Systematic Review With Meta-analysis

The Efficacy of Prebiotics, Probiotics, Synbiotics and Antibiotics in Irritable Bowel Syndrome

Alexander C. Ford; Lucinda A. Harris; Brian E. Lacy; Eamonn M. M. Quigley; Paul Moayyedi


Aliment Pharmacol Ther. 2018;48(10):1044-1060. 

In This Article

Materials and Methods

Search Strategy and Study Selection

We updated our previous systematic review and meta-analysis examining the efficacy of prebiotics, probiotics and synbiotics in IBS,[23] searching the medical literature using MEDLINE (1946 to July 2017), EMBASE and EMBASE Classic (1947 to July 2017), and the Cochrane Central Register of Controlled Trials. Randomised placebo-controlled trials examining the effect of at least 7 days of prebiotics, probiotics, synbiotics or antibiotics in adult patients (over the age of 16 years) with IBS were eligible for inclusion (Table 1), including the first period of cross-over RCTs, prior to cross-over to the second treatment. The diagnosis of IBS could be based on either a physician's opinion or symptom-based diagnostic criteria, supplemented by the results of investigations to exclude organic disease, where studies deemed this necessary.

Subjects were required to be followed up for at least 1 week, and studies had to report response to therapy as either a dichotomous endpoint or via continuous data. Dichotomous assessment could be in the form of either an assessment of global symptom cure or improvement, or abdominal pain cure or improvement, after completion of therapy. Preferably, this information was reported by the patient, but if this was not recorded then data either as documented by the investigator or via questionnaire were accepted. Continuous data of interest were the effect of therapy on global and individual IBS symptom scores at study end. Where studies did not report these types of dichotomous or continuous data, but were otherwise eligible for inclusion in the systematic review, we attempted to contact the original investigators in order to obtain further information.

The literature search was performed as part of a broader exercise to inform the update of the ACG monograph on the management of IBS.[26] Specifically, studies on IBS were identified with the terms irritable bowel syndrome and functional diseases, colon (both as medical subject heading (MeSH) and free text terms), and IBS, spastic colon, irritable colon, or functional adj5 bowel (as free text terms). These were combined using the set operator AND with studies identified with the terms: Saccharomyces, Lactobacillus, Bifidobacterium, Escherichia coli, probiotics, prebiotics, inulin, fructooligosaccharide, fructo-oligosaccharide, galactooligosaccharide, galacto-oligosaccharide, synbiotics, anti-bacterial agents, penicillins, cephalosporins, rifamycins, quinolones, nitroimidazoles, tetracycline, doxycycline, amoxicillin, ciprofloxacin, metronidazole, or tinidazole (both as MeSH and free text terms), or the following free text terms: antibiotic, or rifaximin.

There were no language restrictions and abstracts of the papers identified by the initial search were evaluated by the lead reviewer for appropriateness to the study question. All potentially relevant papers were obtained and evaluated in detail, and foreign language papers were translated where necessary. We hand-searched abstract books of conference proceedings (Digestive Diseases Week, American College of Gastroenterology, and United European Gastroenterology Week) between 2001 and 2017 in order to identify potentially eligible studies published only in abstract form. We then used the bibliographies of all identified relevant studies to perform a recursive search of the literature. Two reviewers assessed all identified articles independently, using pre-designed eligibility forms, according to the prospectively defined eligibility criteria, with any disagreements resolved by consensus. The systematic review was not registered a priori with PROSPERO.

Outcome Assessment

The primary outcomes assessed were the effects of prebiotics, probiotics, synbiotics or antibiotics compared with placebo on global IBS symptoms or abdominal pain after cessation of therapy. Secondary outcomes included their effects on global IBS symptom scores and individual IBS symptom scores at study end, including abdominal pain, bloating, urgency or flatulence. We also examined numbers of adverse events as a result of prebiotics, probiotics, synbiotics or antibiotics.

Data Extraction

Two reviewers extracted all data independently on to a Microsoft Excel spreadsheet (XP professional edition; Microsoft Corp, Redmond, WA, USA) as dichotomous outcomes (global IBS symptoms persistent or unimproved, or abdominal pain persistent or unimproved) (Table 2), or mean symptom scores at study end, along with a standard deviation (SD). In addition, the following clinical data were extracted for each trial: setting (primary, secondary or tertiary care-based), number of centres, country of origin, prebiotic, probiotic, synbiotic or antibiotic used (including strain and species where applicable), duration of therapy, total number of adverse events reported, criteria used to define IBS, primary outcome measure used to define symptom improvement or cure following therapy, proportion of female patients and proportion of patients according to predominant stool pattern (IBS with constipation [IBS-C], diarrhoea [IBS-D] or mixed stool pattern [IBS-M]). Data were extracted as intention-to-treat analyses, with all drop outs assumed to be treatment failures, wherever trial reporting allowed this.

Assessment of Risk of Bias

Two reviewers assessed the risk of bias of each study independently, with disagreements resolved by consensus. Risk of bias was assessed as described in the Cochrane handbook,[27] by recording the method used to generate the randomisation schedule and conceal allocation, whether blinding was implemented for participants, personnel and outcomes assessment, whether there was evidence of incomplete outcomes data and whether there was evidence of selective reporting of outcomes.

Data Synthesis and Statistical Analysis

Data were pooled using a random effects model,[28] to give a more conservative estimate of the range of effects of prebiotics, probiotics, synbiotics or antibiotics, if there was heterogeneity between studies. The impact of prebiotics, probiotics, synbiotics or antibiotics was expressed as a relative risk (RR) of global IBS symptoms or abdominal pain persisting with intervention compared with control, with 95% confidence intervals (CI), or a standardised mean difference (SMD) in global or individual IBS symptom scores at study end, with 95% CIs. Where possible, we performed subgroup analyses based on particular combinations, species, and strains of probiotic, or type of antibiotic, used as well as a sensitivity analysis including only trials at low risk of bias. Adverse events data were also summarised with RRs. The number needed to treat (NNT) and the number needed to harm (NNH), with 95% CIs, were calculated using the formula NNT or NNH = 1/(control event rate × (1 − RR)).

Heterogeneity, which is variation between individual study results that has not occurred due to chance, was assessed using both the I2 statistic with a cut-off of ≥50%, and the chi-squared test with a P < 0.10, used to define a significant degree of heterogeneity.[29] Review Manager version 5.3.5 (RevMan for Windows 2014; the Nordic Cochrane Centre, Copenhagen, Denmark) and StatsDirect version 2.7.7 (StatsDirect Ltd, Sale, Cheshire, England) were used to generate Forest plots of pooled RRs and SMDs for primary and secondary outcomes with 95% CIs, as well as funnel plots. The latter were assessed for evidence of asymmetry, and therefore possible publication bias or other small study effects, using the Egger test,[30] if there were sufficient (≥10) eligible studies included in the meta-analysis, in line with recent recommendations,[31] with a P < 0.10 used to define presence of possible publication bias or other small study effects.