1. No category

Columbia International Publishing
Journal of Contemporary Immunology
(2015) Vol. 2 No. 1 pp. 49-58
doi:10.7726/jci.2015.1003
Research Article
Clinical Follow-up of 96 Patients Affected by Irritable Bowel
Syndrome Treated with a Novel Multi-strain Symbiotic
Renato Rossi1, Lucilla Rossi2, and Filippo Fassio2*
Received 25 February 2015; Published online 18 April 2015
© The author(s) 2015. Published with open access at www.uscip.us
Abstract
Irritable bowel syndrome (IBS) is a very common chronic functional disorder of the lower gastrointestinal
tract. It tipically includes chronic and/or recurrent abdominal pain/discomfort, which can be relieved by
defecation, and alteration of stool form or frequency.
Probiotics have been proposed as a therapeutic approach in several pathologic conditions of the
gastrointestinal tract associated with dysbiosis, including IBS.
In this observational study we investigated the efficacy of a symbiotic formulation (SynGutTM), composed of
four probiotic strains and the prebiotic inulin, in the treatment of adult subjects affected by IBS. Seventy-one
out of 96 patients reported an improvement of IBS symptoms, 19 of them reporting a substantial
improvement. Two patients discontinued the treatment after a few days because of worsening of symptoms,
but no serious adverse effects were reported. In the subgroup of patients (n = 18) who underwent faecal
calprotectin dosage, this marker of gut inflammation was significantly decreased (127,3 vs 78,6, p < 0,0001)
after two months of treatment respect to baseline. Our data confirm that this multi-strain symbiotic is well
tolerated, and support the hypothesis that this symbiotic could improve IBS symptoms.
Further studies and randomized trials with larger patient populations are needed to confirm this positive
effect with particular focus on strain-specific outcomes, usefulness of concomitant prebiotic and probiotic
supplementation, dose optimization, and other relevant manufacturing specifications.
Keywords: Irritable bowel syndrome; Treatment; Probiotics; Prebiotics; Symbiotics
1. Introduction
Irritable bowel syndrome (IBS) is a chronic functional disorder of the lower gastrointestinal tract. It
is one of the most common gastrointestinal conditions worldwide, predominantly affecting younger
people (symptoms frequently date back to childhood) and women (female/male ratio of 2:1) (Ford
__________________________________________________________________________________________________________________
*Corresponding e-mail: fassio.filippo@gmail.com
1 Vita-Salute San Raffaele University, Milan, Italy
2 Medicine Unit, ASL 3 Pistoia, Pistoia, Italy
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(2015) Vol. 2 No. 1 pp. 49-58
and Talley 2012). Its prevalence, according to a systematic review, ranges from 7% in South East
Asia to 21% in South America; in Europe, it is estimated that IBS affects around 12% of the
population (Lovell and Ford 2012).
It tipically includes chronic/recurrent abdominal pain/discomfort, which can be relieved by
defecation, and alteration of stool form or frequency. Abdominal bloating can also be associated
(Ford and Talley 2012).
A patient without lower gastrointestinal alarm symptoms (which include weight loss, abdominal
mass, rectal bleeding, heme positive stools or iron deficiency anemia, family history of colon cancer
or age >50 years with no previous colon cancer screening), who shows longstanding typical
symptoms of IBS can be diagnosed on clinical grounds with routine laboratory tests without the
need of invasive investigative techniques (Ford and Talley 2012). Symptoms-based diagnostic
criteria, known as “Rome criteria”, have been developed for this purpose and updated in 2006
(Longstreth et al. 2006) (Table 1). These criteria divide IBS patients according to the predominant
stool form: patients are classified as constipation-predominant (IBS-C), diarrhea-predominant (IBSD), or mixed (IBS-M). It must be underlined that not every patient can be classified according to
these criteria (IBS-U, unclassified) and that stool form can change over time (Longstreth et al.
2006).
Table 1 Rome criteria for diagnosis of IBS (Longstreth et al. 2006).
Diagnostic Criteria* for Irritable Bowel Syndrome
Recurrent abdominal pain or discomfort** for at least 3 days per month in the last 3 months
associated with 2 or more of the following:
1. Improvement with defecation
2. Onset associated with a change of frequency of stool
3. Onset associated with a change in form (appearance) of stool
* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
** Discomfort means an uncomfortable sensation not described as pain. In pathophysiology research
and clinical trials, a pain/discomfort frequency of al least 2 days a week during screening evaluation
for subject eligibility.
Quite often, as diagnosis remains uncertain, patients are referred to allergy clinics for a suspected
food allergy/intolerance. Sometimes, IBS symptoms begin suddenly after a gastroenteritis and is
therefore termed post-infectious IBS (PI-IBS) (Schwille-Kiuntke et al., 2011). PI-IBS has been
reported after Campylobacter, Salmonella and Shigella infections of the gastroenteric tract (Spiller
2007). Biopsy specimens of the intestinal mucosa, obtained during a Campylobacter jejuni infection,
showed an inflammatory infiltrate, with intraepithelial lymphocytes, calprotectin-positive
macrophages and increase of enterochromaffin cells which in most cases persisted for the following
six months (Spiller, 2007; Spiller et al., 2000). In these cases, it has also been documented an
increase of interleukin (IL)-1β mRNAs and of mucosal permeability.
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Recent studies have demonstrated mast cell infiltration in the colic mucosa, with degranulation in
proximity of mucosal nerve terminations. This could contribute to abdominal pain in IBS patients
(Barbara et al., 2004).
A direct association between IBS symptoms and psychological stress or psychiatric conditions has
been observed (Mayer, Craske, and Naliboff 2001); given the frequent responsiveness of symptoms
to neurotrophic therapies, IBS is often referred to as a “brain-gut disorder”, although its
pathophysiology remains uncertain (Mayer and Paulley 2008).
In a subject affected by IBS, accepting reported symptoms and distress as real while not minimizing
them as a manifestation of anxiety and somatization, usually facilitates the establishment of a
positive patient–doctor relationship and the patient’s compliance to proposed therapies (Mayer
and Paulley 2008).
Currently available drugs for the management of IBS usually target the management of individual
symptoms, such as constipation, diarrhea, and abdominal pain (Mayer and Paulley 2008).
The gut microbiota is a metabolically active complex ecosystem that plays an important role in
health and in the pathogenesis of several diseases, not limited to the gastrointestinal tract (Whelan
and Quigley 2013). Its composition varies significantly among individuals, being influenced by
several factors including age, diet, and disease (Claesson et al. 2011). An increasing number of
diseases is being associated to dysbiosis, from gastrointestinal diseases such as IBS and
inflammatory bowel disease to extra-intestinal diseases such as obesity and diabetes (Shanahan
2013).
Probiotics are live micro-organisms which produce a health benefit when administered in certain
amounts to the host (Sanders et al. 2013). Prebiotics are dietary non-digestible ingredients that
selectively stimulate the growth and activity of one or a limited number of bacterial species of the
intestinal flora. Symbiotic is a combination of probiotic and prebiotic. This formulation allows an
increase in the survival of the probiotic organisms, because it immediately makes its substrate
available for fermentation (Manzotti, Heffler, Fassio, et al. 2014; Manzotti, Heffler, and Fassio 2014).
In recent years, probiotics have been investigated in several pathologic conditions as an approach
to modulate the gastrointestinal microbiota (O’Mahony et al. 2005; Rousseaux et al. 2007; Meltzer
et al. 2004; Wald and Rakel; Astegiano et al. 2008; Mitsuyama and Sata 2008; Seksik et al. 2008;
Guandalini, Cernat, and Moscoso 2014).
In this observational study we investigated the efficacy of a symbiotic formulation (SynGutTM,
Allergy Therapeutics Italia, Milan, Italy), composed of four probiotic strains (Bifidobacterium lactis
W51, Lactobacillus acidophilus W22, Lactobacillus plantarum W21, Lactococcus lactis W19) and the
prebiotic inulin, in the treatment of adult subjects affected by IBS.
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2. Materials and Methods
The aim of this observational study was to evaluate the effect of the administration of a novel
symbiotic multi-strain mixture for the management of IBS.
An industrial combination of Bifidobacterium lactis W51 ≥ 3.3x108 UFC/sachet, Lactobacillus
acidophilus W22 ≥ 109 UFC/sachet, Lactobacillus plantarum W21 ≥ 3.3x108 UFC/sachet, Lactococcus
lactis W19 ≥ 3.3x108 UFC/sachet and inulin 0.375 gr/sachet (SynGutTM, marketed by Allergy
Therapeutics Italia, Milan, Italy; manufactured by Winclove Probiotics, Amsterdam, The
Netherlands) was used in this study. This content is in agreement with the guidelines of the Italian
Ministry of Health on probiotics (Italian Ministry of Health, 2013).
A total of 96 adult subjects (54 females, mean age 34.8 years, range) affected by IBS according to
Rome criteria (Longstreth et al. 2006), attending a single outpatient allergy clinic for a suspected
food allergy/intolerance for the period of April 2013 to December 2015 were enrolled in the study.
Each subject used 1 sachet per day for a period of two months. Patients were instructed to record
improvement, persistence and/or worsening of IBS symptoms such as diarrhea, constipation,
bloating, and abdominal pain/discomfort during the study period.
A follow-up evaluation took place at the end of the two-month period, and patients underwent an
oral interview during which they were asked if they experienced worsening, no significant
improvement, partial improvement or substantial improvement of their IBS symptoms.
In a subgroup of 18 patients, faecal calprotectin has been measured before and after symbiotic
supplementation as a marker of gut inflammation(Däbritz, Musci, and Foell 2014). Statistics were
conducted using Excel Microsoft Office.
3. Results
Of the 96 subjects evaluated, 94 took the symbiotic formulation once daily for two months, as the
schedule prescribed, without reporting any adverse effect. Subjective evaluation of IBS symptoms
after two months of SynGutTM supplementation in our study population is showed in Figure 1.
Seventy-one patients reported an improvement of IBS symptoms, with 19 of them reporting a
substantial improvement. Two patients discontinued the treatment after a few days because of
worsening of symptoms, but no serious adverse effects were reported.
In the subgroup of patients (n = 18) who underwent faecal calprotectin dosage, this marker of gut
inflammation was significantly decreased (127,3 vs 78,6, p < 0,0001) after two months of SynGut TM
supplementation in respect to the baseline (Figure 2).
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Fig. 1. Subjective evaluation of IBS symptoms after 2 months of SynGutTM treatment.
Fig. 2. Faecal calprotectin dosage at baseline and after 2 months of SynGutTM treatment.
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4. Discussion
Bacterial fermentation has been associated with many IBS symptoms such as flatulence, abdominal
distension, and bloating. Moreover, qualitative changes in the microbiota have been described in
IBS, but the contribution of the microbiota to the pathogenesis of IBS is not completely understood
(Ford, Quigley, et al. 2014).
Nonetheless, recent studies have brought a greater understanding of probiotics mechanism of
action in IBS. Some probiotics have considerable metabolic activity, including: capability of
fermentation of nondigested carbohydrates and their conversion into short-chain fatty acids,
modulation of the inflammatory response to some enteropathogens, vitamin synthesis and
deconjugation of bile salts (Whelan and Quigley 2013). It has been demonstrated that some
probiotics are capable of producing and secreting neurotransmitters and neuromodulators that
modify some gastrointestinal functions, such as motility or visceral sensation. Finally, they can also
modulate inflammation and enhance mucosal barrier function (Whelan and Quigley 2013).
Use of probiotics in patients affected by IBS has been investigated by several Authors (Moayyedi et
al. 2010)(Kajander et al. 2005)(Kim et al. 2003)(Brigidi et al. 2001)(Brenner et al. 2009)(Whorwell
et al. 2006), with encouraging results. A recent systematic review on the management of IBS by the
Task Force on the Management of Functional Bowel Disorders of the American College of
Gastroenterology (Ford, Moayyedi, et al. 2014) concluded that probiotics are effective in reducing
IBS symptoms, bloating, and flatulence. In the same review, no recommendations were made
regarding the use of prebiotics and symbiotics, due to the low number of trials available (2 for a
total of 198 patients).
Lactobacillus plantarum (L. plantarum v299) has been tested in a recent clinical trial in patients
affected by IBS; a four week treatment provided effective symptoms relief, with particular efficacy
on bloating and abdominal pain (Ducrotté, Sawant, and Jayanthi 2012).
In the context of the same disease, Lactobacillus acidophilus (L. acidophilus SDC 2012, 2013) was
associated with reduced scores for abdominal pain and discomfort after a four week treatment
(Sinn et al. 2008).
At least two clinical trials assessed the efficacy of Bifidobacterium lactis in the management of IBS.
In the first trial, B. lactis DN-173 010 was demonstrated to improve symptoms and gastrointestinal
transit in 34 patients who were treated for four weeks (Agrawal et al. 2009). In the second trial, a B.
lactis-enriched yoghurt, consumed twice daily for 8 weeks, was shown to improve symptoms in a
group of 130 patients (Min et al. 2012).
In this observational study, a four-week dietary supplementation of SynGutTM multi-strain
symbiotic, composed of Bifidobacterium lactis W51, Lactobacillus acidophilus W22, Lactobacillus
plantarum W21, Lactococcus lactis W19 and inulin, has been associated with an improvement of
symptoms, with respect to the baseline, in 71 of the 96 adult IBS patients (Figure 1). Of these, 19
reported a substantial improvement, while 52 reported a partial improvement. Twenty-three
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patients reported no improvement, while only 2 patients discontinued therapy after a few days
because of a worsening of IBS symptoms (mainly constipation). No serious adverse effects were
reported.
Faecal calprotectin dosage was performed to assess gut inflammation in a subgroup of the patients.
In these subjects, faecal calprotectin was significantly decreased after two months of SynGutTM
supplementation with respect to the baseline (Figure 2).
Our data, obtained from an observational study of 96 adult patients, confirms that the multi-strain
symbiotic, composed of Bifidobacterium lactis W51, Lactobacillus acidophilus W22, Lactobacillus
plantarum W21, Lactococcus lactis W19 and inulin, is well tolerated and supports the hypothesis
that this symbiotic improves IBS symptoms. An increase of dosage or duration of the
supplementation could be taken into account, at least for those patients who reported a partial
improvement of symptoms with the standard dosage of one sachet/day for two months. As far as
we known, possible explanation for the group of 23 patients who did not report any significant
improvement of symptoms rely on the fact that IBS is multifactorial syndrome and that changes in
the microbiota are just one of the involved pathogenic mechanisms.
The main limitations for this study include observational design without a control group and the
lack of a standardized tool and/or scoring system for subjective evaluation of symptoms.
Further studies and randomized trials with larger patient populations are needed to confirm this
positive effect with particular focus on strain-specific outcomes, usefulness of concomitant
prebiotic and probiotic supplementation, dose optimization, and other relevant manufacturing
specifications.
Conflict of Interests
Filippo Fassio is a medical consultant for Allergy Therapeutics Italia s.r.l; Renato Rossi received
consultancy fees from Allergy Therapeutics Italia s.r.l.
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