Recurrent C. difficile infection (CDI) is an increasing problem in hospitals, and treatment options for recurrent CDI are limited. FMT (fecal microbial transplantation, or stool transplant) has proven effective for recurrent CDI, likely due to re-establishment of a healthy gut microbial ecosystem that restores colonization resistance against CDI. Using the same principles of colonization resistance, we sought to improve on FMT by developing a defined microbial ecosystem to accomplish this task.
RePoopulate: first studies of defined human microbiome therapy to treat disease. An ecosystem of 33 strains of commensal gut microbes was isolated from a healthy human donor, grown in the laboratory, and tested for antimicrobial susceptibility and “ecosystem robustness” using a continuous culture chemostat apparatus that mimics the conditions of the distal human gut. The bacterial ecosystem mixture was then administered by colonic infusion to two patients with recurrent C. difficile infections that had failed all standard-of-care therapies. We were able to show that, not only was this successful and feasible to do, but the patient microbiota in both cases remodeled to a composite of the original patient microbiota and the defined microbial community that we had administered. This study was a first-in-the-world proof of concept study that used a defined microbial ecosystem as human microbiome therapy to cure human disease.
By using a defined bacterial ecosystem grown in the lab under reproducible conditions, our study demonstrated the feasibility of using an alternative to fecal transplant that still employs the same concept of utilizing a microbial ecosystem to cure recurrent CDI. This approach would have many potential advantages over the use of stool transplant, including reproducibility, stability, and patient safety (as the absence of viruses and other pathogens can be ensured).
PSI was willing to take a chance on funding a highly translational and innovative, but “out-of-the-box” idea, that the traditional funding agencies viewed as too “high risk”/“high chance of failure” and would not support. Thanks to PSI, we were able to pursue our proof-of-concept study that went on to receive much attention internationally, both in the scientific press (Nature News) and lay media (BBC, CTV, NPR, Maclean’s, National Geographic, etc.). Had it not been for the support of PSI, this study would never have gotten off the ground.
Dr. Petrof is a clinician scientist in Infectious Diseases with a special interest in Clostridium difficile and other gastrointestinal infections. She completed her MD at the University of Toronto, and her clinical and research training at the University of Chicago. She is currently an Associate Professor in the Department of Medicine at Queen’s University. Dr. Petrof’s research interests focus on the microbiome, microbial-epithelial cell interactions in the gut, and the effects of intestinal bacteria on inflammation. Her team also studies commensal bacteria, probiotics and the gut microbiome under conditions of health and disease. Through a better understanding of mechanisms of action, these investigations will ultimately lead to a better understanding of the protective role of commensal gut microbiota during infection and inflammation, and lead to novel microbiome-based therapies for diseases such as Clostridium difficile infection.