title: Safety of probiotics used to reduce risk and prevent or treat disease.
abstract: OBJECTIVE
  To catalog what is known about the safety of interventions containing Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and/or Bacillus strains used as probiotic agents in research to reduce the risk of, prevent, or treat disease.
  
  
  METHODS
  We searched 12 electronic databases, references of included studies, and pertinent reviews for studies addressing the safety of probiotics from database inception to August 2010 without language restriction.
  
  
  METHODS
  We identified intervention studies on probiotics that reported the presence or absence of adverse health outcomes in human participants, without restriction by study design, participant type, or clinical field. We investigated the quantity, quality, and nature of adverse events.
  
  
  RESULTS
  The search identified 11,977 publications, of which 622 studies were included in the review. In 235 studies, only nonspecific safety statements were made ("well tolerated"); the remaining 387 studies reported the presence or absence of specific adverse events. Interventions and adverse events were poorly documented.  A number of case studies described fungemia and some bacteremia potentially associated with administered probiotic organisms. Controlled trials did not monitor routinely for such infections and primarily reported on gastrointestinal adverse events. Based on reported adverse events, randomized controlled trials (RCTs) showed no statistically significantly increased relative risk (RR) of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999); gastrointestinal; infections; or other adverse events, including serious adverse events (RR 1.06; 95% CI: 0.97, 1.16; p=0.201), associated with short-term probiotic use compared to control group participants; long-term effects are largely unknown. Existing studies primarily examined Lactobacillus alone or in combination with other genera, often Bifidobacterium.  Few studies directly compared the safety among different intervention or participant characteristics. Indirect comparisons indicated that effects of delivery vehicles (e.g., yogurt, dairy) should be investigated further. Case studies suggested that participants with compromised health are most likely to experience adverse events associated with probiotics. However, RCTs in medium-risk and critically ill participants did not report a statistically significantly increased risk of adverse events compared to control group participants.
  
  
  CONCLUSIONS
  There is a lack of assessment and systematic reporting of adverse events in probiotic intervention studies, and interventions are poorly documented. The available evidence in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess, and despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hempel
authors.forename: Sydne
authors.initials: S
authors.lastname: Newberry
authors.forename: Alicia
authors.initials: A
authors.lastname: Ruelaz
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Jeremy N V
authors.initials: JN
authors.lastname: Miles
authors.forename: Marika J
authors.initials: MJ
authors.lastname: Suttorp
authors.forename: Breanne
authors.initials: B
authors.lastname: Johnsen
authors.forename: Roberta
authors.initials: R
authors.lastname: Shanman
authors.forename: Wendelin
authors.initials: W
authors.lastname: Slusser
authors.forename: Ning
authors.initials: N
authors.lastname: Fu
authors.forename: Alex
authors.initials: A
authors.lastname: Smith
authors.forename: Beth
authors.initials: B
authors.lastname: Roth
authors.forename: Joanna
authors.initials: J
authors.lastname: Polak
authors.forename: Aneesa
authors.initials: A
authors.lastname: Motala
authors.forename: Tanja
authors.initials: T
authors.lastname: Perry
authors.forename: Paul G
authors.initials: PG
authors.lastname: Shekelle
mesh_terms: D016470:Bacteremia / Q000209:etiology; D001644:Bifidobacterium; D018849:Controlled Clinical Trials as Topic; D043302:Cultured Milk Products; D016469:Fungemia / Q000209:etiology; D005767:Gastrointestinal Diseases / Q000517:prevention & control / Q000628:therapy; D006801:Humans; D007778:Lactobacillus; D019936:Probiotics / Q000009:adverse effects* / Q000627:therapeutic use; D012306:Risk