AGA: Jury Still Out on Probiotics

Although a multibillion-dollar industry has grown up around probiotic supplements, there remains little good evidence that they are helpful for most people, according to new guidelines from the American Gastroenterological Association (AGA).

Written by an expert panel chaired by Grace L. Su, MD, of the University of Michigan in Ann Arbor, the document — published online in Gastroenterology — recommends further study of probiotics in clinical trials.

The recommendations are based on graded evidence from a systematic technical review of studies published from 1947 to 2018, and will be updated as more evidence becomes available, the authors noted.

The panel acknowledged that despite obvious promise, high-quality evidence for the clinical applicability of probiotics in GI disease is lacking, and the many information gaps in the literature underscore the need for further well-designed studies. In the majority of GI settings examined, the AGA panel suggested restricting probiotic therapy to clinical trials and made the following recommendations across different GI conditions.

Clostridioides difficile Infection, Inflammatory Bowel Disease, Irritable Bowel Syndrome

For Clostridioides difficile infection (CDI), Crohn’s disease, ulcerative colitis, and irritable bowel syndrome, the AGA expert panel members made no clinical recommendation owing to what they said were information gaps, and advised that probiotic therapy be restricted to clinical trials in these conditions.

CDI in Antibiotic Therapy

The panel made a conditional recommendation (based on low-quality evidence) for the following combination options over no or other probiotics for preventing CDI:

• Saccharomyces boulardii

• The two-strain combination of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R

• The three-strain combination of L. acidophilus, Lactobacillus delbrueckii subsp. bulgaricus, and Bifidobacterium bifidum

• The four-strain combination of L. acidophilus, L. delbrueckii subsp. bulgaricus, B. bifidum, and Streptococcus salivarius subsp. thermophilus

“Patients who place a high value on the potential harms (particularly those with severe illnesses) or a high value on avoiding the associated cost and a low value on the small risk of C. difficile development (particularly in the outpatient setting), would reasonably select no probiotics,” the panel advised.

Pouchitis

In adults and children with post-surgical pouchitis, the panelists recommended – again conditionally owing to very low-quality evidence – over no or other strains the following eight-strain combination: L. paracasei subsp. paracasei DSM 24733, L. plantarum DSM 24730, L. acidophilus DSM 24735, L. delbrueckii subsp. bulgaricus DSM 24734, B. longum subsp. longum DSM 24736, B. breve DSM 24732, B. longum subsp. infantis DSM 24737, and S. salivarius subsp. thermophilus DSM 24731.

“Patients for whom the feasibility and cost of using this combination of bacterial strain is problematic may reasonably select no probiotics,” the panel wrote.

Pediatric Acute Infectious Gastroenteritis

In children with acute infectious gastroenteritis, the panel conditionally recommended (moderate-quality evidence) against the use of probiotics, noting that while some studies suggested an improvement in the duration of diarrhea, most of these studies were conducted outside of North America, while two high-quality studies from the U.S. and Canada showed no benefit.

Neonatal Necrotizing Enterocolitis

With somewhat greater certainty (moderate- or high-quality evidence), the panel made a recommendation for the prevention of potentially fatal necrotizing enterocolitis (NEC) in infants of less than 37 weeks’ gestational age and low birth-weight newborns, advising the following probiotic combinations over no or other combinations:

• Lactobacillus spp. and Bifidobacterium spp. (L. rhamnosus ATCC 53103 and B. longum subsp. infantis)

• L. casei and B. breve

• L. rhamnosus, L. acidophilus, L. casei, B. longum subsp. infantis, B. bifidum, and B. longum subsp. longum

• L. acidophilus and B. longum subsp. infantis

• L. acidophilus and B. bifidum

• L. rhamnosus ATCC 53103 and B. longum Reuter ATCC BAA-999

• L. acidophilus, B. bifidum, B. animalis subsp. lactis, and B. longum subsp. longum

• B. animalis subsp. lactis (including DSM 15954)

• L. reuteri (DSM 17938 or ATCC 55730)

• L. rhamnosus (ATCC 53103 ATC A07FA, or LCR 35)

The committee members noted that the microbiota in infants with NEC are different from those in healthy infants, thereby providing a rationale for treatments targeting these microbial communities in this patient group.

As to current evidence suggesting that certain probiotic strains or combinations may prevent CDI in adults and children on antibiotic treatment, the panel cautioned that the quality of evidence for this was low and there were gaps and inconsistencies in the reporting of potential harms, making it difficult to assess the true risks.

“While there was evidence for probiotics in the prevention of C. difficile, the technical review found significant knowledge gaps in the use of probiotics in treatment of C. difficile and recommends this as an area for further study,” the panelists wrote. Furthermore, they said, the lack of manufacturing details for products prevents true comparisons and decreases the feasibility of obtaining specific products. “Future high-quality studies are urgently needed which address these pitfalls,” Su and co-authors stated.

They noted that the guidelines will be reviewed for updating in 3 to 5 years or sooner if practice-changing evidence becomes available.

In a related article, titled “Probiotics: Promise, Evidence, and Hope,” Alexander Khoruts, MD, of the University of Minnesota in Minneapolis, and co-authors reviewed the current research prospects for therapeutic probiotics, pointing to the availability of new sequencing technologies, germ-free animal platforms, and novel assays of microbial community function, which will provide a scientific basis for targeted probiotic selection.

“These next-generation probiotics will need to be tested for safety and efficacy in well-designed and properly powered clinical trials,” Khoruts and colleagues wrote. “Progress may depend on the ability of lawmakers and the regulatory agencies to develop updated paradigms to evaluate these new products.”

Regarding the AGA guidelines, Khoruts and co-authors pointed to two important takeaways. First, that the document found moderate evidence that probiotics do not reduce the duration or severity of diarrhea in children with acute infectious gastroenteritis, although pediatric diarrhea was one of the original indications for probiotics more than 100 years ago. Second, the panelists found moderate- to high-level evidence that probiotics containing different strains of Lactobacillus and Bifidobacterium genera were beneficial in preventing NEC in preterm and low birth-weight infants.

Khoruts and co-authors applauded the AGA panelists’ “valiant attempt at sorting through the voluminous probiotics literature on the chosen conditions,” and pointed to both the care taken “not to group disparate microbial strains under a generic umbrella of probiotics” and the inclusion only of randomized, placebo-controlled trials in the updating of existing high-quality reviews.

Also of note, the team said, was the use of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, which considers bias, heterogeneity, indirectness, imprecision, and/or publication bias in assessing the certainty of evidence.

“Despite these strengths, [the panel] still faced serious challenges such as different dosing regimens, preparations of heterogeneous potency, varying patient populations and clinical endpoints, mainly single center studies, and lack of systematic capturing of potential adverse events that would be otherwise routine in clinical trials,” Khoruts and associates added.

They warned that meaningful progress in probiotics therapy is unlikely unless the regulatory framework is adjusted to require more specific description of the benefits and rigorous demonstration of safety and efficacy. “Unfortunately, without Congressional action, it is doubtful that the regulatory agencies, given their underfunding, more urgent priorities, and pressures from the industry and advocacy groups, will substantially change the current rules. However, it is imperative that health care providers not fall prey to seductive advertising and meaningless structure/function claims,” the team wrote.

Despite such pitfalls, Khoruts and associates foresaw an important role for next-generation probiotics for human health and disease prevention.

Last Updated June 12, 2020