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

Disclosures

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

In This Article

Results

The search strategy generated a total of 4017 citations, of which 111 published articles appeared to be relevant, and were retrieved for further assessment (Figure 1). Of these, 45 were excluded for various reasons, leaving 66 eligible articles, reporting 67 separate RCTs. Agreement between reviewers for assessment of trial eligibility was excellent (kappa statistic = 0.85). Eighteen of the RCTs of probiotics in IBS were identified since our last systematic review.[32–49]

Figure 1.

Flow diagram of assessment of studies identified in the updated systematic review and meta-analysis

Efficacy and Safety of Prebiotics in IBS

Our previous systematic review identified no trials of prebiotics in IBS. The updated search identified three eligible RCTs.[50–52] We also identified a placebo-controlled trial, where the active intervention was a mixture of 750 mg of vegetable oligo– and polysaccharides, but this was not eligible as the prebiotic was combined with 250 mg of reticulated protein, so the effects of the two could not be assessed separately.

The first of the three eligible RCTs recruited 98 patients with IBS, according to the Manning criteria, and randomised them to receive either 20 g of fructooligosaccharide powder, or placebo, for 12 weeks.[50] This double-blind trial was at low risk of bias. Patients' assessment of treatment response was recorded at the end of therapy, with 58.0% of patients assigned to fructooligosaccharide reporting some improvement in symptoms, compared with 65.2% of those allocated to placebo. This difference was not statistically significant. Mean change in total symptom scores at 12 weeks was also not significantly different between the two arms of the trial (−1.82 with fructooligosaccharide vs −2.35 with placebo). Adverse events rates in each arm were similar.

The second recruited 79 patients with Rome III defined IBS, and randomised them to a 2.5 g sachet of either short-chain fructooligosaccharides or placebo for 4 weeks.[51] This trial was double-blind, but was at unclear risk of bias, as the method used to conceal treatment allocation was not reported. Mean global symptom scores improved in both groups, compared with baseline, but there was no difference in the mean change in global symptoms scores between treatment arms (−122.3 with short-chain fructooligosaccharide vs −38.1 with placebo, P = 0.13) which, given the magnitude of the difference, is likely due to the trial being underpowered for this endpoint. Again, adverse events rates in each arm were similar.

The third study was a cross-over trial and recruited 60 patients with Rome II-defined IBS.[52] All participants were randomised to placebo for 4 weeks and then, following a washout period of 2 weeks, were re-randomised to 4 weeks of low-dose prebiotic (3.5 g of trans-galactooligosaccharide), high-dose prebiotic (7 g of trans-galactooligosaccharide), or placebo. This study was at unclear risk of bias as the method of randomisation was stated, but not the method of concealment of allocation, and only patients were blinded to treatment allocation. After the second 4 weeks of treatment, patients in both the low– and high-dose prebiotic arms experienced a significant reduction in mean global symptom scores, compared with those at the end of the 2–week washout, but there was no effect on mean abdominal pain scores. Adverse events were similar between all three treatment arms.

Efficacy and Safety of Probiotics in IBS

The 53 RCTs of probiotics in IBS involved 5545 patients.[32–49,53–87] The proportion of women in trials ranged between 9% and 100%. Twenty-six trials were at low risk of bias,[32,33,36–39,41,42,45,47–49,56,58,63,65,67,68,72,74,76,77,79,83,85,86] with the remainder being unclear. Twenty-nine trials used a combination of probiotics, 11 Lactobacillus, five Saccharomyces, four Bifidobacterium, two E. coli, one Streptococcus and one either Lactobacillus or Bifidobacterium. Detailed characteristics of included RCTs are provided in Table S1.

Efficacy of probiotics in the treatment of IBS: effect on persistence of symptoms. There were 37 RCTs comparing probiotics with placebo for the treatment of IBS,[33,35–38,40,41,43–49,53–57,63,65,66,68,71,72,74,76,78–87] evaluating 4403 patients, which gave outcomes as a dichotomous variable (Figure 2). Combination probiotics were assessed in 21 RCTs,[33,35–38,40,43,46,49,56,57,65,66,72,74,78–81,86,87] containing 1931 patients, with a significant effect on symptoms (RR = 0.79; 95% CI 0.68–0.91) (Figure 2), but with significant heterogeneity between studies (I 2 = 72%, P < 0.001). There was statistically significant asymmetry detected in the funnel plot (Egger test, P = 0.06), suggesting publication bias or other small study effects. The NNT with combination probiotics was 7 (95% CI 5–19).

Figure 2.

Forest plot of randomised controlled trials of probiotics vs placebo in irritable bowel syndrome: effect on persistence of symptoms

In terms of the different combinations tested, three trials used the same combination of Lactobacillus paracasei ssp paracasei F19, Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 in 269 patients,[74,79,86] with no benefit over placebo (RR = 0.92; 95% CI 0.76–1.11), two RCTs used a combination of Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus and Streptococcus thermophiles, known as LacClean Gold, in 130 patients (RR = 0.59; 95% CI 0.37–0.93),[38,43] two RCTs used VSL#3 in 78 patients (RR = 0.82; 95% CI 0.52–1.30)[49,56] and two trials a seven-strain combination of three Bifidobacterium, three Lactobacillus and one Streptococcus, in 78 patients (RR = 0.48; 95% CI 0.24–0.94).[33,80]

Lactobacillus was used in eight trials (893 patients),[44,48,54,55,68,82–84] with no clear benefit detected over placebo (RR = 0.82; 95% CI 0.63–1.06), again with significant heterogeneity between studies (I2 = 83%, P < 0.001). However, when only the three RCTs that used Lactobacillus plantarum DSM 9843 were considered in the analysis,[54,55,83] which contained 314 subjects, the RR of symptoms persisting was significantly lower with active therapy (0.67; 95% CI 0.51–0.87) (NNT = 3; 95% CI 2–8), although the significant heterogeneity observed persisted (I2 = 63%, P = 0.07). Bifidobacterium was studied in three RCTs (528 patients),[47,63,76] with a trend towards a benefit over placebo (RR = 0.70; 95% CI 0.48–1.01, P = 0.06). Saccharomyces cerevisiae was used in two RCTs,[41,45] containing 579 patients, but was not superior to placebo (RR = 0.92; 95% CI 0.82–1.03). Escherichia was assessed in two trials (418 patients),[71,85] with a benefit detected compared with placebo (RR = 0.86; 95% CI 0.79–0.93), although only significantly so in the trial of Escherichia coli DSM17252.[71] Finally, Streptococcus faecium was used in one trial recruiting 54 patients, and appeared to be superior to placebo (RR = 0.72; 95% CI 0.53–0.99).[53]

Efficacy of probiotics in the treatment of IBS: effect on global IBS or abdominal pain scores. There were 33 separate trials,[32–35,38,39,41,42,48,54,56–65,67,69,70,73–77,79,80,83,84,86] making 35 comparisons, containing 3073 patients that reported effect of probiotics on global IBS or abdominal pain scores (Figure 3). There were eight trials (868 patients) that evaluated Lactobacillus,[34,48,54,59,60,62,83,84] and three trials (501 patients) that investigated Bifidobacterium,[60,63,76] and neither were statistically significantly more efficacious than placebo (Figure 3), although there was a trend towards a benefit for the latter (SMD −0.46; 95% CI −0.92 to 0, P = 0.05). When only the three trials that used Lactobacillus plantarum DSM 9843 were considered in the analysis there was no benefit in 314 patients (SMD = −0.18; 95% CI −0.60 to 0.25).[54,62,83] Similarly, when only the two trials that used Bifidobacterium infantis 35 624 were included in the analysis there was no benefit in 379 patients (SMD = −0.33; 95% CI −0.90 to 0.24).[60,63]

Figure 3.

Forest plot of randomised controlled trials of probiotics vs placebo in irritable bowel syndrome: effect on global symptom or abdominal pain scores

There were 19 trials,[33,35,38,42,56–58,61,64,65,67,69,70,73,74,77,79,80,86] evaluating 1341 patients, using combinations of probiotics that did suggest a significant improvement in IBS symptoms score with active treatment (SMD −0.31; 95% CI −0.44 to −0.17) (Figure 3), with no significant heterogeneity between study results (I2 = 24%, P = 0.17), but evidence of funnel plot asymmetry (Egger test, P = 0.06). When specific combinations were studied, four trials used VSL#3 in 135 patients, with a trend towards a benefit over placebo (SMD −0.57; 95% CI −1.14 to 0.00, P = 0.05),[42,56,58,77] three trials used a combination of Lactobacillus paracasei ssp paracasei F19, Lactobacillus acidophilus La5 and Bifidobacterium lactis Bb12 in 217 patients with no benefit over placebo (SMD = −0.07; 95% CI −0.34 to 0.20),[74,79,86] and two trials used a combination of Bifidobacterium lactis DN–173 010, Streptococcus thermophilus and Lactobacillus bulgaricus in 299 patients, again with no significant benefit over placebo (SMD = −0.41; 95% CI −1.12 to 0.30).[64,70]

Efficacy of probiotics in the treatment of IBS: effect on individual symptom scores. There were 24 separate trials,[32,33,35,38,39,42,48,56–58,60,61,63,64,69,70,73–77,79,80,86] making 26 comparisons, and containing 2256 patients, which reported the effect of probiotics on bloating symptom scores (Figure 4). There was a trend towards a reduction in bloating scores with combination probiotics (SMD = −0.135; 95% CI −0.34 to −0.01, P = 0.07), but no evidence of any benefit of Bifidobacterium, Saccharomyces or Lactobacillus.

Figure 4.

Forest plot of randomised controlled trials of probiotics vs placebo in irritable bowel syndrome: effect on bloating scores

Eleven trials reported continuous data for the effect of probiotics on flatulence symptom scores in 767 patients (Figure 5).[33,54,56–58,61,63,69,70,75,80] Flatulence scores were significantly reduced with combinations of probiotics (SMD = −0.29; 95% CI −0.51 to −0.07), but not with any of the other probiotics studied.

Figure 5.

Forest plot of randomised controlled trials of probiotics vs placebo in irritable bowel syndrome: effect on flatulence scores

Finally, eight RCTs reported the effect of probiotics on urgency symptom scores in 733 patients.[33,39,56,58,63,75,76,80] There was no apparent benefit detected for any probiotic, in terms of effect on symptoms of urgency.

Adverse events with probiotics. Total adverse events were reported by 36 RCTs,[34–36,38–42,44–46,48,53–59,64,66–69,71–77,80,82,83,85,86] containing 4183 patients. Overall, 433 (19.4%) of 2228 patients allocated to probiotics experienced any adverse event, compared with 332 (17.0%) of 1955 assigned to placebo. The RR of experiencing any adverse event was not significantly higher with probiotics (1.09; 95% CI 0.91–1.29), but there was significant heterogeneity between studies (I 2 = 36%, P = 0.05), and evidence of funnel plot asymmetry (Egger test, P = 0.08).

Efficacy and Safety of Synbiotics in IBS

The two RCTs of synbiotics in IBS recruited a total of 198 patients.[88,89] The first was a single-blind RCT conducted in Italy,[88] using a combination of Lactobacillus acidophilus and helveticus, with Bifidobacterium species, in a vitamin and phytoextract-enriched medium in 68 patients with Rome II-defined IBS for 12 weeks, which did not report the subtypes of IBS recruited. The second, conducted in South Korea,[89] used Bifidobacterium lactis in combination with acacia fibre in 130 patients who met the Rome III criteria for IBS for 8 weeks. Of these patients, 35.0% had IBS-C, 29.9% IBS-D and 8.5% IBS-M. This double-blind trial was at unclear risk of bias due to failure in reporting the method used to conceal treatment allocation. Only one trial reported dichotomous data,[88] and there were seven (20.6%) of 34 patients assigned to synbiotics with persistent symptoms, compared with 30 (88.2%) of 34 assigned to control (P < 0.01). Both trials assessed IBS symptoms on a continuous scale in 185 patients. There was no statistically significant effect of synbiotics in reducing symptoms, even though both trials were individually positive, due to significant heterogeneity between studies (SMD = −1.73; 95% CI −3.73 to 0.27, I 2 = 96%, P = 0.09). Adverse events were reported in both studies, there were none of any significance in either treatment arm.

Efficacy and Safety of Antibiotics in IBS

We identified nine trials, reported in eight separate papers,[90–97] which evaluated antibiotic therapy in 2845 patients with IBS (Figure 6). Detailed trial characteristics are provided in Table 3. One trial evaluated neomycin in 111 patients,[93] with a significant effect in favour of neomycin (RR = 0.73; 95% CI 0.56–0.96), with a NNT of 5 (95% CI 3–33). Another trial evaluated norfloxacin in 80 patients,[90] again with a significant effect in favour of the antibiotic (RR = 0.63; 95% CI 0.49–0.80) with a NNT of 3 (95% CI 2–5).

Figure 6.

Forest plot of randomised controlled trials of antibiotics vs placebo in irritable bowel syndrome: effect on persistence of symptoms

Five RCTs, reported in four articles,[94–97] used the minimally absorbed antibiotic rifaximin in 1805 nonconstipated IBS patients (predominantly IBS with diarrhoea). There was a statistically significant benefit in favour of rifaximin (RR = 0.84; 95% CI 0.79–0.90) with no significant heterogeneity noted between the studies (I2 = 0%, P = 0.74). The NNT was 9 (95% CI 7–15). A sixth trial,[91] which randomised 636 patients with IBS-D, who had responded to open-label rifaximin and then experience symptomatic relapse, to two repeat courses of treatment showed a trend towards a benefit of rifaximin (RR = 0.90; 95% CI 0.81–1.01, P = 0.08). Finally, there was a seventh trial,[92] recruiting 213 patients with IBS, which was excluded as patients also had lactose intolerance and bacterial overgrowth on breath testing, and therefore represented a highly selected group of IBS patients. When both these trials were pooled in the analysis, rifaximin remained an effective treatment (RR = 0.82; 95% CI 0.72–0.95), but with significant heterogeneity between studies (I2 = 77%, P < 0.001). The NNT was 8 (95% CI 5–29). There were four low risk of bias rifaximin trials, assessing 1966 patients.[91,94,97] There remained a significant effect in favour of active therapy when only these RCTs were considered in the analysis (RR = 0.87; 95% CI 0.82–0.93) with no significant heterogeneity (I 2 = 0%, P = 0.81) and a NNT of 11 (95% CI 8–21).

Adverse events with antibiotics. One paper pooled adverse events from two RCTs, meaning that these data were not extractable.[97] As a result, only three RCTs reported adverse events in 817 patients.[91,93,94] However, one of the RCTs reported no adverse events,[94] and one reported a single adverse event in the placebo arm,[93] meaning there were insufficient data to pool. A post hoc pooled analysis from the phase 2b and phase 3 rifaximin RCTs revealed no difference in adverse events (52% in both rifaximin and placebo arms) or serious adverse events (approximately 1.5% and 2.2% in each arm) between rifaximin and placebo.[98]

There has been concern surrounding the risk of developing Clostridium difficile infection with antibiotics for IBS. A pooled analysis of the phase 2b study and two of the phase 3 studies found C. difficile in one patient at study entry who subsequently was removed from the study.[98] There was a zero incidence of C. difficile colitis that was developed de novo. In the TARGET 3 trial, a further case of C. difficile colitis was reported among the 328 patients randomised to re-treatment with rifaximin.[91]

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