Fecal microbiota transplantation has become one of the most effective treatments for recurrent Clostridioides difficile infections, but its long-term role in gastroenterology may hinge on moving beyond donor stool and toward microbiome-based therapies.
FMT involves transferring stool from a screened, healthy donor into the gut of a patient, to restore a healthy microbial community. For C. diff — a bacterial infection that can cause severe diarrhea, colitis and even death — the therapy can break cycles of recurrence that antibiotics alone may not resolve.
According to an article in Clinical Infectious Diseases, observational studies report cure rates exceeding 90% for C diff. However, clinical trials show substantially lower effectiveness — around 68% — highlighting that a significant portion of patients do not respond to FMT methods.
“Twenty-five to 30% of people actually don’t respond to this treatment modality,” Krishna Rao, MD, an associate professor of internal medicine at the University of Michigan in Ann Arbor and co-founder and director of its FMT program, told Becker’s. “To make progress, we need to know what’s actually happening at a mechanistic level — why a healthy community resists C. difficile while an unhealthy one doesn’t — and how to convert an unhealthy community into one that has colonization resistance.”
He noted that some case reports have shown patients improve even when donor stool is processed to remove bacteria, suggesting components such as bile acids, short-chain fatty acids or viruses may contribute to recovery.
The COVID-19 pandemic also reshaped FMT practice. When stool banks such as OpenBiome paused operations in 2020 to implement SARS-CoV-2 screening, Dr. Rao relied on vancomycin and fidaxomicin taper regimens, which worked for more than 90% of his recurrent C. diff patients. FMT was reserved for the small subset who did not respond.
Looking ahead, Dr. Rao expects the field to shift toward precisely designed microbiome treatments made up of selected bacterial strains, each chosen for a specific purpose — for example, producing compounds that block C. diff toxins. One example already in use is an FDA-approved, spore-based therapy.
“For C. diff, FMT works, but it’s barely working for anything else,” he said. “To make progress in other microbiome-mediated conditions, we need rationally designed products with known mechanisms of action.”
He also cited gut-specific beta-lactamase enzymes, which break down antibiotics in the gut before they harm beneficial bacteria, and monoclonal antibodies such as bezlotoxumab that target C. diff toxins.
But even effective products can face financial hurdles. Bezlotoxumab, for example, was approved by the FDA but recently pulled from the market.
“Even when you have something that’s proven to work and saves lives, if the incentives aren’t aligned, it can die on the vine,” Dr. Rao said, noting that several gut-specific antibiotics and other candidates have failed despite strong clinical results.
