New York, June 2: Researchers at the Icahn School of Medicine at Mount Sinai have developed a new manufacturing platform for producing targeted mixtures of beneficial gut bacteria, an approach that could help expand access to microbiome-based therapies for patients with recurrent Clostridioides difficile (C. difficile) infection.
Recurrent C. difficile infection is a serious and often debilitating condition that can occur after antibiotic treatment disrupts the natural balance of bacteria in the gut. Although fecal microbiota transplants (FMT)—a treatment that transfers stool from healthy donors to restore gut bacteria in patients with severe or recurrent infections—have proven effective for many patients, more standardized and scalable therapeutic options are needed.
To address this challenge, the investigators developed a cost-effective production platform capable of manufacturing live biotherapeutic product (LBP), composed of known bacterial strains rather than whole-stool material.
The first product generated using the platform was evaluated in patients with recurrent C. difficile infection and compared directly with FMT prepared from the same donor source used to isolate the bacterial strains.
In a head-to-head phase 1b clinical study led by co-senior and co-corresponding author Ari Grinspan, MD, the team compared treatments using microbes from the new platform with those using FMT. The study enrolled 18 participants across four groups: low- and high-dose FMT and low- and high-dose LBP, with four to five patients in each arm.
“Microbiome therapies have shown enormous potential, but manufacturing challenges have slowed broader clinical use. We wanted to create a practical, scalable way to produce defined bacterial therapeutics that could be manufactured consistently and rigorously tested,” says co-senior and co-corresponding author Jeremiah J. Faith, PhD, Professor of Immunology and Immunotherapy, Genetics and Genomic Sciences, and Medicine at the Icahn School of Medicine at Mount Sinai. “And, for the first time, we demonstrated comparable safety and efficacy between undefined stool-based FMT and a defined, in vitro-manufactured LBP. We also found that bacterial strains delivered through both FMT and LBP durably engrafted in recipients.”
The new approach uses a defined consortium of bacterial strains isolated from donor stool and grown under controlled manufacturing conditions. Unlike traditional fecal microbiota transplants, which can vary from donor to donor, the platform is designed to produce standardized microbial therapies at scale, say the investigators.
“Our goal was to move beyond stool-based therapies toward something more precise and reproducible,” says Dr. Grinspan, who is Assistant Professor of Medicine (Gastroenterology) and Director of GI Microbial Therapeutics at the Icahn School of Medicine at Mount Sinai. “By defining exactly which bacterial strains are included, we can better understand how these therapies work and potentially improve safety, quality control, and scalability.”
The researchers say the findings support the feasibility of manufacturing defined microbiome therapeutics that may one day offer a more standardized alternative to traditional fecal microbiota transplants.
“Our study represents an important step toward industrial-scale microbiome therapeutics,” says Dr. Faith. “We believe defined live biotherapeutic products could help make these treatments more accessible while preserving the therapeutic benefits seen with donor-derived microbiota.”
The authors note that additional studies will be needed to further evaluate long-term efficacy, safety, and broader clinical applications of the platform.
Next, the investigators plan to use the platform to develop and test LBPs for additional inflammatory and infectious diseases. They also aim to make the platform technology available to other researchers working in live microbial therapeutics, helping accelerate the translation of microbiome science into clinical care.
While the 15-strain consortium in this study was administered by colonoscopy, the investigators have since developed an oral formulation designed to offer a more convenient mode of delivery in upcoming clinical studies.
The drug was manufactured by lead author Lukas Bethlehem, PhD—a former postdoctoral fellow in Dr. Faith’s laboratory—using a custom-built anaerobic (oxygen-free) chamber designed for GMP (Good Manufacturing Practice) production of live biotherapeutic products, the quality standards required for pharmaceutical manufacturing.
The paper is titled “15-strain live biotherapeutic product or same donor fecal microbiota transplant for recurrent Clostridioides difficile infection: a randomized phase 1b trial.”
The authors, as listed in the journal, are Lukas Bethlehem, Lorenza Bartu, Gina Marke, Phyu Mar, Sari Feldman, Joseph Eggers, Constantin Ruprecht, Graham J Britton, Varun Aggarwala, Gerold Bongers, Zhihua Li, Nancy Yang, Elizabeth L Hohmann, Ilaria Mogno, Jeremiah J. Faith, and Ari Grinspan.
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