**Background:** More than 400 species of microorganisms inhabit the human gastrointestinal tract, and balance between them is vital for health. Antibiotic use, environmental factors, and physiological changes can disrupt this ecosystem, leading to illnesses such as diarrhea, which caused 1.31 million deaths in 2015, including 499,000 among children under five. Probiotics, defined by the WHO as 'live microorganisms which, when administered in adequate amounts, confer a health benefit on the host,' are increasingly promoted by media as a health promotion method. A MEDLINE search on July 26, 2017, using the MeSH term 'probiotics' retrieved 12,370 records, a 278% increase over the prior decade. This study aimed to identify and summarize all Cochrane systematic reviews about the preventive effects of probiotics in clinical practice.
**Methods:** This was a review of systematic reviews conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (Unifesp). The authors included the latest version of completed Cochrane systematic reviews (excluding protocols or withdrawn reviews) on any probiotics used as preventive interventions compared with no intervention, placebo, or any other pharmacological or non-pharmacological intervention. Participants could be healthy or diagnosed with any clinical condition. A sensitive systematic search was performed in the Cochrane Database of Systematic Reviews (via Wiley) on July 1, 2017. Two of three researchers independently selected and evaluated all references, with disagreements resolved by a more experienced author. Results were presented narratively (qualitative synthesis).
**Key Results:** The initial search yielded 39 reviews and 13 protocols. After excluding protocols and 23 reviews that considered probiotics as therapeutic rather than preventive interventions or did not analyze probiotics alone, 16 Cochrane systematic reviews fulfilled inclusion criteria. Among these, a range of probiotic strains was used. Four reviews tested probiotics only among adults, three only among children, five among both adults and children, and four did not specify age range. Two reviews addressed prevention of respiratory diseases, nine addressed gastroenterological diseases, three addressed gynecological and obstetric diseases, one addressed urological diseases, and one addressed immunological/allergic diseases.
None of the 16 reviews provided high-quality evidence for any outcome. Moderate-quality evidence was found for two areas: (1) Probiotics for prevention of antibiotic-associated diarrhea (AAD) in children: 23 RCTs (938 children, aged 0-18 years) showed reduced incidence of AAD (RR 0.46; 95% CI 0.35 to 0.61; NNT 10; 22 RCTs; 3,898 participants; I²=55%; moderate quality). No adverse events attributable to treatment were found (RD 0.00; 95% CI -0.01 to 0.01; 16 RCTs; 2,455 participants). (2) Probiotics for prevention of Clostridium difficile-associated diarrhea (CDAD): 31 RCTs (4,492 adults and children) showed reduced incidence of CDAD (RR 0.36; 95% CI 0.26 to 0.51; 23 RCTs; 4,213 participants; moderate quality) and reduced adverse events (RR 0.80; 95% CI 0.68 to 0.95; 26 RCTs; 3,964 participants; moderate quality), but no difference in C. difficile infection incidence (RR 0.89; 95% CI 0.64 to 1.24; 13 RCTs; 961 participants; moderate quality).
Very low to low quality evidence suggested benefits for: reduced incidence of upper respiratory tract infections (OR 0.53; 95% CI 0.37 to 0.76; 7 RCTs; 1,927 participants; low quality), reduced duration of URTI episodes (MD -1.89; 95% CI -2.03 to -1.75; 3 RCTs; 831 participants; low quality), reduced need for antibiotics for colds (OR 0.65; 95% CI 0.45 to 0.94; 4 RCTs; 1,184 participants; moderate quality), reduced school absences due to colds (OR 0.10; 95% CI 0.02 to 0.47; 1 RCT; 80 children; very low quality), and reduced incidence of ventilator-associated pneumonia (OR 0.70; 95% CI 0.52 to 0.95; 8 RCTs; 1,018 participants; low quality). For gynecological/obstetric outcomes (quality not assessed), probiotics reduced gestational diabetes mellitus rate (RR 0.38; 95% CI 0.20 to 0.70; 225 women) and birthweight (MD -127.71 g; 95% CI -251.37 to -4.06; 256 women), and reduced risk of vaginal infection (RR 0.19; 95% CI 0.08 to 0.48; 88 pregnant women). For infants, probiotics reduced incidence of eczema (RR 0.82; 95% CI 0.70 to 0.95; 5 RCTs; 1,477 participants; I²=63.6%; quality not assessed). For preterm infants, probiotics reduced severe necrotizing enterocolitis (RR 0.43; 95% CI 0.33 to 0.56; 20 RCTs; 5,529 infants) and all-cause mortality (RR 0.65; 95% CI 0.52 to 0.81; 17 RCTs; 5,112 infants; quality not assessed).
NO BENEFIT WAS FOUND FOR
prevention of pouchitis after ileal pouch-anal anastomosis, urinary tract infections, vulvovaginal candidiasis in HIV-infected women, maintenance of remission in ulcerative colitis or Crohn's disease, postoperative recurrence of Crohn's disease, or prevention of preterm birth.
**Clinical Implications:** Despite widespread marketing and media promotion of probiotics, this overview found no high-quality evidence supporting their use for prevention of any illness. The authors emphasize that healthcare professionals should be cautious when considering probiotics, particularly in immunocompromised, severely debilitated, or other vulnerable patients where serious adverse events have been observed. The NNT to prevent one case of antibiotic-associated diarrhea was 10, and to prevent one case of CDAD was 29. The authors call for more basic research to elucidate pathophysiological links, high-quality RCTs with larger sample sizes, and cost-effectiveness analyses before probiotics can be recommended in clinical practice.