Have We Made Progress in Fecal Microbial Transplantation?
Fecal Microbiota Transplantation (FMT) is a therapy in which fecal material from a single (or multiple) healthy donor(s) is transferred to a diseased individual to restore health. The technique was first described in the 4th Century in China, practiced since the 1950’s and re-discovered relatively recently. Different delivery techniques of the fecal material have been used using enemas and oral applications in capsule form. In a recent article in the Microbiome Times, Luis Gosalbez discussed the current status of this intriguing therapeutic modality.
FMT was the therapeutic strategy that sparked considerable interest in microbiome drug development back in 2013, with the publication of the results of a human trial in which FMT was shown to be highly efficacious in the treatment of recurrent Clostridium difficile (C. difficile) colitis, a serious condition affecting the large intestine.
C. difficile colitis results when the normal microbial ecosystem in the colon is severely disrupted, a situation generally induced by the intake of antibiotics in vulnerable individuals. Characteristic symptoms include diarrhea, belly pain, and fever. The disease can cause severe damage to the colon and can even be fatal. Its prevalence has been increasing and affects about 200,000 individuals per year. Paradoxically, even though antibiotics are the most common cause of the disease, the most common treatment includes antibiotics, even though recurrence rates with this approach are high, and scientists have tried to find a more effective and long-lasting therapeutic modality.
Multiple research groups and companies have been involved in the development and evaluation of FMT treatments for different conditions, including C. difficile infection, irritable bowel syndrome, inflammatory bowel diseases, autism spectrum disorder and metabolic syndrome. Despite some promising results in some studies, results have been conflicting and largely disappointing, and the dramatic benefits seen in the treatment of C. difficile could not be demonstrated in other disease areas, raising fundamental questions about the usefulness of this approach for disorders other than C. difficile.
Initially, FMT was performed after little processing of the original fecal material. However, advances in microbiome science have allowed to identify the key microbial species or activities thought to be responsible for its efficacy. At the same time, safety concerns, such as transmission of enteric infections, or induction of metabolic and psychiatric disorders (as has been observed in animal models) have also made it necessary to design processes which eliminate or rule out the presence of infectious agents, donors with psychiatric disorders, or microbial metabolites with potential systemic effects. Whereas some current FMTs are still the result of simple processing (e.g., filtration, centrifugation), some companies have designed sophisticated procedures to further refine the original material, creating products composed of defined consortia of microorganisms.
A logical step in the search to develop gut microbiome-based therapeutics was to replace the actual stool transplantation with transfer of gut microbial communities (or consortia), or by the metabolites produced by these consortia. Drugs based on FMT-derived defined consortia of microorganisms are amongst the most advanced clinical programs of the entire microbiome drug development industry.
In 2021, two leading companies, namely Seres Therapeutics and Rebiotix-Ferring Pharmaceuticals, reported positive results from their respective Phase 3 clinical trials in recurrent C. difficile infection using microbial consortia, and this month, Seres announced further confirmatory results from an additional study with their lead candidate for this indication. Both companies are now involved in the process of approval to become the first FDA-authorized microbiome therapeutic for C. difficile.
Whereas infectious diseases (primarily recurrent C. difficile) have classically been the main application of FMT, oncology indications have been gaining significant traction over the last years. The exploration of the therapeutic benefit of FMT in cancer patients started with applications in supportive care as a means to preserve or restore the gut microbial ecosystem damaged or impoverished after cancer treatments, for instance aiming at preventing colitis and chemotherapy-induced diarrhea. These applications have followed a mechanistic rationale somehow similar to the one of FMT in C. difficile.
However, after it became clear that the gut microbiome plays an important role in mediating and predicting the benefits of some cancer treatments, in particular immunotherapy-based approaches, efforts have started to explore FMT as an adjuvant therapy to immunotherapy in the treatment of melanoma, leukemia and other malignancies. Given its potential immune-modulatory capacity, also a large share of FMT research programs have focused on immune-mediated diseases, mostly Inflammatory Bowel Disease.
In summary, based on available clinical data from high quality clinical trials, several questions about the clinical benefits of FMT and its more commercial variants can be addressed:
- Has the initial excitement about the possibility to treat a range of serious and common disorders with FMT from a healthy individual to a patient turned into tangible benefits for diseases other than C. difficile colitis? Despite multiple clinical trials and research studies, the answer to date is negative. The reason that FMT works in C. difficile patients and in germfree (gnotobiotic) animals (which don’t have any microbes in their gut) but not in other conditions may be due to several reasons: one has to do with the resilience and stability of microbial ecosystems. Even though many of the disorders in which FMT has been tried have been found to have altered gut microbial communities (so called dysbiosis), these altered microbial ecosystems still provide a high degree of resilience and stability which prevents the transplanted microbiome to colonize the gut with the transplanted bacteria, a phenomenon called colonization resistance. Alternatively, in many of these conditions, the observed state of dysbiosis may not play a causative role in the pathophysiology of a disease but may be an epiphenomenon.
- Has there been progress towards replacing the somewhat archaic technique of transferring actual fecal material from one person to another with a more scientific approach? Based on the recent positive studies with such microbial consortia in patients with C. difficile colitis, the answer is a definitely yes.
- Will FMT become an important strategy in the prevention and treatment of medical, psychiatric, and neurological conditions in which an altered gut microbiome has been identified, including metabolic syndrome, some forms of depression and Alzheimer’s disease? the answer is a careful yes. Barriers to overcome in this approach include a better understanding of the role of dysbiosis, including the virome in these disorders, identification of consortia of microbes that are effective, and ways to temporarily overcome colonization resistance of the gut microbiome to allow the transplanted microbes to “take roots” in the gut of the patient. Until these barriers have been overcome and objective effectiveness of FMT has been demonstrated, this approach should not be used.
Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA, the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience and the Founding Director of the Goodman-Luskin Microbiome Center at UCLA.