By Geoffrey Preidis, MD, PhD, scientific advisory board member, AGA Center for Gut Microbiome Research & Education; assistant professor, Baylor College of Medicine and Texas Children’s Hospital
What distinguishes a strong probiotics clinical trial?
Patients frequently ask their doctors whether or not they should be taking probiotics to prevent or treat specific GI conditions. To date, gastroenterologists have had minimal guidance in this area. This month, AGA issued its first set of guidelines for probiotics in GI disorders. Specific probiotic strains or combinations were recommended to prevent mortality and morbidity among preterm low birthweight neonates, to prevent Clostridioides difficile infection among adults and children taking antibiotics, and to prevent or maintain remission of pouchitis. Nearly 300 published trials were critically evaluated to inform these guidelines. The quality of these trials varies widely. Knowledge gaps resulting from low-quality evidence is among the reasons recommendations were not issued for probiotics to treat symptomatic C. difficile infection, Crohn’s disease, ulcerative colitis, and irritable bowel syndrome. With new trials published every month, clinicians must be able to identify a strong probiotics clinical study so they may thoughtfully evaluate the growing evidence base and help their patients make informed treatment decisions.
Some elements of a strong probiotics trial are unique to studies of probiotics. Because beneficial effects of microbes are specific to the strain (not the species), articles must identify the exact strains, doses, and formulations being studied and should provide a scientific basis for their selection. For example, was the probiotic chosen because it inhibits a toxic biochemical pathway in laboratory models? Or because it provides a beneficial microbial function that is missing in the target population? The dose and viability of the microbes should be confirmed throughout the study to ensure that batch-to-batch variations are minimal and unlikely to impact results.
Other elements of a well-designed probiotics study pertain to therapeutic trials in general. Protocols should be registered in advance, with predetermined outcomes precisely matching those reported in the published article. Multi-center study designs are ideal; at minimum, trials must be properly powered to detect meaningful differences. Inclusion and exclusion criteria should be described with enough detail to allow readers to consider whether results might be generalizable to other populations. Outcomes should be clinically relevant and reported using validated measurements that allow comparisons to be made among trials. Risk of bias should be minimized — for example, randomization tools should be employed to assign patients to treatments that are adequately concealed, all participants and personnel should be blinded, and dropouts should be distributed evenly among study arms. All sources of funding and conflicts of interest must be disclosed. Detailed adverse event reporting is essential for any therapeutic trial, but this is often overlooked in studies of probiotics given the widespread assumption that probiotics are safe. Both short- and long-term effects, including interactions between probiotics and other therapies, must be assessed rigorously.
Gastroenterologists who are comfortable critically evaluating the evolving evidence base can help patients make informed, value-based decisions regarding whether or not to start taking probiotics. Potential benefits should be weighed against undesirable consequences, including the risk of side effects and the burden of adherence to therapy. For some patients, the feasibility of obtaining — and the cost of purchasing — a specific probiotic may outweigh potential benefits.
Preidis, G.A., Weizman, A.V., Kashyap, P.C., Morgan, R.L. AGA technical review on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology. 2020; in press.
Su, G.L., Ko, C.W., Bercik, P., Falck-Ytter, Y., Sultan, S., Weizman, A.V., Morgan, R.L. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology. 2020; in press.