Abstract

Objective: To examine the relationship between Probiotics and its efficacy in reducing the symptoms of Irritable Bowel Syndrome (IBS). Methods: A meta-analysis was conducted to evaluate the quality of the clinical trials and evidence with respect to the efficacy of probiotics for the treatment of IBS. Medline, PubMed, Google Scholar, NIH registry of clinical trials, and Cochrane Central Register of Controlled Trials were reviewed from the year 1990-2017 to identify studies that fulfilled inclusion criteria and exclusion criteria. Findings: 1650 studies were found on probiotics use in IBS. From that, only 70 studies fulfilled inclusion and exclusion criteria that were defined for this study. After assessment with Linde Internal Validity Scale, around 18 clinical trials were identified for data extraction. From those studies, it was seen that probiotic use was associated with improvement in global IBS symptoms compared to placebo [pooled relative risk (RRpooled) 0.77, 95% confidence interval (95% CI) 0.62-0.94]. Probiotics were also associated with less abdominal pain compared to placebo [RRpooled = 0.78 (0.69-0.88)]. Of the 11 species and species mixtures, Lactobacillus rhamnosus GG was the most frequent tested probiotics. None of the 18 trials reported any serious adverse events with probiotic use. Conclusion: For management of IBS, probiotics were significantly more protective and effective than placebo.

1. Introduction

Irritable bowel syndrome (IBS) is a gastrointestinal disorder that occurs with repeated pain in the abdomen and changes in the bowel movement, which may constitute diarrhoea, constipation, or both. IBS is a multifactorial disease that can be caused by autoimmune disorder, chronic inflammation or significant changes in gut microflora ¹. IBS is one of the most common gastrointestinal digestive disorders (GI) with worldwide prevalence rates generally ranging from 10-15% ^{2, 3}. Risk factors include gender (2-3 times more common in female) occurring at age around 30-50 years old ⁴, acute gastrointestinal infections (eg Campylobacter or Salmonella) and psychological factors ². Management of IBS is big challenges as there no clear therapy that can cure IBS. Most of the time, the treatment is symptomatic whereby episodes of diarrhea are best managed with loperamide, while constipation often will respond to fiber supplements. Antispasmodics or anticholinergic agents may help relieve the abdominal pain of irritable bowel syndrome. Refractory cases are often treated with tricyclic antidepressants. Newer agents such as tegaserod and ondansetron target neurotransmitter receptors in the gastrointestinal tract. However these therapies for IBS are supportive, targeting certain symptoms, but not satisfactory ⁴. While 30% of patients report a symptom resolution within one year, nearly 70% reported the symptoms repeated within five years ³.

Studies have observed modified intestinal microflora in IBS patients and elevated symptoms after enteric infection ^{5, 6}, suggesting that the recovery of intestinal microflora can be a useful therapeutic goal. A strategy to restore normal flora can be achieved by the use of probiotics ^{5, 7}. Probiotics have been defined as "living microbes that benefit health" ⁸. The group of probiotics that are most prominently studied are genera lactobacilli and bifidobacteria ^{5, 9}. These genera have an excellent safety profile in both fermented foods industry, where they have been used for many years, and, more recently, in probiotic foods. Thus, this group of probiotics have been investigated for its effectiveness in various gastrointestinal tracts diseases and disorders ¹⁰.

However, evidence from probiotic clinical trials for IBS have resulted in conflicting results and inadequate conclusions. This is due to a variety of factors: small sample sizes; variability in experiment design; probiotic tension heterogeneity, dose and duration of treatment; and patient characteristics. Thus, there were no real conclusive evidence on probiotic efficacy and adverse events. To address this deficit, we conducted a meta-analysis of randomized, controlled, placebo-controlled and double-blind trials published as full articles or abstract meetings for: ¹ appraise the component and aspect of random clinical trials in this area and ² orchestrate evidence across efficacy studies probiotics for IBS.

PubMed, Google Scholar, and Medline was scouted from 1990-2017 for articles globally written in the English language. Two online based clinical trial registers were searched: Cochrane Central Register of Controlled Trials (www.cochrane.org) and National Institutes of Health (www.clinicaltrials.gov). Secondary and hand searches of reference lists, other studies cross-indexed by authors, reviews, commentaries, books and meeting abstracts also were performed. Search item included: irritable bowel syndrome, probiotics, placebo-controlled, randomized controlled trials, Manning criteria, Rome criteria, and double blinding. Search strategies were broad-based initially, then narrowed to the disease of interest to increase the search network. Participant-Intervention-Comparator-Outcomes (PICO) Framework was used as a baseline for inclusion and exclusion criteria and standardized data extraction. Abstracts of all citations and retrieved studies were reviewed and rated for inclusion. Full articles were retrieved if specific treatments were given for IBS. In some cases, only published abstracts from meetings were available. Published abstracts from meetings were included to lessen the potential for publication bias due to failure to publish negative findings.

This meta-analysis was conducted to deduce the overall efficacy of IBS by comparing a common outcome in treated patients with a control group. Inclusion criteria comprises of randomized, controlled, blinded efficacy trials in humans published as full articles or meeting abstracts in peer-reviewed journals. Exclusion criteria includes pre-clinical studies, safety studies, case reports or case series, reviews, duplicate reports, trials of unspecified treatments, uncontrolled studies, prebiotic treatments only, presence of antibiotics or insufficient data in article.

Studies that met the inclusion criteria were graded for quality using the Linde Internal Validity Scale (LIVS), which includes the following six items: method of allocation to groups, concealment of allocation, baseline comparability of intervention and placebo groups, blinding of patients, blinding of evaluators, and intention to treat/handling of withdrawals and drop-outs. Authors were contacted for further information if there were no information provided for an item or if it was unclear. If the given information was still insufficient, then zero points were given to that item. Total possible scores range from 0 to 6. All trials included in the meta-analysis had a total quality score of 3 or more and those with a score less than 3 were excluded. Two independent reviewers independently assessed inclusion criteria and quality of the trials. Inconsistencies were resolved by discussion.

Studies were considered to have adhered to intention-to-treat principles if all subjects who were randomized were analysed with the group to which they were originally assigned and if exclusions were primarily due to patient withdrawal or loss to follow-up. If the investigators excluded patients after randomization due to use of non-study medications or antibiotics, noncompliance with assigned treatment, or non-response to therapy, the analysis was not considered to be ITT.

Information on study design, methods, interventions, outcomes, adverse effects and treatments was extracted from each article using a standardized extraction table. When necessary, authors were contacted for data not reported in the original article.

We documented the types of outcomes for trials involving IBS and probiotic in the literature. Outcomes were reported by different studies as either the proportion of subjects reporting improvement or the change in symptom scores from baseline. We did not attempt to synthesize results from studies reporting changes in symptom scores because of numerous challenges including heterogeneity in scales and scoring systems across studies and inconsistent or incomplete reporting of numeric symptom scores. Thus, we selected the proportion of subjects with improvement in global IBS symptoms as the primary outcome for this meta-analysis. Secondary outcomes included the proportion of subjects with improvement in one of three common IBS symptoms: abdominal pain, bloating or flatulence. Documentation of the outcome was based on subject self-report and/or clinician assessment.

2. Meta Analysis Method

To estimate pooled relative risks across studies, we first evaluated heterogeneity between and within trials using s forest plot. The relative risks of responding to probiotic therapy were pooled using a random-effects model if significant heterogeneity was found or a fixed-effects model if the studies were homogenous. (The forest plot is able to demonstrate the degree to which data from multiple studies observing the same effect overlap with one another. Results that fail to overlap well are termed heterogeneous and is referred to as the heterogeneity of the data-such data is less conclusive. If the results are similar between various studies, the data is said to be homogeneous, and the tendency is for these data to be more conclusive.) ¹¹. P values less than 0.05 were considered significant. Data collected were tabulated and analysed using the Statistical Package for the Social Sciences (SPSS) version 20.0.

Because there is heterogeneity throughout the study, we examine the design features of the hypotheses that we hypothesize may be associated with probiotic prolapse on placebo. This analysis examines the results for major yield variables, the reduction of global IBS symptoms. We classify the study as a probiotic option if RR was unpooled 0.67 or less. The study by Whorwell ¹² et al encompasses 3 different doses of probiotics but is considered a single study for the purposes of this analysis. Since one of the 3 arm shows the probiotic support results, we classify this study as a probiotic choice. Characteristics examined as possible predictors include sample size, LIVS quality score, female subject proportion, probiotic dose, treatment duration, 20% shift, ITT analysis and proprietary (commercial) and non-feasible product use. Forest plot also show strong indication probiotics are better than placebo in terms of reducing global IBS symptoms.

The literature search yielded 1650 citations on probiotics, of which 401 addressed probiotics and IBS. Based on review of abstracts, 70 were selected for detailed screening.

The study selection process is shown in a QUOROM (Quality of Reporting of Meta-analysis) flow diagram (Figure 1) ¹³. Overall, 52 studies that were screened failed to meet 1 or more of the inclusion criteria: 24 (46%) quality score<3, 2 (0.03%) meta-analysis study, 11 (21%) combine with antibiotics, 13 (25%) not related with IBS study or other disease. A total of 18 articles met inclusion criteria and provided data on probiotic treatment arms for 1515 patients with IBS (Table 1). An additional seven trials were excluded after article retrieval and screening for issues related to quality and/or study design (Table 2).

The study quality of 18 studies were assessed using LIVS quality score >3.0 were included (Table 3). The median quality score was 4 (range 3-6). 0.5 marks were given to unclear data. All studies gave treatment allocation. Blinding for both patient and evaluators information were provided in all studies. 3 studies did not provide randomization method, 2 studies did not state baseline comparison, and 4 studies did not perform intention-to-treat analysis and/or did not fully describe withdrawals. Only three studies clearly documented their adherence to intention-to-treat principles. All the 5 studies did excluded participants who used prohibited/non-study medications, including antibiotics, during the treatment phase while 5 studies excluded subjects who demonstrated poor compliance with study medications. 2 studies reported that subjects either dropped out or were excluded due to inadequate response to treatment.

3. Probiotic Strain

Lactobacillus rhamnosus GG was the most frequent tested probiotics. It was tested in four trials. Lactobacillus plantarum and Bifido. infitis were both tested in three trials.

The outcomes assessed and reported varied widely across 18 studies. The effect on global IBS symptoms was reported in 66.7% of studies and was the primary outcome for 12/18 of studies. Effects on abdominal pain were reported by all studies, but only 4 studies (22.22%) used this as an outcome for primary measure.

Other symptoms were less consistently assessed (e. g. flatulence, 10/18 studies; stool frequency 13/18 mucus in stool, 4/18 studies; bloating, 15/18 studies).4 studies collected some measure of quality of life. 6 studies reported data for 3 or more symptoms or outcomes without specifying a primary outcome. Most studies reported in improvement in subjects, while others reported a change in numeric score since baseline. There were a variety of scales used to measure the severity of IBS symptoms across all studies, hence making it challenging to compare results across studies. Likert scales were used by 3 studies, and specific validated scales were used by several studies Gastrointestinal Symptom Rating Scale (GSRS) and IBS Severity Scoring System (IBS-SSS). Several studies used their own study-specific scale or scoring system. Often it was unclear whether this scale had been validated.

Although many studies assessed a wide range of IBS symptom, few reported detailed results across the spectrum of symptoms. For instance, only 5 out of 10 studies reported that they had collected data on flatulence and only 3 of 12 reporting they had collected data on stool consistency reported any such data in their paper.

The primary outcome selected for this analysis was the proportion of patients in each group with global IBS symptoms by the end of treatment, with ‘responders’ being a dichotomous variable defined by study investigators. Of the 18 treatment arms, all 18 (100%) had evaluable data for this outcome.

The forest plot, weighted on sample size, is shown in Figure 2. Compared to placebo, probiotics were significantly protective (less global IBS symptoms compared to placebo at the end of the study) [pooled relative risk (RR pooled)].

Nine studies (50%) stated that no serious adverse reaction was noted but failed but failed to provide any information on how adverse events were ascertained or what types of reactions were considered (Table 6). Six studies (33%) did not provide any information on adverse effects of the intervention. All the papers also did not state regarding any serious illness or death during the studies were conducted. Two trials (11%) provided minimal data on adverse reactions. The reactions that were mentioned in one of the study were dyspepsia and headache where else the other study did not mention the symptoms of the adverse effects.

We identified 18 clinical trials that met inclusion criteria and provided relevant information about the efficacy of probiotics for IBS symptoms. These trials included 18 probiotic treatment arms and 1515 subjects. Trials were generally small and of short duration and had moderate quality. Overall, probiotic use was associated with less likelihood of global IBS symptoms compared to placebo.

4. Strength and Limitations

A comprehensive review of the literature was made to minimize the likelihood of bias by including a wider range of studies and studies that only met the criteria. PICO formatted question scores and data extraction were performed by two reviewers independently using standardized templates and differences were resolved by discussions. GRADE criteria and internal validity was also used determine the quality of the information in these articles. Studies of poor quality with usage of antibiotics were excluded. Primary outcome (global improvement in IBS symptoms) that is clinically relevant and of great concern to IBS patients were selected.

Heterogeneity was another important limitation of the published literature, including heterogeneity in the strain and dose of probiotic (which prevented analysis of effects of specific strains); sample size (smaller studies resulted in low power to detect effects in individual studies); duration of treatment and follow-up (short trials do not allow adequate follow-up given the chronic relapsing nature of IBS); and in the assessment and reporting of outcomes. All these sources of heterogeneity made it difficult to combine data from all twenty studies. Another important problem is the lack of systematic data collection and reporting about adverse effects. As a result, it is difficult to be sure that the probiotics studied have been adequately evaluated for safety.

This systematic review showcases the possibilities for the involvement of probiotics as a treatment or preventive measure for IBS. With that being said, there is a need for a larger study to be conducted, a more specified type of probiotic stain preferably with longer duration of treatments and a smaller gap in between follow ups. Future studies should consider a better standardization tool to measure outcome. It would also be recommended that future studies examine overall relief of IBS symptom as an outcome.

Though the findings indicate that probiotics may be useful in the treatment of IBS, more research should be conducted before usage in the clinical practice. The pooled relative risks reported here are based on studies with significant methodological limitations, and bias cannot be ruled out as the explanation for these positive findings. Since we did not find any evidence of significant adverse effects from these treatments, and given the lack of available conventional treatments, clinicians should strongly consider discussing the evidence of benefits and risks of probiotics with their patients with IBS No universal quality assurance programs exist to ensure that commercial products contain the probiotic strain and concentration that are claimed, or to ensure the absence of contamination that could pose risks to consumers.

5. Conclusion

In conclusion, our meta-analysis containing 18 studies with 612 patients shows that in general, probiotics are beneficial in treatment of IBS. 18 out of the 18 studies (89%) showed that probiotics helped in symptom reduction of IBS in a duration between two up to twenty-four weeks predominantly the symptoms of abdominal pain and bloating. Future studies particularly larger studies with a more specific strain of probiotics as well as dosage need to be conducted to measure its efficacy.

Reference