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.