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    The potential and pitfalls of fecal transplants

    Fecal microbiota transplantation, or FMT, has emerged as an effective treatment for recurrent Clostridium difficile infection. But there’s still much scientists don’t know about the procedure.

    Chalk illustration of the digestive system

    For patients with recurrent Clostridium difficile infection (CDI), every day presents a host of gastrointestinal struggles that impair their quality of life. Fed up with the abdominal pain, nausea, and constant diarrhea, some patients have found relief outside antibiotic therapy, turning to an unconventional but highly effective procedure known as fecal microbiota transplantation (FMT).

    FMT involves transplanting the stool of a healthy donor into the gastrointestinal tract of a sick patient to restore good bacteria in the gut microbiome. It’s often performed via colonoscopy but can also be done through retention enema or by consuming an oral capsule, among other methods.

    The gut microbiome can be compared to a forest, which is destroyed over time by a combination of infection and antibiotic use, says Majdi Osman, MD, clinical program director at the nonprofit stool bank OpenBiome. FMT helps to repopulate the gut ecosystem and restore its biodiversity.

    “The jury's still out on exactly what component of FMT is the one that is leading to the clinical effects,” says Osman. But it could be that through FMT, “all of these different pieces of the gut microbiome … are working together and are restored at the same time.”

    “It’s really hard to convey how awful it is to have recurrent C. difficile infection …. [But] that’s actually the best scenario to use the fecal transplant, because those are the patients in whom it appears to be 90% or more effective for curing and breaking the cycle of recurrent C. difficile infection.”

    Michael Woodworth, MD
    Emory University School of Medicine

    Its mechanisms may not be fully understood, but FMT is often a last resort for patients with recurrent CDI. And academic health centers are increasingly offering the procedure to meet a growing, urgent need. Research from the Centers for Disease Control and Prevention found that in 2011, CDI led to nearly half a million infections and about 29,000 deaths in the United States.  In addition, nearly 20% of people who have had CDI will get it again, according to the agency.

    “It’s really hard to convey how awful it is to have recurrent C. difficile infection,” says Michael Woodworth, MD, assistant professor of medicine at the Emory University School of Medicine. He notes that patients may be unable to work or go out in public because they can’t control their bowel movements. Add prolonged hospital stays and diminishing returns on antibiotic effectiveness to the situation, and patients have a recipe for despair.

    However, “that’s actually the best scenario to use the fecal transplant, because those are the patients in whom it appears to be 90% or more effective for curing and breaking the cycle of recurrent C. difficile infection,” says Woodworth.  

    Scientists are approaching the procedure with a combination of excitement and vigilance, as FMT’s potential is countered with many questions about its use in clinical practice.

    Fecal transplants go mainstream

    Using healthy human waste to treat illness is not a new practice, with records of bacteriotherapy dating as early as the fourth century in ancient Chinese medicine. But it wasn’t until the publication of a study in the New England Journal of Medicine in 2013 that FMT took off in current clinical research and practice. The study found the use of FMT to be significantly more effective than a regimen of vancomycin, an antibiotic commonly used to treat CDI.

    “That was the first time you had actually had an extremely well-designed, randomized clinical trial comparing different treatment options for C. diff and showing that one was remarkably better than the others. And that one, of course, was FMT,” says Daniel Uslan, MD, director of the University of California, Los Angeles (UCLA), Health Antimicrobial Stewardship Program and assistant clinical professor in the department of medicine. Following publication of the study, UCLA Health created its own FMT program to help patients with recurrent CDI.

    It was around this time that several other academic health centers launched FMT programs. Emory University established its Fecal Transplant Program in 2012 and created the Emory Microbiota Enrichment Program in 2016 to recruit participants for clinical research related to the microbiome.

    The institution has seen positive outcomes for patients using FMT: A 2018 study published in Clinical Infectious Diseases of FMT conducted at Emory Hospital found that 82% of patients with recurrent CDI had durable cure at follow-up. Nearly all patients said they would do FMT again, and about 70% of those patients said they would prefer FMT first to taking antibiotics, speaking to their frustration and desperation, says Woodworth.

    Emory is also part of a consortium funded by the National Institutes of Health along with Duke University Medical Center and Vanderbilt University Medical Center to study FMT for CDI and develop standards for the procedure.

    Safety first

    There is still much that remains to be known about FMT, due in part to a lack of high-quality evidence.

    “We need to have a better understanding of not only how these patients do long term, but a better understanding of what the risks of FMT might be in the short and long term,” says Uslan, who notes that without such information, it is difficult to counsel patients.

    Monika Fischer, MD, associate professor of medicine at the University of Indiana School of Medicine, created and leads the school of medicine’s fecal transplant program. But even she is cautious about recommending FMT for patients with recurrent CDI, offering the treatment only after going through patients’ entire health history and making sure they have exhausted any alternatives.

    “FMT is so widely available, and it really gained acceptance … among physicians as well as patients [as] the best treatment for refractory C. diff.,” she says. “That’s my experience too, but we really don't have great-quality evidence to back this up.”

    “We need to have a better understanding of not only how these patients do long term, but a better understanding of what the risks of FMT might be in the short and long term.”

    Daniel Uslan, MD
    University of California, Los Angeles

    Providers like Fischer have reason to be prudent about FMT. Concerns about the procedure resurfaced in June when the U.S. Food and Drug Administration released a safety alert after two immunocompromised adults who received FMT developed invasive infections from antibiotic-resistant Escherichia coli (E. coli). One of these patients died.

    Such cases underscore the need for rigorous screening standards, says Osman. The donor stool associated with the illnesses wasn’t screened for antibiotic-resistant E. coli. OpenBiome ⁠— which provides fecal matter to academic health centers that administer FMT ⁠— has intensive donor screening and monitoring processes to ensure that recipients won’t be exposed to infectious pathogens. The organization’s screening process is so selective, in fact, that Osman likes to note the greater likelihood of being accepted to Harvard University than becoming an OpenBiome stool donor.

    Receiving FMT at hospitals that use carefully screened stool can prevent tragedies like the deadly E. coli infection. Reports of do-it-yourself FMT have sprung up over the past several years, encouraging some patients to take matters into their own hands. But people who attempt the procedure without clinical supervision open themselves up to infection, says Osman.

    Expanding the evidence base

    With the growing interest surrounding the role of the gut microbiome in health, use of FMT has been considered as a potential treatment for illnesses beyond recurrent CDI. A 2016 review published in Therapeutic Advances in Gastroenterology pointed to “preliminary indications” for FMT in potentially treating inflammatory bowel disease, obesity, metabolic syndrome, and functional gastrointestinal disorders. Gastrointestinal disorders are not the only illnesses that FMT is poised to treat: OpenBiome is involved with clinical research studying FMT for depression, food allergies, liver disease, and more.  

    With much less evidence available for FMT outside of recurrent CDI treatment, it could be long before patients can easily and safely access the procedure for other illnesses — even those related to gastrointestinal health. “For other indications at this point, FMT is not ready to use in clinical practice,” says Fischer.

    However, she says that research conducted through academic health centers can get patients and providers closer to understanding FMT by creating prospective, randomized, double-blinded trials to determine the safety and efficacy of FMT.

    Uslan notes that bacteriotherapy is a discipline connecting experts across the health care spectrum, including infectious disease specialists, gastroenterologists, microbiologists, and primary care physicians who are coordinating care and working toward solutions. And while scientists are still exploring the mechanisms behind FMT, the procedure does offer some hope.

    “We are just now at the cusp of really trying to understand exactly how the microbiome influences a lot of health conditions other than C. diff,” he says. “There is tremendous interest, but mostly people are just glad to have an option for patients who are suffering.”