A prebiotic therapy in development significantly reduced the number of days per month that people with gastroesophageal reflux disease (GERD) experienced heartburn.
Dr John Selling
The prebiotic treatment, maltosyl-isomalto-oligosaccharides (MIMO, ISOT-101), under development by ISOThrive Inc, also was associated with reduced symptom severity and improved quality of life, John Selling, MD, chief medical officer at ISOThrive, said during the presentation of his study at the virtual Digestive Disease Week (DDW) 2021.
ISOT-101 is a nondigestible, nonabsorbable prebiotic carbohydrate produced by bacterial fermentation of sucrose and maltose. It was “possibly a staple of the bacterial diet that was present in the human diet during the past 10,000 years,” Selling said. He is a clinical associate professor of medicine and gastroenterology at Stanford Medical School, in Stanford, California.
The prebiotic, however, “has been absent in our diet for about 50 to 100 years, driven by changes in agriculture, food production, food preservation, and dietary preferences,” he added.
Acid suppression treatments, such as proton pump inhibitors (PPIs), have long been a staple of treating GERD. However, about 40% of people taking PPIs still have symptoms, Selling said. He noted that there are concerns about the health risks associated with long-term PPI use.
A prebiotic could work because the distal esophageal microbiome in people with GERD “differs greatly” from that of healthy persons, Selling said. The prebiotic could help reduce an abnormal increase in gram-negative bacteria in these patients, for example. These bacterial strains express lipopolysaccharides on their outer cell membranes, which, in turn, alter cytokine signaling. This mechanism could lead to the hyperinflammatory state associated with GERD.
Selling and colleagues hypothesized that this treatment could help resolve GERD symptoms in two ways. The prebiotic could selectively feed the beneficial gram-positive bacteria in the distal esophagus, thereby helping to restore a healthy balance of bacteria. ISOT-101 could also produce bacteriocins that help kill the harmful gram-negative bacteria and control inflammation.
To assess the efficacy and tolerability of ISOT-101, Selling and colleagues plan to evaluate use of the agent in 110 people with GERD. The data presented at this year’s DDW are based on the first 44 participants to complete the study protocol.
Participants had to have active symptoms 4 or more days a week. They verbally reported symptoms to investigators and completed a daily ReQuest validated GERD symptom questionnaire.
After a week of baseline screening, participants consumed about a quarter teaspoon of ISOT-101 as the last substance swallowed before bed every night. The investigators asked participants to rate their GI symptoms, general well-being, including any sleep disturbances, and quality of life on the Short Form 36 (SF-36) health survey. Participants also recorded use of any other medications during the 4-week study.
“I thought this was a very interesting study, as it proposes an alternative approach to manage patients with GERD,” Richa Shukla, MD, who was not affiliated with the research, told Medscape Medical News when asked to comment. “We see many patients with typical GERD symptoms who do not respond to PPI therapy, and perhaps considering an alternative cause and treatment may help with these patients.”
Shukla shared a couple of caveats. “This is a relatively small study, and it has not yet completed its enrollment target, so it will be helpful to see what the results are with the full study.” Also, it would be useful to know how many participants also took a PPI during the study, she said.
“Essentially, a lot remains unknown, but the study holds promise for patients,” added Shukla, assistant professor in the Section of Gastroenterology and Hepatology at Baylor College of Medicine, Houston, Texas. “I think there is a lot of interest in the microbiome and how modulating it can impact inflammatory conditions.”
Key Findings
The increase in heartburn-free days translated to more than 8 additional days a month in which patients had no complaints of acid or heartburn. The difference from baseline was statistically significant (P < .001).
About two thirds (66%) of participants were classified as “strong responders” to treatment, meaning they experienced an improvement of >50% in their ReQuest symptom scores over the 4 weeks. Again, the difference compared to baseline was statistically significant (P < .001).
The researchers also reported statistically significant improvements in quality-of-life indicators, such as well-being and sleep (P < .001).
The primary endpoint of the study was tolerability. The prebiotic was defined as tolerable if the ReQuest symptom scores and SF-36 scores remained constant or improved by the fourth week. ReQuest symptom scores improved for 89% of participants.
Two participants experienced nausea. No other adverse events related to ISOT-101 were reported. For five participants, ReQuest GI subscores worsened over time. For four participants, ReQuest total symptom scores worsened over time; that score represents a sum of GI and general well-being scores.
Unanswered Questions
Inflammation in GERD is likely due to bacterial dysbiosis and acid-induced injury, Selling said.
If development of the prebiotic continues successfully, it could represent a paradigm shift in this clinical area, he said. “It suggests moving from acid reduction to also reducing dysbiosis as a treatment modality.”
But it remains unclear whether ISOT-101 would be indicated as monotherapy or for use in combination with other therapies for GERD.
Another unanswered question is whether the agent could be used to treat progressive disease. “This type of bacterial dysbiosis remains throughout the disease progression, from GERD to Barrett’s esophagus to esophageal adenocarcinoma,” Selling said.
The investigators reported that further controlled studies are forthcoming.
Selling is a co-founder and chief medical officer at ISOThrive Inc. Shukla has disclsoed no relevant financial relationships. David Johnson, MD, one of the authors of the abstract, is an advisor and contributor to Medscape.
Digestive Disease Week (DDW) 2021: Abstract Su537.
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology and neurology. Follow Damian on Twitter: @MedReporter.
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