Ligaarden et al.

BMC Gastroenterology 2010, 10:16

http://www.biomedcentral.com/1471-230X/10/16

RESEARCH ARTICLE Open Access

A candidate probiotic with unfavourable effects

in subjects with irritable bowel syndrome: a
randomised controlled trial
Solveig C Ligaarden1,2*, Lars Axelsson3, Kristine Naterstad3, Stian Lydersen2, Per G Farup1,2

Abstract
Background: Some probiotics have shown efficacy for patients with irritable bowel syndrome (IBS). Lactobacillus
(L.) plantarum MF1298 was found to have the best in vitro probiotic properties of 22 strains of lactobacilli. The aim
of this study was to investigate the symptomatic effect of L. plantarum MF1298 in subjects with IBS. Primary
outcome was treatment preference and secondary outcomes were number of weeks with satisfactory relief of
symptoms and IBS sum score.
Methods: The design was a randomised double blind placebo-controlled crossover trial. 16 subjects with IBS
underwent two three-week periods of daily intake of one capsule of 1010 CFU L. plantarum MF 1298 or placebo
separated by a four-week washout period.
Results: Thirteen participants (81%; 95% CI 57% to 93%; P = 0.012) preferred placebo to L. plantarum MF1298
treatment. The mean (SD) number of weeks with satisfactory relief of symptoms in the periods with L. plantarum
MF1298 and placebo were 0.50 (0.89) and 1.44 (1.26), respectively (P = 0.006). IBS sum score was 6.44 (1.81) in the
period with L. plantarum MF1298 treatment compared with 5.35 (1.77) in the period with placebo (P = 0.010). With
a clinically significant difference in the IBS sum score of 2 in disfavour of active treatment, the number needed to
harm was 3.7, 95% CI 2.3 to 10.9.
Conclusions: This trial shows for the first time an unfavourable effect on symptoms in subjects with IBS after
intake of a potential probiotic.
The trial registration number: Clinical trials NCT00355810.

Background effect of probiotics in IBS [6]. Lactobacillus (L.) plan-

Irritable bowel syndrome (IBS) is the most frequent tarum 299v reduced flatulence and abdominal pain in
functional gastrointestinal disorder, with a prevalence of patients with IBS [7]. L. plantarum MF1298 was found
5-11% in most countries [1]. The workload generated by to have the best in vitro probiotic properties of 22
IBS is considerable and constitutes approximately one- strains of lactobacilli isolated from fermented food pro-
third of all visits to gastroenterologists [2]. It is a biopsy- ducts. This strain was confirmed to adhere to the
chosocial disorder that requires a multifactorial human colon adenoma cell line CaCo2, to strengthen
approach [3]. No proper treatment is available. transepithelial resistance of a CaCo2 cell layer and to
The human gut contains over 1000 different bacterial increase production of certain tight junction proteins, to
species and an indeterminate number of strains of have antimicrobial activity against potential pathogens,
which a minority of the strains is cultivable [4] Probio- and to survive passage through the human gastrointest-
tics are defined as “live microorganisms which when inal tract [8-10]. L. plantarum MF1298 was therefore
administered in adequate amounts confer a health bene- proposed as a potential candidate probiotic strain.
fit on the host” [5]. Some studies have shown beneficial The aims of this randomised placebo-controlled cross-
over trial were to study the effect of L. plantarum
* Correspondence: [email protected]
1
Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway

© 2010 Ligaarden et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Ligaarden et al. BMC Gastroenterology 2010, 10:16 Page 2 of 7
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MF1298 on treatment preference, satisfactory relief of classical and genetic methods, and were checked for the
symptoms and symptoms in subjects with IBS. presence of common pathogens. The capsules looked
identical and were prescribed to be taken once daily with
Methods liquid. The participants and health care providers were
Participants blinded until data entry was complete.
Participants were recruited from a hospital-based gastro-
enterology outpatient clinic and a private gastroentero- Assessments
logical practice. Subjects 18 to 75 years of age with IBS The participants were asked about treatment preference
according to the Roma II criteria and symptoms the last (the period with least symptoms) at the last visit, and
three months were eligible for inclusion. All subjects about satisfactory relief of symptoms (yes/no) at the end
had had a sigmoidoscopy or colonoscopy performed of the run-in and washout periods and at the end of each
within the last five years to exclude organic disease. week during the treatment periods. Seven gastrointestinal
Other tests to confirm the diagnosis were performed at symptoms were recorded. Abdominal pain/discomfort,
the physicians’ discretion. Pregnant and breast-feeding urgency and bloating were recorded as none, mild, mod-
women and subjects with major psychiatric, mental or erate, or severe (score 0-3); stool frequency as number of
behavioural disorders, coexisting gastrointestinal and stools per day; stool consistency according to Bristol
other disorders that might influence the symptoms, or stool scale form (score 1-7); and straining and incomplete
poor knowledge of language were excluded, as were bowel movement as yes/no (score: 1 or 0) [11]. An IBS
those who had used probiotics more than once a week sum score (score 0-15) was calculated as the sum of
in the previous three weeks or antibiotics or laxatives in these seven scores after “normalisation” of stool fre-
the previous five weeks. The study was made in accor- quency and consistency to achieve low scores for normal
dance with the Helsinki Declaration and all participants bowel habits. The “normalisation” was performed as fol-
gave written informed consent to participation before lows: Stool frequency: 0 stool/day = 1; 1-3 stools/day = 0;
enrolment. The Regional medical research ethics com- 4-5 stools/day = 1; ≥ 6 stools/day = 2. Stool consistency:
mittee, Central Norway approved the study protocol. Bristol stool scale 3-5 = 0; Bristol stool scale 2 and 6 = 1;
Bristol stool scale 1 and 7 = 2. A diarrhoea score was cal-
Study design culated as the sum of the “none normalised” scores of
The study was a randomised double blind, placebo-con- stool frequency and stool consistency. Assessment of
trolled, crossover trial with a one-week run-in period compliance was based on returned capsules.
followed by randomisation and two three-week treat- Faecal samples, frozen in Carey Blair medium (Oxoid
ment periods separated by a four-week washout period. Ltd, Basingstoke, Hampshire, UK), were analyzed for
Participants with satisfactory relief of symptoms in the detection of L. plantarum by real-time PCR using 50
run-in period were excluded from further participation. cycles. Primers: 5’-TGG ACC GCA TGG TCC GAG-3’
IBS symptoms were recorded on diary cards every eve- (F) and 5’-GTG AGC CGT TAC CCC ACC AT-3’ (R),
ning during the run-in period, during the last week of and the Taqman probe 5’-TCC CGC GGC GTA TTA-
the washout period, and the last week of the two treat- 3’, targeting a specific L. plantarum region of the con-
ment periods. Satisfactory relief of symptoms was served 16S rDNA sequence, were used in the analysis.
recorded on diary cards at the end of the run-in and Verification of specificity and control of efficiency of the
washout periods and at the end of each week during the primer-probe pair were performed according to stan-
treatment periods. At the end of the study, the partici- dard procedures, and will be documented elsewhere
pants recorded treatment preference for one of the (Rudi et al., manuscript in preparation).
treatment periods. Faecal samples were collected at the
end of the run-in, washout period, and the two treat- Outcomes
ment periods. All data were collected at the hospital The primary outcome measure was treatment prefer-
based gastroenterology outpatient clinic at Innlandet ence. Secondary outcomes were the number of weeks
Hospital Trust, Gjøvik. with satisfactory relief of symptoms and the IBS sum
The computer-based randomisation was performed at score. All comparisons were between treatment with L.
the Unit for Applied Clinical Research, Norwegian Univer- plantarum MF1298 and placebo. Presence of L. plan-
sity of Science and Technology, Trondheim, Norway. Faun tarum MF1298 was assessed by analysis of faeces as
Pharma, Norway, provided packed and numbered contain- described above. Adverse events were noted.
ers with the capsules containing 1010 CFU live, freeze-
dried L. plantarum MF 1298 or placebo according to the Statistical methods
randomisation list. The capsules were confirmed to con- The sample size calculation was based on the treatment
tain the correct number of pure L. plantarum MF1298 by preference (the proportion of participants preferring one
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treatment period to the other). Nineteen participants score between active treatment and placebo was 1.09
were required to reveal a treatment preference of 80% (1.47). The resulting proportion of subjects with a score
compared with the null hypothesis value of 50%, with difference of at least 2 in disfavour of active treatment was
80% power at a two-sided significance level of 5%. 27% (CI 9% to 44%), and the number needed to harm was
Changes within and between groups were compared 3.7 (CI 2.3 to 10.9).
with paired t test and independent t test, respectively. L. plantarum was not detected in the faeces in any of
The confidence interval and P value for treatment pre- the subjects in the run-in period, in the washout period
ference were calculated with the Wilson (score) method. (except for in one subject given active treatment in the
The difference between treatment periods as regards first period), nor in the placebo period. However, L.
number of subjects with satisfactory relief of symptoms plantarum was detected in all faecal samples at the end
for zero, one, two and three weeks was tested with the of the active treatment period, indicating that the analy-
marginal homogeneity test for matched ordinal vari- sis was targeting strain MF1298.
ables. The number needed to harm was calculated by Compliance with intake of drugs was 95%. Two parti-
the method described by Walter, with a difference ≥ 2 cipants did not return their unused drugs after the last
in the IBS sum score between L. plantarum MF1298 treatment period.
and placebo regarded as clinically significant [12]. Two- One participant had a short stay in hospital for cervi-
sided P values < 0.05 were considered statistically signif- cobrachialgia during the washout period, two weeks
icant, and the 95% confidence interval (CI) was calcu- after the end of active treatment. There was no organic
lated for the main outcomes. Modified intention-to-treat explanation and she continued in the trial. Three minor
analysis was performed. All results are given as mean adverse events were noted.
(SD) unless otherwise indicated.
Discussion
Results The study shows an unfavourable effect on symptoms in
Twenty-eight participants were included between Janu- subjects with IBS after intake of L. plantarum MF1298
ary and April 2006. Figure 1 shows the flow of partici- compared to placebo. To our knowledge, similar unfa-
pants through the trial. Sixteen participants (five males vourable effects of probiotics have not been reported in
and eleven females) with a mean age of 50 (11) years subjects with IBS. Other studies with probiotics in sub-
and BMI 24 (3) kg/m2 were available for the modified jects with IBS show either no effect or a favourable
intension-to-treat analysis; one had constipation-predo- effect [6]. The divergent results could be related to dif-
minant, nine alternating, and six diarrhoea-predominant ferent probiotic properties and health effects of the gen-
IBS. The IBS sum score at run-in was 6.21 (1.63), and era, strains, and species in use. Quigley assumed the
the duration of symptoms was 31 (17) years. Four parti- possible superiority of Bifidobacterium spp for treatment
cipants with protocol violations were included in the in IBS [13]. Bifidobacterium (B.) animalis DN-173010
modified intention-to-treat analyses; two had inade- increased stool frequency in subjects with constipation
quately completed diary cards (three and five days, at entry in a large study [14]. O’Mahony et al. compared
respectively), one used an antibiotic during the active the symptomatic effect of L. salivarius UCC4331 and B.
period, and one received supplementary treatment for infantis 35624 in subjects with IBS [15]. B. infantis
IBS in the placebo period. 35624 induced a favourable effect on IBS symptoms. In
Thirteen participants (81%; CI 57% to 93%; P = 0.012) a second study by the same researchers, the beneficial
preferred placebo to L. plantarum MF1298 treatment. effect of B. infantis 35624 was confirmed [16]. Lactoba-
The number of weeks with satisfactory relief of symptoms cilli have been evaluated in several trials with inconsis-
was statistically significantly higher in the placebo period tent results, but no deleterious effects have been
compared with the L. plantarum MF1298 period (Table 1 reported. One trial of L. reuteri ATCC 55730 showed
and 2) and the IBS sum score and the score for diarrhoea no significant effect on gastrointestinal symptoms in
were significantly higher in the period of L. plantarum patients with IBS, while another trial also in patients
MF1298 treatment than with placebo (Table1). The sub- with IBS showed no effect of L. casei strain GG [17]. L.
classes of IBS (diarrhoea predominant, constipation predo- casei strain GG in combination with other probiotics
minant, and alternating) showed the same tendency for showed a positive effect on IBS symptoms in one study
higher IBS sum scores in the period with L. plantarum by Kajander [18]. Two trials with L. plantarum 299v
MF1298 compared with placebo (data not shown). Figure showed a reduction of abdominal pain and flatulence,
2 shows the IBS sum scores during the trial by allocation while a small crossover study found no effect on symp-
group. The IBS sum score in the active period was 6.44 toms of IBS [19].
(1.81), in the placebo period 5.35 (1.77), and the correla- Reports of unfavourable effects of probiotics are rare
tion between these was 0.66. The difference in IBS sum and probiotics have until recently been regarded as safe
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Figure 1 Flow chart of the participants through the trial.

[6]. Untoward effects were reported in only three out of report was published in 2008, showing increased mortal-
185 human studies [20]. A strain of L. acidophilus ity of severe acute pancreatitis following treatment with
increased faecal protein catabolites in healthy volunteers a multispecies probiotic preparation [22].
in one study, while Saccharomyces cerevisiae increased The doses of probiotics used for the treatment of IBS
disease activity in patients with stable Crohn’s disease in in other trials vary from 2 × 108 to 2 × 1010 CFU per
one study, and in another study increased serum glucose day [7,15,19,23,24]. In a dose-finding study, the optimal
in healthy volunteers [20]. Sepsis has been reported in dose of B. infantis 35624 was 1 × 108 CFU which was
some subjects using probiotics [21]. The most alarming superior to placebo, 1 × 10 6 CFU and 1 × 10 10 CFU.

Table 1 Daily symptom scores and number of weeks with satisfactory relief of symptoms during the two treatment
periods.
Symptoms LpMF1298 Placebo Paired differences, mean (CI) Statistics
Number of weeks with satisfactory relief of symptoms 0.50 (0.89) 1.44 (1.26) -0.94 (-1.57 to -0.31) P = 0.006
Individual symptoms
Abdominal Pain/Discomfort 1.55 (0.57) 1.14 (0.55) 0.41 (0.09 to 0.73) P = 0.016
Stool frequency (normalised) 0.15 (0.18) 0.19 (0.21) -0.03 (-0.14 to 0.07) P = 0.48
Stool consistency (normalised) 0.86 (0.55) 0.61 (0.55) 0.25 (-0.12 to 0.61) P = 0.17
Urgency 1.54 (0.59) 1.12 (0.56) 0.42 (0.17 to 0.66) P = 0.002
Bloating 1.23 (0.59) 1.16 (0.68) 0.07 (-0.31 to 0.46) P = 0.69
Straining 0.51 (0.37) 0.58 (0.40) -0.07 (-0.17 to 0.03) P = 0.13
Incomplete bowel movement 0.59 (0.35) 0.54 (0.41) 0.05 (-0.06 to 0.17) P = 0.35
Sum symptoms
IBS sum score 6.44 (1.81) 5.35 (1.77) 1.09 (0.31 to 1.87) P = 0.010
Stool characteristics
Stool frequency 1.52 (0.68) 1.33 (0.58) 0.19 (-0.07 to 0.45) P = 0.15
Stool consistency 4.84 (1.51) 4.17 (1.31) 0.67 (0.20 to 1.13) P = 0.008
Diarrhoea (consistency + frequency) 6.36 (1.99) 5.50 (1.71) 0.86 (0.33 to 1.39) P = 0.004
The results are given as mean(SD).
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Table 2 Number of subjects with satisfactory relief of symptoms for 0, 1, 2, and 3 weeks in the two treatment periods.
Number of subjects with satisfactory relief of symptoms for 0, 1, 2, and 3 weeks Total no. of subjects
in the placebo period
0 week 1 week 2 weeks 3 weeks
Number of subjects 0 week 4 4 1 2 11
with satisfactory relief 1 week 1 0 0 2 3
of symptoms for 0, 1, 2, and 2 weeks 0 0 1 0 1
3 weeks
in the LpMF1298 period 3 weeks 0 0 0 1 1
Total no. of subjects 5 4 2 5 16
The difference in favor of placebo was statistically significant (P = 0.012).

However, the 1 × 1010 CFU dose was associated with of high doses, we cannot exclude that a too high dose
significant formulation problems [16]. The only previous might have contributed to the unfavourable outcome of
study in humans with L. plantarum MF1298 is a study this study.
of the survival and persistence of the strain in the gas- It has been proposed that the most potent probiotics
trointestinal tract in 17 healthy volunteers. They were may have increased pathogenicity [21]. The multispecies
given 6 × 10 9 CFU per day of L. plantarum MF1298 probiotic preparation used in the study of acute, severe
either as a freeze-dried preparation or present in 15 g pancreatitis where mortality was increased, was com-
fermented sausage. No gastrointestinal symptoms or posed of six strains [22]. These strains, selected from 69
other adverse events were spontaneously reported, but different probiotic bacteria, had better probiotic proper-
such symptoms were not systematically recorded [10]. ties in combination than the individual components. L.
The dose of 1 × 10 10 CFU L. plantarum MF1298 plantarum MF1298 had the best in vitro probiotic prop-
selected for this study was in the same order as the erties of 22 strains [8-10]. The probiotic with the best
doses used in other studies with lactobacilli [20]. Despite probiotic properties as determined in vitro is not
the lack of evidence for a reduced or detrimental effect

Figure 2 IBS sum score during the trial by allocation group. The results are given as mean with SEM.
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necessarily the best one to “confer a health benefit on fitted for stable chronic diseases [26]. Although IBS is a
the host”. fluctuating disease, Figure 2 shows that the prerequisites
The possibility of contamination of capsules by patho- for the use of this design were fulfilled. The IBS sum
gens was excluded in our study, but the presence of scores in the two periods were not significantly different.
endotoxins in the L. plantarum MF1298 and placebo The detection of L. plantarum MF1298 in one faecal
preparations was not checked. This is, however, unlikely sample at the end of the washout period indicates that
to be the reason for the unfavourable effect, because the the washout period was too short in this subject. How-
company providing the capsules is a reliable producer of ever, because the amount of L. plantarum MF1298
food supplements. detected was small and the recording of symptoms took
The serious adverse event and three minor adverse place in the last week of the three-week treatment per-
events reported were judged to be unrelated to the iod, the possibility for a carryover effect is negligible. In
treatment. summary, the crossover design turned out to be
appropriate.
Strengths and weaknesses
Probably due to the heterogeneity of the sample in Conclusions
terms of bowel habit predominance, we cannot point to The results from our study contribute to focus on the
aggravation of a specific symptom. But all outcomes, risks of using strains with probiotic properties without
both the primary outcome (treatment preference) and scientific evaluation. Not all strains with in vitro demon-
the secondary outcomes (number of weeks with satisfac- strated probiotic properties actually “confer a health
tory relief of symptoms and IBS sum score), show the benefit on the host”, and their use may even be asso-
same unfavourable direction for active treatment. This ciated with unfavourable effects. L. plantarum MF1298
strengthens the internal validity, but a type I error can- might be an unfavourable strain and this should stimu-
not be excluded. late basic research on the molecular basis of probiotic
With an IBS sum score difference of 2 chosen as clini- properties.
cally significant, the number needed to harm was 3.7. A
2-point difference on a scale with a range of 15 means
Acknowledgements
13%, and a change of 10% is often regarded as signifi- We thank Dr Ole Breder, specialist in internal medicine, for his assistance in
cant on such scales. However, the IBS sum score was recruiting participants, and Prof Knut Rudi and research scientist Birgitte
not validated for responsiveness and clinically significant Moen at Nofima Mat AS for faecal analyses.

differences. Considering that the mean IBS sum score in Author details
the run-in period was 5.97, the score difference of 2 1
Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway. 2Unit for
chosen as clinically significant might be rather high. Applied Clinical Research, Department of Cancer Research and Molecular
Medicine, Norwegian University of Science and Technology, Trondheim,
In this study the mean age of subjects was 50 years Norway. 3Nofima Mat AS, Ås, Norway.
and the proportions of subjects with diarrhoea predomi-
nant, constipation predominant, and alternating IBS Authors’ contributions
SCL, LA, KN, and PGF wrote the protocol. SCL and PGF enrolled subjects and
were 38%, 6%, and 56%, respectively. In corresponding collected data and SCL imported data. SCL, SL, and PGF performed statistical
studies the participants were younger and the propor- analyses. SCL and PGF drafted the paper, which was reviewed by the other
tions of subjects in the subgroups were more balanced authors. All authors read and approved the final manuscript.
[1,25]. The older age and the somewhat different distri- Competing interests
bution of subgroups in our study raise the question of SCL and PGF have received funding from Nofima AS (former Matforsk AS)
external validity. A beneficial effect in younger subjects, through LA and KN which in turn have received funding from Nortura BA
(former Gilde BA).
in subjects with more or less symptoms compared with
our participants, in subgroups of subjects (such as con- Received: 20 April 2009
stipation predominant), or in populations with other Accepted: 10 February 2010 Published: 10 February 2010

dietary habits and gut microflora cannot be excluded.

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