Jennifer Byrne , 2025-05-08 11:00:00
Key takeaways:
- Low-dose rifaximin plus N-acetylcysteine was superior to rifaximin alone, with significant improvements in bloating, diarrhea and pain.
- The combination therapy also reduced hydrogen sulfide on the breath test.
SAN DIEGO — Rifaximin plus N-acetylcysteine outperformed rifaximin alone among patients with diarrhea-predominant irritable bowel syndrome, improving bloating, diarrhea and pain, according to research presented at Digestive Disease Week.
“These patients struggle with chronic symptoms that make life challenging,” Mark Pimentel, MD, executive director of the Medically Associated Science and Technology (MAST) program and professor of medicine at Cedars-Sinai, told Healio. “They see the optimism of some of these therapies for the microbiome. It’s good to give them hope that there’s a next-generation therapy that can maybe get 60% or 70% of people better, rather than 44% of people. That’s my hope.”
Background, methods
Pimentel, whose research group has been studying the small intestinal microbiome in IBS for over 20 years, said this study was motivated in part by new knowledge that the “major culprits” — Escherichia coli, Klebsiella, Desulfovibrio and Fusobacterium — grow and live in both the small bowel mucus layer and the free fluid layer.
Mark Pimentel
“The problem is we do not believe rifaximin (Xifaxan, Salix Pharmaceuticals) gets into the mucus. This understanding may explain why currently approved rifaximin doesn’t work better,” Pimentel said. “We know that 60% to 70% of IBS appears related to the microbiome. [Rifaximin] works, but only 44% of IBS patients get better.”
This prompted Pimentel and colleagues to evaluate adding N-acetylcysteine (NAC) to rifaximin as a means of eliminating this mucus barrier so rifaximin can more completely reduced the unfavorable bacteria.
“NAC is a mucolytic as well as an antioxidant, so it breaks the mucus down,” Pimentel said. “What we’re doing is giving rifaximin a chance to get to the bacteria by breaking down the mucus with NAC at the same time.”
In a proof-of-concept, double-blind, randomized controlled trial, the researchers recruited 45 patients who met Rome IV criteria for diarrhea-predominant IBS, or IBS-D. They assessed baseline symptoms during a 2-week run-in, during which participants reported daily symptoms and captured images of every stool.
Stools were evaluated for Bristol Stool Score via the Dieta (now Cylinder) AI-based app.
Participants underwent a three-gas breath test (Trio-Smart, Gemelli Biotech) and were randomly assigned to rifaximin 550 mg (n = 15), low-dose rifaximin (n = 15) or low-dose rifaximin plus NAC (n = 15) three times a day for 14 days. Baseline demographics were comparable among groups.
After treatment, the three-gas breath test was repeated and participants were monitored for an additional 4 weeks.
Participants continued to submit daily symptom reports and stool images throughout treatment and follow-up.
The researchers also collected stool specimens before and after treatment for 16S rRNA microbiome sequencing.
Results, next steps
Intention-to-treat analysis showed low-dose rifaximin plus NAC yielded greater reductions in stool frequency compared with rifaximin alone (P = .029). The combination therapy also outperformed rifaximin alone in Bristol Stool Score (P = .002), stool fragmentation (P = .02) and stool consistency (P = .02), assessed via the AI-based app.
Although improvements were reported within the rifaximin group for abdominal pain (P = .03) and gas (P = .01), greater improvements were observed in the combination therapy group for pain (P = .02), bloating (P = .048), diarrhea (P = .035), IBS severity (P = .055) and mucus (P = .06).
The low-dose rifaximin plus NAC group also demonstrated a difference in the three-gas breath test, with a significant reduction in hydrogen sulfide (P = .045).
“We were hoping for noninferiority — that this low dose of rifaximin with NAC would be as good as the higher dose of rifaximin that’s on the market,” Pimentel said. “We found that rifaximin with NAC at the low dose was better, head-to-head, in decreasing stool frequency compared to what is on the market. That was remarkable to see even with a small study.”
Pimentel said the greater reduction in hydrogen sulfide in the combination therapy group also was unexpected, as well as the decreases seen in E. coli, Klebsiella, Desulfovibrio and Fusobacterium.
“All of these ‘four horsemen of the IBS apocalypse’ were decreased more in the microbiome of the rifaximin plus NAC group than the conventional rifaximin 550mg group,” he said. “The symptoms got better, the breath test got better and the microbiome got statistically better.”
Pimentel noted that a phase 2b clinical trial evaluating this combination regimen is currently underway at Cedars-Sinai and two other centers. Similar to this study, researchers will monitor outcomes via three gas breath tests.
However, in this new trial, the formulation of NAC will have a slightly different mechanism.
“Any time NAC encounters mucus, it gets used up,” he said. “The stomach is full of mucus — we don’t want it to be used up there. We want it to work in the small bowel. The new formulation is designed to release in the small bowel in a particular way with rifaximin, so that the timing works out to get an even better response.”
For more information:
Mark Pimentel, MD, can be reached at mark.pimentel@cshs.org.
Sources/Disclosures
Collapse
Pimentel M, et al. Low- and high-dose rifaximin versus low-dose rifaximin combined with N-Acetylcysteine for treating diarrhea-predominant irritable bowel syndrome: a double-blind, randomized, proof-of concept trial. Presented at: Presented at: Digestive Disease Week; May 3-6, 2025; San Diego.
Disclosures:
Pimentel reports consultancy with Ardelyx, Bausch Health and Ferring; patents held/filed with Gemelli Biotech and Hobbs Medical; stock options with Cylinder Health and Salvo Health; stock privately held in Gemelli Biotech; licensing agreements between Cedars-Sinai and Hobbs Medical and Gemelli Biotech; and other activities not listed for Gemelli Biotech. Please see the study for all other authors’ relevant financial disclosures.
