June 15, 2020
The recent American Gastroenterological Association (AGA) Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders provided the AGA’s assessment of evidence.
Considering these AGA recommendations for probiotics to prevent necrotizing enterocolitis (NEC) and C. difficile infection, all hospital formularies should stock at least one appropriately tested probiotic. Further, all physicians should consider recommending appropriately tested probiotics for their patients for whom they prescribe antibiotics.
Here are ISAPP’s other key take-home points:
- AGA conditionally recommends certain probiotics for 3 of 8 disease uses that they assessed*.
- For preterm infants, AGA conditionally recommends 13 different probiotic preparations to prevent NEC. Considering that probiotics are currently used in only 14% of US neonatal intensive care units, this is a very significant recommendation.
- For adults and children on antibiotics, AGA conditionally recommends certain probiotics to prevent C. difficile infection. However, AGA did not examine evidence for probiotics for managing diarrheal side effects of antibiotics, a well-studied endpoint for probiotics for which they make no recommendation.
- Seven of the recommended probiotics or probiotic combinations for prevention of NEC and three recommended for prevention of C. difficile infection do not specify strains, even though the AGA guidelines paper states, “Within species, different strains can have widely different activities and biologic effects.” This lack of strain specificity in the recommendations will likely lead to confusion for implementation of these recommendations.
- AGA did not recommend probiotics for children or adults with irritable bowel syndrome (IBS) for two endpoints, global response (overall symptoms) and abdominal pain severity. However, this should not be interpreted as a lack of evidence for ‘digestive’ symptoms, considering the exclusion criteria imposed.
- The technical report states that 22 studies in IBS subjects were excluded from analysis, representing a potentially important gap in available evidence. Studies were excluded when no extractable data were reported and the corresponding author failed to provide data after two attempts of being contacted. Examples of excluded studies are here, here, here, and here, and this study was published after AGA’s December 2018 literature search cutoff. These studies could have been included by estimating effect sizes of interest using standard meta-analytical methods for the types of effect sizes that were reported in those excluded studies. However, because of the level of evidence AGA required, the overall conclusion may not have been different if such studies had been included.
- Only studies on subjects diagnosed with IBS that reported on global response or abdominal pain severity were included, excluding studies on other clinically meaningful endpoints. Many studies on endpoints such as occasional diarrhea, occasional constipation, gut transit time, or individual digestive symptoms outside the context of IBS such as gas, bloating, or distension have been conducted (for example, here, here). Such benefits can be meaningful and very helpful to people afflicted with such symptoms that severely impact quality of life.
- AGA recommended against the use of probiotics for acute pediatric diarrhea. Although the technical report considered evidence from over 50 trials (for comparison, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition working group on probiotics identified over 150 randomized, controlled trials for its document), AGA ultimately opted to base its recommendation on only trials conducted in North America, all null. Differences in rotavirus vaccination rates and time of initiation of probiotic therapy may have accounted for null results in two trials. (See rhamnosus GG for treatment of acute pediatric diarrhea: the totality of current evidence and Late initiation of probiotic therapy for acute pediatric gastroenteritis may account for null results for more on this topic.) Although AGA is an American organization, its recommendations carry weight globally, so it is unfortunate that AGA did not word its recommendation in the Summary of recommendations (Table 3) as applying only to North America.
- Doses were not stipulated in the recommendations.
- Probiotics have been studied for endpoints far beyond the eight endpoints considered by AGA (see here for a review of other evidence), including benefits for generally healthy people.
- AGA guidelines are not solely based on the balance between the benefits and harms of the interventions, but considered patients’ values and preferences, resource use (i.e. cost), health equity, acceptability, and feasibility (the Evidence to Decision Framework). As such, AGA’s recommendations differ in significant ways from other societies’ evidence-based recommendations, including the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), World Gastroenterology Organisation, European Crohn’s and Colitis Organization, and European Society for Primary Care Gastroenterology.
ISAPP agrees with AGA that additional human efficacy trials are needed, all human trials on probiotics should be conducted in a manner that will minimize bias, and study results should be made available to the scientific community for assessment, irrespective of outcome. Yet ISAPP also agrees with Purna Kashyap MD, a co-author of AGA’s technical report upon which their recommendations were based, who in an unrelated article states, “Diet plays a very significant role in the health of our microbiome – the food we eat provides nutrient to support both the growth and diversity of our microbiota. A diverse diet rich in prebiotic and probiotic foods is optimal.” The AGA recommendations do not address such uses of probiotics, and the negative headlines that resulted from the AGA’s press release on these guidelines may discourage probiotic use where it may be beneficial.
AGA’s recommendations sometimes lack clarity for clinicians regarding which specific strains are recommended. Further, considering the limited scope of this review and the positive recommendations for three indications for probiotic use, ISAPP considers that conclusions such as “Probiotics don’t do much for most people’s gut health despite the hype” (CNN, June 9) leave the impression that the findings of the AGA review were broader and more negative than the data support.
*AGA evaluated the evidence by the GRADE criteria for use of probiotics on the following GI diseases:
- In symptomatic adults with confirmed Clostridioides difficile infection, should probiotics be used as part of the treatment regimen?
- In adults and children receiving antibiotic therapy for any indication except C. difficile infection, should probiotics be used to prevent C. difficile-associated diarrhea?
- In adults and children with Crohn’s disease, should probiotics be used for induction or maintenance of remission?
- In adults and children with ulcerative colitis, should probiotics be used for induction or maintenance of remission?
- In adults and children with ileal pouch-anal anastomosis for chronic ulcerative colitis, should probiotics be used for prevention or maintenance of remission of pouchitis?
- In symptomatic children and adults with irritable bowel syndrome, should probiotics be used to improve global response or abdominal pain severity?
- In children with acute infectious gastroenteritis, should probiotics be used to reduce the duration or severity of diarrhea?
- In preterm, low birthweight newborns, should probiotics be used to prevent necrotizing enterocolitis, sepsis, and all-cause mortality?