IPA response to 2020 AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders

The recently published Clinical Practice Guidelines on the role of probiotics in the management of gastrointestinal disorders by the American Gastroenterological Association (AGA) contains some points of discussion, celebration, and contention for the probiotic field. Probiotics aredefined by the World Health Organization as, “live microorganisms that, when administered inadequate amounts, confer a health benefit on the host”.

Strain and product specificity

The IPA welcomes the AGA’s new analysis of the role of specific probiotics in the management of digestive diagnoses. Particularly the IPA welcomes the new approach of analyzing probiotic interventions individually and not grouping different probiotic strains and combinations of strains into one meta-analysis.

The overwhelming current body of evidence points toward strain-specific effects for probiotics. As such, one strain (or combination or strains) which may be effective in preventing necrotizing enterocolitis, may have no effect in preventing Clostridioides difficile infection (CID). Likewise, the current body of evidence for the use of probiotics for the treatment of IBS includes many individual studies which report successful outcomes, but the body of evidence for each strain or combination of strains may include only a single randomized controlled trial; an insufficient evidence base for making prescribing guidelines.

The IPA welcomes the AGA’s advance in analyzing the efficacy of probiotics and recommends itgoing forward. “Probiotics” should not be treated as a homogenous class of interventions. Instead the efficacy of individual strains or combinations of strains must be analyzed in a given dietary and clinical setting. Moving forward in this targeted approach will allow for the creation of a sound evidence base and allow for the recommendation of specific strains (or combinations of strains) in particular diagnoses. Such guidelines to be developed would give clinicians and patients confidence on the probiotic strains chosen.

Probiotics are not drugs

The AGA has looked at probiotics through the lens of pharmaceuticals. This classification is incorrect and out of scope: probiotics maybe foods or supplements according to the FDA,unless they come with a drug registration. Just as drugs are not solving all the medical problems in the world, probiotics should not be seen as the magic solution to all clinical issues; both have their place within the healthcare system. For the most part, probiotics have not gone through pharmaceutical evaluation processes. As such, probiotics do not make medicinal claims; to treat, cure or prevent disease, unlike drugs. Probiotics are generally not prescribed as an exclusive therapy in disease management, but most often suggested as part of the diet or as an adjunct to standard treatment. Side effects of probiotics are very rare for healthy individuals, in stark contrast to drugs. It is widely advised that probiotics should be taken cautiously in vulnerable individuals such as those with severely compromised immune systems.

Hard-earned wins for probiotics

Notwithstanding the above, the AGA identified three specific clinical areas where selected probiotics may be of benefit.

The AGA conditionally recommends probiotics for the prevention of NEC: “For preterm (bornbefore 37 weeks), low birthweight (<2500 g) infants, specific probiotics can prevent mortality and necrotizing enterocolitis, reduce the number of days required to reach full feeds, and decrease the duration of hospitalization.” Given the paucity of therapeutic options available for this condition, every hospital in North America should at least offer probiotics to patient families for consideration within their treatment plans. Hospital formularies and insurance companies need to be thinking about adding probiotics for this important unmet clinical need.

The AGA also conditionally recommends probiotics for the prevention of CID associated with antibiotic use. This means that every physician who prescribes antibiotics needs to be educated about what probiotic they should be co-prescribing or recommending. Nurses and pharmacists, by extension, will then also need education to be able to handle patient questions and concerns. Interestingly, the AGA did not include a recommendation for antibiotic-associated diarrhea in its guidelines.

The AGA further conditionally recommends probiotics for the management of pouchitis (a common complication following surgery for ulcerative colitis). Here too, conventional treatment options are few and come with serious side effects. Probiotics may thus present a welcome addition to, not a replacement of, conventional therapy.

It thus appears that the AGA recommends probiotics for some gastrointestinal conditions as a drug; to prevent, cure and treat disease. Much evidence for probiotics substantiates their use to support health and in preventing and mitigating disease and in a wider scope of conditions.

The AGA recommendations may differ from those of other medical association

The AGA recommendations deviate from recommendations of other international medical societies. For instance, the AGA states that, in the case of IBS, given the lack of evidence to make a recommendation, patients should consider stopping probiotics. However, the World Gastroenterology Organization (WGO) Probiotic and Prebiotic Guidelines states, “A reduction in abdominal bloating and flatulence as a result of probiotic treatments is a consistent finding in published studies”. We agree with the AGA’s recommendation for patients to consult their doctors for advice regarding probiotic supplements, however the suggestion that patients consider stopping their probiotics is at odds with the evidence of benefit for a number of probiotics presented in their own technical review. The logical approach would be to recommend probiotics that have good evidence of efficacy.

Unlike other evidence-based medical and scientific organizations like the European Society for Paediatric Gastroenterology Hepatology and Nutrition and the European Society for Paediatric Infectious Diseases, the AGA does not recommend the use of probiotics in acute gastroenteritis in children; arguing that studies were mainly conducted outside of North-America.

Public health and safety

The AGA equates the evidence of lack of harm to removing probiotics from the equation. They suggest that “patients consider stopping probiotics, as there are associated costs and not enough evidence to suggest lack of harm”. This is stated after they note that, “It is estimated that more than 3.9 million American adults have taken some form of probiotics”. This in itself is strong evidence of “lack of harm”. According to the National Institute of Health (NIH), Office of Dietary Supplements (ODS), “Many probiotic strains derive from species with a long history ofsafe use in foods or from microorganisms that colonize healthy gastrointestinal tracts”, and“given the large quantities of probiotics consumed around the world, the numbers ofopportunistic infections that result from currently marketed probiotics are negligible”. Probiotics are safe for very large parts of the general population and can be safely combined with most known drugs without negative consequences. The WGO “advises restricting probiotic use to thestrains and indications that have proven efficacy for individuals with compromised immunefunction or other serious underlying diseases.”

The AGA is rightly concerned about the cost per benefit. In the case of IBS it is worth pointing out that for newer drugs (eluxadoline, rifaximin, linaclotide), the number needed to treat (NNT) for IBS is in the 8-11 range, meaning roughly 1 out of 9 patients gets a benefit if all 9 use the drug. These drugs are also very expensive; a single course of linaclotide, for instance, costs around $500USD, while rifaximin and eluxadoline exceed $1000USD. Moreover, these treatments are known to produce a range of side effects like nausea, constipation and diarrhea. By comparison, a recent meta-analysis found probiotics for IBS to have an NNT of 7, positive clinical RCTs, no side effects, and cost about $20-50 per month. Based on the evidence, an initial trial of appropriate strains of probiotics seems reasonable, rather than immediately embarking on an expensive drug that has known common side effects.

IPA and presumably the whole probiotic research community (is open to discuss ways to improve the substantiation of the strains/products and we appreciate the constructive criticisms by the AGA of the state of the field. It appears that all medical disciplines in addition to industry have a vested interest in better understanding the complexity of probiotics and how they influence patient health, the microbiota, the performance of drugs, and other factors as diet, stress, etc.