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Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) in the treatment of irritable bowel syndrome: a multicentre, randomised, double-blind, placebo-controlled clinical trial

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Summary

Background

Bifidobacterium bifidum MIMBb75 is one of a few probiotic strains that have been shown to be effective in the treatment of irritable bowel syndrome (IBS) and its symptoms. Non-viable strains might have advantages over viable bacteria for product stability and standardisation, as well as for tolerability because safety concerns have been raised for specific patient groups who are susceptible to infection. We aimed to assess the efficacy of non-viable, heat-inactivated (HI) B bifidum MIMBb75 (SYN-HI-001) in the treatment of IBS and its symptoms.

Methods

We did a double-blind, placebo-controlled trial in which patients with IBS were recruited from 20 study sites in Germany and randomly assigned to receive either two placebo capsules or two capsules with a combined total of 1 × 109 non-viable B bifidum HI-MIMBb75 cells to be taken orally once a day for 8 weeks. Eligible patients were diagnosed with IBS according to Rome III criteria and had abdominal pain (≥4 on an 11-point numerical rating scale) on at least 2 days during a 2-week run-in phase. Patients with chronic inflammatory bowel diseases, systemic diseases, cancer, autoimmune diseases, with an intake of antipsychotic medications 3 months before study start, or with an intake of systemic corticosteroids within 1 month before study start were excluded. Randomisation was in a 1:1 ratio according to a computer-generated blocked list. Patients, investigators, clinical monitors, project managers, and statisticians were masked to the randomisation. The primary composite endpoint was the combination of at least 30% improvement of abdominal pain and adequate relief of overall IBS symptoms being fulfilled in at least 4 of 8 weeks during treatment. Analysis of the primary endpoint included all randomly assigned patients receiving at least one dose of study medication and who had no severe protocol violation. Safety analysis included all patients who had taken at least one dose of the study medication and was based on frequency and severity of adverse events, laboratory evaluation, and global assessment of tolerability. This trial is registered with the ISRCTN registry, ISRCTN14066467, and is completed: the results shown here represent the final analysis.

Findings

Patients were screened between April 15, 2016, and Feb 3, 2017, and 443 patients were allocated to the placebo group (n=222) or the B bifidum HI-MIMBb75 group (n=221). The composite primary endpoint was reached by 74 (34%) of 221 patients in the B bifidum HI-MIMBb75 group compared with 43 (19%) of 222 in the placebo group (risk ratio 1·7, 95% CI 1·3–2·4; p=0·0007). No serious adverse events occurred in the B bifidum HI-MIMBb75 group; seven adverse events suspected to be related to the study product were reported in the B bifidum HI-MIMBb75 group as were eight in the placebo group. No deaths were reported in this study. The most common reported adverse event with a suspected relationship to the study product was abdominal pain, which was reported in two (<1%) patients in the B bifidum HI-MIMBb75 group and one (<1%) in the placebo group. Tolerability was rated as very good or good by 200 (91%) patients in the B bifidum HI-MIMBb75 group compared with 191 (86%) in the placebo group.

Interpretation

This study shows that B bifidum HI-MIMBb75 substantially alleviates IBS and its symptoms in a real-life setting. These results indicate that specific beneficial bacterial effects are mediated independently of cell viability.

Funding

Synformulas.

Introduction

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, with an estimated prevalence of up to 15% in the European population.1, 2 This disease is characterised by recurrent episodes of gastrointestinal symptoms, such as abdominal pain, flatulence, bloating, diarrhoea, and constipation, and by the absence of relevant abnormal findings in routine diagnostic tests. In the absence of distinct biomarkers, IBS is typically diagnosed on the basis of symptom criteria, such as the Rome IV or Rome III criteria.3, 4 Patients with IBS have a distinct impairment of their quality of life, which has been found to be even worse than in patients with other chronic diseases.5

Research in context

Evidence before this study

We searched PubMed for the terms “bacteria”, “probiotics”, “non-viable”, “inactivated”, and “irritable bowel syndrome” for relevant published randomised placebo-controlled studies and meta-analyses investigating the efficacy of viable and non-viable bacterial strains in irritable bowel syndrome (IBS), up to July 31, 2019. We did not use any language restrictions. We found that the efficacy of viable probiotic strains is highly strain-specific and only a few strains have been shown to significantly alleviate IBS symptoms. Bifidobacterium bifidum MIMBb75 has been particularly intriguing because of its therapeutic efficacy. Although generally, the use of viable probiotic strains is considered to be safe, severe infections or even septic complications have been reported rarely, particularly in severely ill or immunocompromised patients. Therefore, non-viable bacterial strains could be a safe alternative and have further advantages over viable bacteria with regard to product stability and standardisation, which could be particularly relevant for patients who are travelling or who are living in warm and humid climate zones. However, to our knowledge, there have been no placebo-controlled studies investigating the efficacy of non-viable bacteria in IBS compared with placebo.

Added value of this study

To our knowledge, this is the first time that the efficacy and safety of a non-viable bacterial strain has been investigated in a placebo-controlled study for the treatment of IBS. The findings show that non-viable, heat-inactivated (HI) B bifidum MIMBb75 (SYN-HI-001) improves IBS and its symptoms significantly more than does placebo, and thus are the first demonstration of substantial and clinically relevant efficacy of non-viable bacteria in the treatment of IBS. The treatment was not associated with any safety risk and the tolerability was rated very good.

Implications of all the available evidence

These results show that some beneficial bacterial effects are mediated independent of cell viability and can be preserved in non-viable bacterial preparations. B bifidum HI-MIMBb75 has been rendered non-viable but still morphologically intact, and its strong adhesive properties have been preserved (and even increased). In this study, B bifidum MIMBb75 in its non-viable form appears to reach or even to surpass the effects observed in response to the corresponding viable form. Because of these promising results, we expect more research will be done to understand the applications of non-viable bacterial strains in IBS and potentially in other gastroenterological diseases.

The cause of IBS has not yet been fully elucidated. However, several colonic biopsy studies show that the intestinal barrier is altered in patients with IBS, with statistically significantly higher permeability than in healthy individuals.6, 7, 8 It is thought that an impaired intestinal barrier facilitates the translocation of intraluminal content, including facultative pathogenic bacteria, causing alterations of mucosal enteric neural functions, leading to IBS and its symptoms.6, 7, 8, 9 Accordingly, enhancing the gut barrier is a useful treatment approach for patients with IBS.

Some probiotic strains can adhere well to epithelial cells and strengthen intestinal barrier function, providing an explanation for the efficacy of at least some probiotics in the treatment of IBS.10, 11, 12 Lactobacillus rhamnosus GG has been shown to accelerate the maturation of the intestinal barrier in an animal model, and Saccharomyces bouldarii has been shown to decrease intestinal permeability in patients with Crohn's disease.10 Furthermore, cytokine-induced epithelial barrier dysfunction in human epithelial cells can be prevented by Lactobacillus casei and by a combination of Streptococcus thermophilus and Lactobacillus acidophilus.11, 12 The potential of Bifidobacterium bifidum MIMBb75 as a treatment for IBS has been particularly intriguing because of its therapeutic efficacy in improving symptoms of IBS and simultaneously improving quality of life for patients.9 Furthermore, B bifidum MIMBb75 has been shown to exert strong adhesion to human intestinal epithelial Caco-2 cells, with an observed adhesion index markedly exceeding that of other commercial probiotics.9, 13 It has been suggested that the clinical effects of B bifidum MIMBb75 involve, and are likely to be mediated by, its marked mucosal adhesive properties.9, 13 Adhesion of Bifidobacteria strains such as B bifidum MIMBb75 to epithelial cells depends mainly on the cell surface hydrophobicity and occurs by attractive physical forces between the hydrophobic cell surface and the epithelial cells—so-called hydrophobic interactions.14 Notably, following gentle heat inactivation, the B bifidum strain heat-inactivated (HI)-MIMBb75 (SYN-HI-001) has been rendered non-viable but still morphologically intact, and has preserved (and even increased) its Caco-2 cell-adhesive properties (unpublished). The efficacy of various bacterial strains for the treatment of IBS is highly strain-specific and even closely related strains might differ substantially in their efficacy and related properties such as adhesion to Caco-2 cells.15, 16, 17, 18 Strains such as B bifidum MIMBb75 or Bacillus coagulans MTCC5856 have been found to be efficacious in IBS.9, 19 Viable B bifidum MIMBb75 has been shown to effectively alleviate IBS and its symptoms such as abdominal pain, discomfort, distension, and bloating in a placebo-controlled trial.9 In patients with diarrhoea-predominant IBS, supplementation of B coagulans MTCC5856 together with standard care for this condition significantly decreased clinical symptoms (bloating, vomiting, diarrhoea, abdominal pain, and stool frequency) compared with placebo.19 However, several other multistrain and monostrain preparations were found to be ineffective in IBS.20, 21

Non-viable bacteria might have advantages over some living probiotics because the use of non-viable bacteria is associated with better standardisation, greater stability, and improved safety.22 However, inactivation of bacteria has repeatedly been found to decrease their efficacy.23, 24, 25 For example, Tsuchiya and colleagues25 reported that the viable but not the non-viable form of a specific strain composition could alleviate IBS symptoms. So far, clinical effects of non-viable bacteria on IBS symptoms have not been shown in controlled trials.26 Therefore, we aimed to assess the efficacy of non-viable B bifidum HI-MIMBb75 in IBS compared with placebo.

Section snippets

Study design

This was a large-scale, multicentre, double-blind, randomised, placebo-controlled, two-arm interventional clinical study. Participants were recruited in 20 primary care and referral centres in Germany (see appendix p 1 for full list of participating centres). The study protocol was approved by the Hamburg State Ethics Committee before the study started and the trial was done in compliance with the Declaration of Helsinki and the Guideline for Good Clinical Practice (CPMP/ICH/135/95).

Participants

Results

507 patients were assessed for eligibility from April 15, 2016, to Feb 3, 2017, and 443 patients were enrolled and randomly assigned to receive either placebo (n=222) or B bifidum HI-MIMBb75 (n=221). All 443 patients were included in the primary and safety analyses (intention-to-treat [ITT] population). The median follow-up for the ITT population was 71 days (IQR 70–74). 66 patients (35 in the placebo group and 31 in the B bifidum HI-MIMBb75 group) dropped out (13 from the placebo group and 14

Discussion

In previous studies, the viable strain of B bifidum MIMBb75 has been shown to significantly alleviate IBS and its symptoms. However, it was unclear whether the non-viable form of B bifidum MIMBb75 also has a substantial effect on IBS. This randomised, placebo-controlled study shows that B bifidum HI-MIMBb75 significantly reduces the entire symptom spectrum of IBS of all subtypes, and thus, to the best of our knowledge, is the first demonstration of substantial efficacy of a non-viable bacterial

Data sharing

Besides the data presented in the Results and appendix, the authors have not made arrangements to share further supporting data.

References (34)

  • T Piche et al.

    Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators

    Gut

    (2009)
  • M Vivinus-Nébot et al.

    Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells

    Am J Gastroenterol

    (2012)
  • JK Marshall et al.

    Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario

    Aliment Pharmacol Ther

    (2004)
  • S Guglielmetti et al.

    Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life—a double-blind, placebo-controlled study

    Aliment Pharmacol Ther

    (2011)
  • LR Lopetuso et al.

    The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors

    Eur Rev Med Pharmacol Sci

    (2015)
  • CS Eun et al.

    Lactobacillus casei prevents impaired barrier function in intestinal epithelial cells

    APMIS

    (2011)
  • S Guglielmetti et al.

    Implication of an outer surface lipoprotein in adhesion of Bifidobacterium bifidum to Caco-2 cells

    Appl Environ Microbiol

    (2008)
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