-
ment Pharmacol Ther 17:895–904
22. Kim HJ, Vazquez Roque MI, Camilleri M et al (2005) A ran-
domized controlled trial of a probiotic combination VSL# 3 and
placebo in irritable bowel syndrome with bloating. Neurogas-
troenterol Motil 17:687–696
23. Ringel-Kulka T, Palsson OS, Maier D et al (2011) Probiotic
bacteria Lactobacillus acidophilus NCFM and Bifidobacterium
lactis Bi-07 versus placebo for the symptoms of bloating in
patients with functional bowel disorders: a double-blind study.
J Clin Gastroenterol 45:518–525
24. Spiller R (2008) Review article: probiotics and prebiotics in
irritable bowel syndrome. Aliment Pharmacol Ther 28:385–396
25. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS (2009) The
utility of probiotics in the treatment of irritable bowel syndrome:
a systematic review. Am J Gastroenterol 104:1033–1049
26. Schrezenmeir J, de Vrese M (2001) Probiotics, prebiotics, and syn-
biotics–approaching a definition. Am J Clin Nutr 73:S361–S364
27. Ng SC, Hart AL, Kamm MA, Stagg AJ, Knight SC (2009)
Mechanisms of action of probiotics: recent advances. Inflamm
Bowel Dis 15:300–310
28. Forsythe P, Bienenstock J (2010) Immunomodulation by com-
mensal and probiotic bacteria. Immunol Invest 39:429–448
29. Ohland CL, Macnaughton WK (2010) Probiotic bacteria and
intestinal epithelial barrier function. Am J Physiol Gastrointest
Liver Physiol 298:G807–G819
30. Poulton EC, Freeman PR (1966) Unwanted asymmetrical transfer
effects with balanced experimental designs. Psychol Bull 66:1–8
31. Cook TDCT (1979) Quasi-experimentation: design & analysis
issues for field studies. Houghton Mifflin Co, Boston
32. Bramwell ATBAJ, Morrissey SJ (1992) Repeated-measures
analysis: issue and options. Int J Ind Ergon 10:185–197
33. Rosenthal R (1966) Experimental effects in behavioral research.
Appleton-Century-Crofts, New York
34. Hrobjartsson A (2002) What are the main methodological prob-
lems in the estimation of placebo effects? J Clin Epidemiol
55:430–435
Tech Coloproctol
123
	A pilot study on the effect of a symbiotic mixture in irritable bowel syndrome: an open-label, partially controlled, 6-month extension of a previously published trial
	Abstract
	Background
	Methods
	Results
	Conclusions
	Introduction
	Materials and methods
	Inclusion and exclusion criteria
	Concomitant medications
	Study design
	Study treatments
	Assessment of symptoms and bowel functions
	Diet registration
	Compliance
	Tolerability and safety
	Statistical analysis
	Results
	Demographic characteristics
	Primary outcomes
	Secondary outcomes
	Diet
	Compliance
	Tolerability and safety
	Discussion
	Study limitations
	Conclusions
	Conflict of interest
	References