A systematic review and meta-analysis: probiotics in the treatment of irritable bowel syndrome

Irritable Bowel Syndrome (IBS) is a common chronic gastrointestinal disorder, characterized by abdominal pain, bowel dysfunction and bloating in the absence of structural abnormality [1]. In the West, about 15% of the population is affected at some time during their life, and it is more common in females [2]. IBS is also recognized in children [3]. The burden of illness associated with IBS is considerable. A UK study [4, 5] found that IBS sufferers reported substantially lower quality of life scores (as measured by the SF36 health survey questionnaire). They had more time off work and used healthcare more often. IBS accounts for 12% of visits to primary care physicians and 28% of visits to gastroenterologists [6, 7].

Patients with IBS may be classified by their predominant bowel habit: diarrhoea-predominant IBS, constipation-predominant IBS, or IBS with alternating bowel movements [8]. Diagnostic criteria such as Manning, Rome I, II and III have proved useful for research purposes by ensuring homogeneity of patient populations, though their applicability in clinical practice is limited and they are seldom used [1].

The evidence for efficacy of most drug therapies in the treatment of IBS is weak [9]. A popular alternative is probiotics, which have been used in several conditions [10, 11] including IBS. Probiotics are live microbial food supplements. Examples include lactic acid bacteria and bifidobacteria which are widely used in yogurts and other dairy products. They retain viability during storage and survive passage through the stomach and small bowel [12]. The colonic microflora normally presents a barrier to invading organisms. However, when the integrity of the microbiota is impaired through illness, stress, antibiotics treatment, physiological alterations in the gut, or change in diet, pathogens may become established [12]. Bifidobactetrium resist the colonization of pathogens in the large bowel [13]. We aimed to assess whether probiotics alleviated symptoms in patients with IBS.

We identified 497 citations, 178 of which were duplicate records and were therefore excluded. Two authors screened 319 abstracts and identified potentially relevant articles. Twenty two retrieved articles were independently reviewed for inclusion and exclusion criteria. The reviewers were not masked to any aspect of the studies (e.g. journal type, author's names etc). On further analysis of retrieved articles, 8 trials were excluded for being non-controlled studies. Therefore, a total of 14 articles met the inclusion criteria [17‐30] (figure. 1). As a number of studies included symptoms of flatulence this was included in the analysis. For example, in Gade's study [18] published in 1989, the IBS definition of constipation and/or diarrhoea, abdominal pain, meteorism, borborygmus and flatulence was used.

Trials were from USA (three), Poland (two), Ireland (two), UK (one) France (one), Israel (one), Finland (one), Italy (one), Sweden (one) and Denmark (one). One trial included women only [30]; the remainder included female and male participants with the majority being women (table 1). Two studies included children [17, 19], though Bausserman's study [17] included an age range of 6–20 years. Trials varied in relation to the type, dose and strengths of probiotic(s) used. Number of probiotics varied from one to multiple, e.g. VSL#3 (contains 8 different bacterial strains). Three studies included more than one arm in the intervention group[27, 29, 30] (table 1).

In six studies the length of treatment was four weeks, in three studies eight weeks, in two studies six weeks and in two studies six months (table 1). One study was a cross over of 20 weeks (two weeks wash in and washout) [28]. Diagnostic criteria for IBS used were as follows: ten trials used Rome II, two trials used Rome, and one trial used Manning. However, in Gade's study [18] published in 1989, the IBS definition of constipation and/or diarrhoea, abdominal pain, meteorism, borborygmus and flatulence was used. One study included constipation predominant IBS [20]; one included diarrhea-predominant symptom [22].

Measured outcomes varied, from overall gastrointestinal (GI) function to individual symptoms such as abdominal pain, flatulence and bloating. Four studies included quality of life using different questionnaires: Kajander et al [21] used RAND 36 item health survey [31] Guyonnet et al [20] used FDDQL questionnaire [32]. Whorwell [30] and O'Mahony [27] used IBS specific quality of life questionnaire [33].

In patients with IBS, probiotics showed a modest improvement in overall symptoms, using both dichotomous and continuous data. However, it is interesting to note that neither of the two studies [20, 30] which contributed most of the weight in the analysis, were statistically significant. It is likely that the two Bifidobacterium strains used in these two studies may have been ineffective. Based on average control event rates the Numbers Needed to Treat is estimated to be between 9 and 21 to have 1 patient improve. By removing studies with quality scores less than four, the results remained stable to sensitivity analysis.

For individual symptoms the results differed between the pooled dichotomous and pooled continuous data. Using dichotomous data probiotics also improved symptoms of abdominal pain, flatulence and bloating. However using continuous data, the improvement in these symptoms were not statistically significant. One study used a cross-over design [28]. The data presented allowed us to include it for dichotomous outcomes (bloating and abdominal pain). Excluding this study did not affect the findings for abdominal pain, but rendered the effect on bloating non-statistically significant. The heterogeneity was also high for symptoms of abdominal pain and flatulence. This is likely to be due to use of different scales in different studies.

Other therapies for IBS include antispasmodics, antidiarrhoeal agents, laxatives and antidepressants [1], but overall the evidence for efficacy of these existing drug therapies for IBS is weak [9]. Probiotics have been used previously in different conditions [10, 11]. On entering the gastrointestinal tract, probiotics are unaffected by acid, bile salts and proteolytic enzymes. In the small bowel they multiply and live on the surface of epithelial cells. Their main beneficial effect is to act as a barrier to harmful organisms by adherence and production of substances that have an antibiotic effect, as well as stimulating immune processes in the host [11]. In the colon they have a major role of fermenting undigested carbohydrates and soluble dietary fibre, producing short-chain fatty acids [11]. Probiotics may change the flora, effecting the fermentation process, so less gases are produced that may cause symptoms, or they may interfere with the growth or harmful effect of producing diarrhoea, or they may stimulate the immune process to prevent some unidentified antigen response [34].

As there were inconsistencies in the reporting of adverse events, it was not possible to adequately estimate the frequency of the adverse events. However, nine studies reported that there were no adverse events. Clearer reporting of adverse events in future studies would be helpful. In addition, a review of probiotics in Crohn's Disease found they were generally well tolerated and few side effects were reported. The reported side effects included bloating, diarrhoea, constipation, nausea and epigastric pain [35]. Occasionally probiotics can cause infections in immunocompromised individuals [36, 37].

One of the limitations of this review is exclusion of non-English language publications which may lead to an over-representation of positive studies. Other limitations include the clinical and statistical heterogeneity between studies. For example, the age and gender of the study populations varied as did the length of follow up and dosage and type of probiotics used. There was also variation in the definition of overall symptoms in different studies: two studies included only subcategories of the IBS population (constipation – [20] or diarrhea-predominant participants [22]. Studies varied in relation to the length of treatment, number, type, dosage and strengths of probiotic(s) used. Whilst some studies used one probiotic, others used a combination e.g. VSL#3 which contains a cocktail of 8 different bacterial strains. In three studies more than one treatment arm was used [27, 29, 30]. Whorwell et al [30] studied a probiotic (B. infantis 35624) at three different strengths of 10⁶, 10⁸, 10¹⁰ against placebo. The study found B. infantis 35624 at a dosage level of 10⁸ cfu is effective in reducing the symptoms of IBS at four weeks. They suggested that this may be because the highest dose formulation 1 × 10¹⁰ cfu, "coagulated" into a firm glue like mass. As Whorwell's study had more than one intervention arm, in our meta-analysis a conservative estimate (i.e. the intervention with the least effect) was used. The majority of trials [11] lasted eight weeks or less. This is important in a condition that is chronic and usually intermittent. Therefore, longer term studies would be more helpful. In some trials, we could not include data as they were incomplete or missing despite writing to authors. Specifically, trials should report individual outcomes for IBS. These should include important symptoms such as urgency and difficult defecation. We could not carry out subgroup analysis based on sex and probiotics used. Problems due to different scales used occurred for reporting of continuous outcomes. For instance, some studies used Likert scales ranging from 0 to 6 whereas others used visual analogue scales and face pain scales. The use of different scales may explain high heterogeneity observed in pooling of continuous data for abdominal pain and flatulence. High heterogeneity, due to small number of participants, may also have occurred in the case of subgroup analysis of children. As the number of studies was small it was difficult to draw conclusions on publication bias. For overall assessment with the largest number of studies (seven studies), only one study with negative result was reported, raising the possibility that small studies with negative findings may not have reached publication. Finally, in this review flatulence was included despite not strictly being part of the IBS criteria. This was due to a number of early studies including flatulence as a symptom [18]. Our meta-analysis was carried out before the publication of a study by Kajander et al [38] published in 2008. This randomized placebo controlled trial using multispecies probiotic further strengthens our findings.

Probiotics may have a role in alleviating some of the symptoms of IBS, a condition for which currently evidence of efficacy of drug therapies is weak. Longer term trials are recommended as IBS is a condition that is chronic and usually intermittent. However, further research should focus on the type, optimal dose of probiotics and the subgroups of patients who are likely to benefit the most.