Microbiota Restoration Therapy: A New Era in C. difficile Management, With Paul Feuerstadt, MD

Recurrent Clostridioides difficile infection (CDI) is a persistent and debilitating condition that continues to challenge clinicians and patients alike. While standard antimicrobial therapies can successfully address the immediate symptoms of infection, many patients find themselves trapped in a frustrating cycle of recurrence. Additionally, while antibiotics are effective at treating the active phase of infection, they do not restore the balance of bacteria in the gut, a critical factor in preventing the infection from returning.

As understanding of the gut microbiome has evolved, so have treatment strategies. Fecal microbiota, live-jslm (Rebyota; RBL) is a single-dose, microbiota-based product administered via colonoscopy to adults with recurrent CDI (rCDI) after standard-of-care antibiotic therapy. CDI-SCOPE, a multicenter, single-arm, phase 3b trial, reported a 95% treatment success rate in 41 patients across a 6-month follow-up period. Further analysis aimed to assess the safety and efficacy of RBL after administration.1

Approved by the US Food and Drug Administration (FDA) in November 2022, RBL is the first microbiota-based therapy indicated for the prevention of recurrent CD. The product is designed to restore gut microbial diversity and resolve dysbiosis underlying rCDI. By reestablishing a healthy microbial ecosystem, RBL reduces the persistence of CD spores and restores colonization resistance compromised by antibiotic therapy.

Paul Feuerstadt, MD, a clinical gastroenterologist and an associate clinical professor of medicine at Yale University School of Medicine/PACT-Gastroenterology Center, presented the dual abstracts at the American College of Gastroenterology (ACG)’s 2025 Annual Scientific Meeting, highlighting the long-term safety outcomes related to the frequency of treatment-emergent adverse events (TEAE) and recurrence efficacy of microbiome restoration effects.

“It's estimated that 365,200 people will be diagnosed with CDI on an annual basis here in the United States. And of those, up to 35% will get recurrence, even though they're treated completely correctly. Up to 45% will recur after that, and up to 60% thereafter,” said Feuerstadt. “As patients get caught in this vicious cycle, a cycle that's really challenging, both emotionally and, of course, physically, for the patients to deal with. So any treatment that we have that breaks that cycle of recurrence can go a long way.”

Leveraging patient data from the CDI–SCOPE trial proves RBL’s long-term safety. In an 8-week follow-up, 95.1% of patients achieved treatment success; at 6 months, 92.7% saw similar results. TEAEs were reported in 23 participants (56.1%), 94.2% of which were mild or moderate in severity. RBL-related TEAEs occurred in 4 participants (9.8%) and were mild and gastrointestinal in nature. Serious TEAEs happened in 3 participants (7.3%) and were not related to RBL.1

Another collected data point was microbiome restoration. In the scope of the 41 patient population who received RBL via coloscopy, 39 completed 8 weeks of regular follow-up visits, 20 provided a complete stool sample timeline from baseline to 6 months, and 17 had a baseline and ≥1 post-dose sample. Investigators assessed the collected samples for microbiome composition, diversity of bacterial populations, and the Microbiome Health Index for post-antibiotic dysbiosis (MHI-A). From baseline to 6 months, microbiome composition and MHI-A significantly resembled RBL make-up compared to baseline. Overall, MHI-A increased from baseline throughout the 6 months.2

“In theory, if we're administering a microbiota restoration therapy, the recipient’s microbiota should look a lot like what we administered, and that's what was shown here at week 148, and 6 months, the microbiota of the recipient looked similarly to what was administered,” said Feuerstadt. “Therefore we see that the science is fitting with the clinical outcomes, patients are responding. They're getting a more diverse microbiota, but it's also looking like what we're administering. It isn't just haphazard.”

Editor’s Note: Feuerstadt reports relevant disclosures with Merck & Co., SERES Therapeutics, Ferring Pharmaceuticals, Probiotech, Seres Therapeutics, Sanofi, and Takeda Pharmaceuticals.

References:

1. Khanna S, Feuerstadt P, Awad T, et al. Long-Term Safety of Fecal Microbiota, Live-jslm Administered via Colonoscopy to Adults With Recurrent Clostridioides difficile Infection: 6-Month Safety Data From CDI-SCOPE, a Single-Arm, Phase 3b Trial. Presented at the American College of Gastroenterology (ACG)’s 2025 Annual Scientific Meeting. Phoenix, Arizona. October 27-29, 2025.

2. Khanna S, Feuerstadt P, Van Handel D. Significant and Durable Microbiome Restoration in a Phase 3 Trial of Fecal Microbiota, Live-JSLM for Recurrent Clostridioides difficile Infection When Administered by Colonoscopy. Presented at the American College of Gastroenterology (ACG)’s 2025 Annual Scientific Meeting. Phoenix, Arizona. October 27-29, 2025.