Fecal microbiota transplant (FMT) has been highly successful in treating patients who are ill with Clostridioides difficile. However, research is just beginning to determine its potential for treating other inflammatory conditions.
At Monroe Carell Jr. Children’s Hospital at Vanderbilt, pediatric gastroenterologist Maribeth R. Nicholson, M.D., M.P.H., was the senior author on a Cochrane Review article that synthesized the findings of 12 randomized controlled trials on FMT for inflammatory bowel disease (IBD), namely ulcerative colitis (UC) or Crohn’s disease.
“The challenge is that everybody does these treatments a little bit differently.”
“Given that there were a lot of differences in protocols and other influences on individual center study outcomes, we wanted to aggregate the results to provide a better landscape of how effective these interventions are,” Nicholson said.
Several of the studies reported significant lowering of inflammation in UC, inducing remission, but the ability to sustain this remission was less certain. Both initial and longer-term outcomes in FMT for Crohn’s disease were equivocal between patients and controls, but included significantly fewer studies and participants.
FMT in the Clinic
FMT can be administered by enema, nasoduodenal tube, or in oral-capsule formulations, but colonoscopy is often favored because biopsies can be taken to help monitor disease progress, Nicholson says.
FMT has a good safety profile, but there are legitimate concerns about infections, including COVID-19, particularly in immunocompromised patients. If administered through colonoscopy, procedural complications like perforation may also occur.
The included studies varied in their methods, dosages, and frequencies of FMT administration, as well as the types of donors and baseline severity of disease. Nicholson’s team combined this data and rated their confidence in the evidence, based on factors like study methods, sample sizes, and participant awareness of the treatment.
“The challenge is that everybody does these treatments a little bit differently, so you’re not fully comparing apples to apples,” Nicholson said. “We don’t yet have enough studies to answer some of the big questions, like how many repeated administrations and which delivery method are optimal. This is likely not one size fits all, like it is for C. difficile infections. No one method has shown clear superiority so far.”
Short-term Remission for UC
The most definitive finding was FMT reduced colonic inflammation in UC assessed at a 6-to-12-week follow-up, inducing clinical and endoscopic remission. This was borne out in 10 studies, one of which was pediatric, with 468 participants total. The risks of adverse events and improvement in quality of life were equivocal, as was the long-term remission data provided by just two studies.
None of the studies found evidence that FMT modulates active Crohn’s disease or maintains remission in patients with controlled Crohn’s disease, although there were far fewer studies in these patients.
“It may make sense that more patients with UC are helped than in Crohn’s, since it is a disease of the colon, where FMT has its direct impact,” Nicholson said. “Crohn’s tends to affect the entire gastrointestinal system, but we need to do more studies to see if FMT may benefit these patients as well.”
Trajectory of Care for IBD
Without similarly robust improvements for patients with IBD, as has been seen in those with C. difficile, better solutions may be found by probing the impact of repetitive FMT, the targeting of particular microbes, or escalating antibiotic pretreatment before FMT, Nicholson said.
“I do think learning to properly target the microbiome is one of the pieces of treating IBD that we’re missing,” she said. “We’re really good at targeting the immune system, but not good at this. Is it specific bacteria that we need to target more closely or specific metabolites, or do we need to do it for longer periods of time?”
Toward this end, she and her colleagues are enrolling patients to analyze their intestinal microbiome.
“We know the microbiome has a role in the development of inflammatory conditions, autoimmune conditions, and allergic conditions,” she said. “We also know that antibiotic use in early life is associated with a later risk of inflammatory conditions such as IBD. But these are areas we still don’t have our heads wrapped around. I think in the next two decades or so, there’s going to be dramatically improved understanding of this.”
Future Treatments
Patients with C. difficile have an expanding array of treatments, including two new FDA-approved microbial therapeutics for adults. Some of these new treatments may be effective for patients with IBD in the future with more research. Nicholson says they have also learned much about how certain diets can induce and maintain remission in some patients with IBD, likely due to their effects on metabolites and the intestinal microbiome.
On the horizon are more refined and non-human-derived FMT products that avoid the infection risk associated with FMT, she says.
As a pediatrician, Nicholson laments the sparse research in children, in whom these diseases are less common but often have an enormous impact on quality of life.
“We need to include pediatric patients in a lot of these trials.”
“Sometimes it is harder to convince pharmaceutical companies to study some of these treatments in kids, because the numbers are just not high enough,” she said. “I’m always advocating that we need to include pediatric patients in a lot of these trials.”
C. difficile and IBD
C. difficile treatment has been the most studied and successful use for FMT. Nicholson previously authored a retrospective review of 396 pediatric patients with C. difficile, 148 of whom had IBD, finding FMT success in curing recurrent C. difficile infection in children with and without IBD, similar to adult findings.
She is now investigating the presence and absence of symptoms in patients with C. difficile infection.
“It’s really fascinating that some patients will have C. difficile in their colon, with significant toxins associated with it, but they are asymptomatic, even though they have the same strains and amount of toxin that could cause death in somebody else,” she said. “What is protecting that first group from disease – some metabolite or bacteria or the intestinal mucus? If we can solve this mystery, we can hopefully use this knowledge to protect others.”
