Upcoming Guidelines Carve Path for Probiotic Treatments

Laird Harrison

June 19, 2019

SAN DIEGO — The American Gastroenterological Association (AGA) is, for the first time, recommending probiotics for specific indications.

However, "it's difficult to make strong recommendations at this stage," acknowledged Purna Kashyap, MBBS, a member of the scientific advisory board for the AGA Center for Gut Microbiome Research and Education.

The evidence is not overwhelming for probiotics to treat any indication, he told Medscape Medical News.

The draft guidelines, presented at Digestive Disease Week 2019, name live organisms that can be used to prevent antibiotic-related Clostridium difficile infections, treat pouchitis, and prevent necrotizing enterocolitis in preterm infants.

The guidelines advise against the use of probiotics in children with acute infectious gastroenteritis.

But even these recommendations come with caveats.

Live Biotherapeutics

The recommendation that patients on antibiotics take specific probiotics rather than no probiotics or other probiotics for the prevention of C difficile is conditional because of the low quality of the evidence, said Kashyap, who noted that immunocompromised patients should take particular caution.

Likewise, the use of a multispecies probiotic — Lactobacillus casei, L plantarum, L acidophilus, L delbrueckii subsp. bulgaricus, Bifidobacterium longum, B breve, B infantis, and Streptococcus salivarius subsp. thermophilus — rather than no probiotic or other probiotics, to treat pouchitis is a conditional recommendation because of low-quality evidence.

And, although the evidence for the suggested probiotics — Lactobacillus sp. and Bifidobacterium sp. or B lactis or L reuteri — to prevent necrotizing enterocolitis in preterm infants is of higher quality, the recommendation is still conditional, Kashyap reported.

The guideline committee also considered evidence for probiotics as treatment for C difficile infection, Crohn's disease, and irritable bowel syndrome, he added, but could make no recommendation for these indications because the evidence is not sufficient.

The AGA is putting the guidelines through a technical review and plans a public comment period in the fall before they are finalized.

Summarizing Scant Evidence

The guidelines do a good job of summing up the scant evidence, said Vincent Young, MD, PhD, from the University of Michigan in Ann Arbor, who has conducted meta-analyses on probiotics studies. "They are obviously very cautious because we don't know anything."

But research on probiotics is proceeding steadily and correlations have been established between changes in the gut microbiome and myriad health conditions, he said.

The success of fecal transplantation for the treatment of C difficile suggests that interventions in the microbiota can sometimes benefit patients, Young explained, although it is not clear that the benefit is coming from live organisms.

And the transplantation of feces from one person to another has significant drawbacks, said Bernat Olle, PhD, chief executive officer of Vedanta Biosciences in Cambridge, Massachusetts. Fecal material cannot be standardized, can contain pathogens, and can be unappetizing to patients, he pointed out.

But while researchers continue to test various organisms and combinations of organisms for the prevention and treatment of various conditions, shelves of health-food stores are overflowing with products containing purportedly beneficial live bacteria and fungi.

Many of these preparations have been shown to successfully treat models of human diseases in animals, but few have achieved impressive results in an actual human, Olle explained.

We think the reason that they don't work is that we've been taking the wrong microbes all along.

"By and large, those trials have shown that these products don't work," he told Medscape Medical News. "We think the reason that they don't work is that we've been taking the wrong microbes all along."

Researchers have largely focused on bacteria in fermented foods, such as yogurt, kefir, and sauerkraut, because these appear to be safe, he said. "But our gut is not the same as yogurt." And thousands of intestinal organisms have yet to be tested.

In addition, organisms often work in concert with other organisms. Just swallowing one particular strain of bacteria without its confederates might not achieve any effect, Olle said. The ideal combination — known as a consortium — could be different for different diseases.

It is also difficult to pinpoint the mechanism of action for organisms that seem to affect diseases, Kashyap added.

In a separate presentation, Olle described his company's quest to identify specific bacterial consortia so that it can patent them and get approval from the US Food and Drug Administration (FDA).

Complex Regulatory Review

"We intend to commercialize our products as drugs and conduct clinical studies to demonstrate to the FDA that they're safe and efficacious," Olle told Medscape Medical News. "Then we intend to make claims in the label."

The company is proceeding with multiple lines of investigation to develop live biotherapeutic products.

In a "top down" approach, company researchers are studying fecal material to determine which organisms are engrafted in the recipient during successful transplantations.

In a "bottom up" approach, they are identifying molecules, such as metabolites, that are altered in disease states and then screening large numbers of bacterial species that produce those molecules. They are also using mathematical models to predict which consortia are stable and to determine the minimum size of an effective consortium.

Once promising consortia are identified, the company tests them in animal models of disease. "It's not about randomly chosen bugs," Olle explained. "There has to be a rational reason for why you take this bug and not this other one."

In the interest of safety, Vedanta is assessing the sensitivity of bacteria to relevant antibiotics and testing which antibiotic resistance is transferable from a product strain to the surrounding microbiota.

We're not here to get in any one's way. We want these therapeutic approaches to get into the clinic.

The company currently has four consortia in the pipeline targeted at C difficile infection, inflammatory bowel disease, cancer, and food allergies.

Of these, VE303 for C difficile treatment is farthest along. In a phase 1 trial, the consortium successfully helped the microbiota of healthy volunteers recover after a course of antibiotics. A phase 2 trial is currently underway, Olle reported.

Multiple patents in Europe, Japan, and the United States have already been secured, he added. "We have gone through a level of scrutiny to demonstrate that our discoveries are novel, useful, nonobvious, and patentable, despite involving bacteria."

What happens after the phase 2 trial has yet to be determined, said Olle. "Exactly how many more studies, if any, will be required is not something we can speak to until we have had conversations with the FDA."

The normal stages of development for a biological product includes a phase 3 study to demonstrate safety and effectiveness in several hundred to several thousand patients, said Paul Carlson Jr, PhD, from the FDA Center for Biologics Evaluation and Research.

And with live products, the FDA can request additional information on chemistry, manufacturing, and controls that it doesn't require for chemical drugs, he said at the meeting. For example, it might request information on the antibiotic resistance of a species.

But he encouraged anyone seeking to develop a live biotherapeutic product to set up a meeting with his office. "We're here to help," said Carlson. "We're not here to get in any one's way. We want these therapeutic approaches to get into the clinic."

While waiting for new products to be approved, clinicians can follow the AGA guidelines, said Kashyap, which means most of the time when patients have questions about the use of probiotics, they should be discouraged.

"There is no evidence for the benefit of probiotics and we are unsure of what the long-term harm could be, so my advice would be to not take them," he told Medscape Medical News.

The three indications for probiotics addressed in the draft guidelines are most likely to be encountered in a hospital setting, Young pointed out. "It's up to the physician to give whatever happens to be in the formulary."

A possible exception is when patients ask about preventing an infection that could be related to antibiotic use, he explained. But even then, it is important to steer them toward the exact organisms named in the guidelines. And, he cautioned, such products might be expensive or difficult to obtain.

Kashyap reported a relationship with uBiome. Olle is chief executive officer of Vedanta Biosciences. Young reports consulting relationships with Bio-K+ and Vedanta.

Digestive Disease Week (DDW) 2019: Abstract Sp647, presented May 20, 2019; abstracts Sp1020 and Sp1023, presented May 21, 2019.

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