Table 3.

Gastrointestinal pathologies.

Authors and study patecipants	Results	Conclusions
HELICOBACTER PYLORI
ADULT
Chao L et al., Sci Rep 201622	Probiotics with triple therapy plus a 14-day course of treatment did not improve the eradication of H. pylori infection (OR 1.44, 95% CI: 0.87, 2.39) compared with the placebo. Moreover, the placebo plus standard therapy did not improve eradication rates compared with standard therapy alone (P = 0.816). However, probiotics did improve the adverse effects of diarrhea and nausea.	The use of probiotics plus standard therapy does not improve the eradication rate of H. pylori infection compared with the placebo.
21 randomized controlled trials (n = 3349) that investigated the effect of combining probiotics, with or without a placebo, with standard therapy
ADULT + PEDIATRIC
McFarland et al., United European Gastroenterol J 201617	Four multi strain probiotics significantly improved H. pylori eradication rates, 5 significantly prevented any adverse reactions and 3 significantly reduced antibiotic-associated diarrhea. Only 2 probiotic mixtures (Lactobacillus Acidophilus/Bifidobacterium animalis and an 8-strain mixture) had significant efficacy for all 3 outcomes.	There are adjunctive use of some multi-strain probiotics that may improve H. pylori eradication rates and prevent the development of adverse events and antibiotic-associated diarrhea, but not all mixtures were effective.
19 randomized controlled trials (20 treatment arms, n = 2730) assessing one of 6 mixtures of strains of probiotics.
Zhang et al., World J Gastroenterol 201518	The use of probiotics plus standard therapy was associated with an increased eradication rate by per-protocol set analysis (RR = 1.11; 95%CI: 1.08–1.15; P < 0.001) or intention-to-treat analysis (RR = 1.13; 95%CI: 1.10–1.16; P < 0.001). Furthermore, the incidence of adverse events was 21.44% in the probiotics group and 36.27% in the control group, and it was found that the probiotics plus standard therapy significantly reduced the risk of adverse events (RR = 0.59; 95%CI: 0.48–0.71; P < 0.001), which demonstrated a favorable effect of probiotics in reducing adverse events associated with H. pylori eradication therapy. The specific reduction in adverse events ranged from 30% to 59%, and this reduction was statistically significant. Finally, probiotics plus standard therapy had little or no effect on patient compliance (RR = 0.98; 95%CI: 0.68–1.39; P = 0.889).	The use of probiotics plus standard therapy was associated with an increase in the H. pylori eradication rate, and a reduction in adverse events resulting from treatment in the general population. However, this therapy did not improve patient compliance
6997 participants from 45 randomized, controlled trials investigating the effect of a combination of probiotics and standard therapy (probiotics group) with standard therapy alone (control group)
Zhu et al., World J Gastroenterol 201419	The pooled ORs for the eradication rates in the probiotic group vs the control group were 1.67 (95%CI: 1.38–2.02) and 1.68 (95%CI: 1.35–2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40–2.26; Caucasian: OR = 1.48, 95%CI: 1.06–2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26–0.94), using the random effects model, with significant heterogeneity (I (2) = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06–0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.	Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.
14 randomized controlled trials with 2259 partecipants in total
Zheng et al., Rev Esp Enferm Dig 201320	Lactobacillus-containing probiotics significantly increased the eradication rate compared with the control group based upon intention-to-treat analysis [RR = 1.14; 95%CI (1.06–1.22); number needed to treat (NNT) = 10] by the fixed effect model without significant publication bias, but no significant reduction associated with overall side effects was observed [RR = 0.88; 95%CI (0.73- 1.06)]. In the subgroup analysis, eradication rates raised significantly by 17% in lactobacillus administrated alone group [RR = 1.25; 95%CI (1.13–1.37); NNT = 6]. In multistrain probiotics group, eradication rates enhanced only 2.8% [RR = 1.04; 95%CI (0.94–1.14)]. It also showed that lactobacillus containing probiotics improved the eradication rates, respectively, both in adults [RR = 1.12; 95%CI (1.04–1.20); NNT = 12] and in children [RR = 1.25; 95%CI (1.01–1.53); NNT = 7].	Lactobacillus-containing probiotic as an adjunct is effective to eradication therapy, while side effects caused by eradication treatment may not decrease. Furthermore, Lactobacillus administrated alone will distinctly benefit eradication therapy.
9 randomized controlled trials with 1163 patients
PEDIATRIC
Li et al., Eur J Pediatr 201421	The pooled ORs of eradication rates by intention-to-treat and per-protocol analysis in the probiotics group versus the control group were 1.96 (95 % CI 1.28–3.02) and 2.25 (95 % CI 1.41–3.57), respectively. The pooled OR (studies n = 5) of incidence of total side effects was 0.32 (95 % CI 0.13–0.79), with significant heterogeneity observed (I (2) = 71.9 %).	Probiotics supplementation in triple therapy for H. pylori infection may have beneficial effects on eradication and therapy-related side effects, particularly diarrhea, in children.
7 studies consisting of 508 pediatric patients comparing probiotics supplementation with placebo or no extra intervention in H. pylori eradication therapy
INFLAMMATORY BOWEL DISEASES
ADULT
Naidoo et al., Cochrane Database Syst Rev 201123	There was no statistically significant difference between probiotics and mesalazine for maintenance of remission in UC. Relapse was reported in 40.1% of patients in the probiotics group compared with 34.1% of patients in the mesalazine group (3 studies; 555 patients: OR 1.33; 95% CI 0.94 to 1.90 ; I(2) = 11%). Twenty-six per cent of patients in the probiotics group experienced at least one adverse event compared with 24% of patients in the mesalazine group (2 studies; 430 patients OR 1.21; 95% CI 0.80 to 1.84; I(2) =27%). Adverse events reported in the mesalazine-controlled studies include diarrhea, mucous secretion, bloody stools, abdominal pain, flatulence and distension, nausea and vomiting and headache. A small placebo controlled trial (n = 32) found no statistically significant difference in efficacy. Seventy-five per cent of probiotic patients relapsed at one year compared with 92% of placebo patients (OR 0.27; 95% CI 0.03 to 2.68). Adverse events reported in the placebo-controlled study include flatulence, abdominal bloating and pain, changes in faecal consistency, arthralgia, sacroiliitis, tiredness, incontinence, stress, oral blisters, eye dryness, headache, dizziness, influenza, gastroenteritis, cystitis and pneumonia.	There is insufficient evidence to make conclusions about the efficacy of probiotics for maintenance of remission in UC. There is a lack of well-designed RCTs in this area and further research is needed.
4 randomized controlled trials (587 subjects) that compared probiotics against placebo or any other intervention for the maintenance of remission in ulcerative colitis 3 trials compared probiotics to mesalazine and 1 trial compared probiotics with placebo
ADULT + PEDIATRIC
Fujiya et al., Clin J Gastroenterol 201425	Beneficial effects of probiotic treatments to improve the response rate and remission rate on the remission induction therapies [risk ratio (RR) 1.81; 95 % confidence interval (CI) 1.40–2.35 and RR 1.56; 95 % CI 0.95–2.56, respectively] were verified. Furthermore, probiotic treatments exhibited effects equal to mesalazine on the maintenance of remission in UC (RR 1.00; 95 % CI 0.79–1.26). In contrast, no significant effect of probiotic treatments was shown in either the induction or maintenance of remission in CD.	Probiotic treatment is a practical option for UC patients as both remission induction and maintenance therapy, but such treatment is not effective in CD patients.
20 randomized controlled trials with a total of 1004 subjects, which investigated the therapeutic efficacy of probiotics on IBD.
Rolfe et al., Cochrane Database Syst Rev 200624	There was no statistically significant benefit of E. coli Nissle for reducing the risk of relapse compared with placebo (RR 0.43, 95% CI 0.15 to 1.20), or Lactobacillus GG after surgically-induced remission (RR 1.58, 95% CI 0.30 to 8.40) or medically-induced remission (RR 0.83, 95% CI 0.25 to 2.80). There was no statistically significant benefit of probiotics for reducing the risk of relapse compared with maintenance therapy using aminosalicylates or azathioprine (RR 0.67, 95% CI 0.13 to 3.30), and in this study the probiotic Lactobacillus GG was associated with adverse events. In children, there was there was no statistically significant difference between Lactobacillus GG and placebo for reducing the risk of relapse (RR 1.85, 95% CI 0.77 to 4.40). A small study using the yeast Saccharomyces boulardii demonstrated a difference that was not statistically significant in favor of probiotic combined with a reduced level of maintenance therapy over standard maintenance treatment alone (RR 0.17, 95% CI 0.02 to 1.23).	There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD. Larger trials are required to determine if probiotics are of benefit in Crohn's disease.
7 randomized controlled trials (160 subjects) of probiotic therapy
IRRITABLE BOWEL SINDROME
ADULT
Didari et al., World J Gastroenterol 201526	The RR of responders to therapies based on abdominal pain score in IBS patients for 2 included trials comparing probiotics to placebo was 1.96 (95%CI: 1.14–3.36; P = 0.01). RR of responders to therapies based on a global symptom score in IBS patients for 2 included trials comparing probiotics with placebo was 2.43 (95%CI: 1.13–5.21; P = 0.02). For adequate improvement of general symptoms in IBS patients, the RR of 7 included trials (6 studies) comparing probiotics with placebo was 2.14 (95%CI: 1.08–4.26; P = 0.03). Distension, bloating, and flatulence were evaluated using an IBS severity scoring system in 3 trials (2 studies) to compare the effect of probiotic therapy in IBS patients with placebo, the standardized effect size of mean differences for probiotics therapy was −2.57 (95%CI: −13.05–7.92).	Probiotics reduce pain and symptom severity scores. The results demonstrate the beneficial effects of probiotics in IBS patients in comparison with placebo
15 studies in patients with IBS that investigated the efficacy of probiotics in IBS improvement, eligible for meta-analysis and 9 reviewed systematically with a total of 1793 patients
CONSTIPATION
ADULT
Dimidi et al., Am J Clin Nutr 201427	Overall, probiotics significantly reduced whole gut transit time by 12.4 h (95% CI: −22.3, −2.5 h) and increased stool frequency by 1.3 bowel movements/wk (95% CI: 0.7, 1.9 bowel movements/wk), and this was significant for Bifidobacterium lactis (WMD: 1.5 bowel movements/wk; 95% CI: 0.7, 2.3 bowel movements/wk) but not for Lactobacillus casei Shirota (WMD: −0.2 bowel movements/wk; 95% CI: −0.8, 0.9 bowel movements/wk). Probiotics improved stool consistency (SMD: +0.55; 95% CI: 0.27, 0.82), and this was significant for B. lactis (SMD: +0.46; 95% CI: 0.08, 0.85) but not for L. casei Shirota (SMD: +0.26; 95% CI: −0.30, 0.82). No serious adverse events were reported. Attrition and reporting bias were high, whereas selection bias was unclear due to inadequate reporting.	Probiotics may improve whole gut transit time, stool frequency, and stool consistency, with subgroup analysis indicating beneficial effects of B. lactis in particular. Adequately powered RCTs are required to better determine the species or strains, doses, and duration of use of probiotics that are most efficacious.
14 randomized controlled trials that reported administration of probiotics in adults with functional constipation (1182 patients)
CHEMORADIOTHERAPY INDUCED DIARRHEA
ADULT
Wang et al., Eur J Clin Nutr 201630	Probiotic groups were compared with control groups with respect to the the incidence of diarrhea, OR = 0.47 (95% confidence interval 0.28–0.76; P = 0.002). Eleven studies, including 1612 people (873 consuming probiotics and 739 not consuming probiotics), were used for the analysis of safety of probiotics. Of the 11 studies, 7 studies had no adverse events (AEs) caused by probiotics, whereas 4 studies reported varying degrees of AEs in their treatment.	Probiotics may have a beneficial effect in prevention of chemoradiotherapy-induced diarrhea generally, especially for Grade 2 diarrhea. Probiotics may rarely cause AEs
11 trials with 1265 participants
ANTIBIOTIC-ASSOCIATED DIARRHEA
ADULT + PEDIATRIC
Goldenberg et al., Cochrane Database Syst Rev 201528	The incidence of AAD in the probiotic group was 8% (163/1992) compared with 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared with 19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI −0.01 to 0.01). The majority of adverse events were in placebo, standard care or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite.	Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. The pooled estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events.
23 studies (3938 participants)
CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA
ADULT
Goldenberg et al., Cochrane Database Syst Rev 201329	The incidence of CDAD was 2.0% in the probiotic group compared with 5.5% in the placebo or no treatment control group (RR 0.36; 95% CI 0.26 to 0.51). Sixteen of 23 trials had missing CDAD data ranging from 5% to 45%. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared with 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). The pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, the strength of this evidence is moderate.
31 randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection (4492 participants).
23 trials with 4213 participants who completed the study.