Microbiota therapeutics, such as fecal microbiota transplantation (FMT), could offer more diverse, personalized treatment options for patients with inflammatory bowel disease (IBD), particularly for those with no response or resistance to existing therapies, according to a new review.
Treatments that target the microbiome could help when combined with current drugs that alter the immune system, the study authors wrote.
“Our current drug therapies for IBD achieve remission in only a fraction of patients. We have seen the remarkable potency of microbiota-based therapies, specifically FMT, to treat patients with Clostridioides difficile infections,” co-author Ari Grinspan, MD, director of GI microbial therapeutics at the Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
“Initial reports of FMT to treat IBD, specifically ulcerative colitis, have been promising, but there are currently no approved therapies that treat IBD by directly targeting the gut microbiota,” he said. “We aimed to look back at prior studies exploring microbiota-based therapies to treat C difficile and IBD to gain insight on how to pave the way forward.”
The review was published in the May issue of The Lancet Gastroenterology and Hepatology.
Learning From Previous Trials
Grinspan and colleagues reviewed 15 FMT clinical trials published from 2015 to 2023, including eight for ulcerative colitis, two for Crohn’s disease, and five for recurrent C difficile infections (rCDIs). The learnings from the use of microbiota therapeutics in past studies could help move the field forward and inform the drug development pathway for IBD, the authors noted.
In initial rCDI studies, patients were given standard-of-care antibiotics (eg, vancomycin and fidaxomicin) to suppress both the C difficile strain and their own microbiota to allow for new microbiota, in addition to undergoing bowel preparation before FMT to further reduce pre-transplant microbiota and residual antibiotics. Then, a fecal slurry was administered to the duodenum through an esophagogastroscopy or a nasogastric tube or to the terminal ileum or right colon through a colonoscopy.
While little is known about the influence of dose on outcome or the minimal effective dose, FMT has been successful in rCDIs with one or only a few doses, resulting in clinical resolution in up to 92% of patients, the authors pointed out.
Less invasive routes have been developed, including oral and enema formulations. But a review of studies shows that “FMT via colonoscopy is superior to an enema or nasogastric tube but similar to an oral capsule for the treatment of rCDIs, suggesting colonoscopy as the gold standard and oral capsules as the future of microbiota interventions,” the authors wrote.
In IBD, maintenance dosing will likely be required to achieve durable remission, the authors noted. For exploratory studies in ulcerative colitis, enema dosing has been more widely applied and required multiple doses during an induction period of 8-12 weeks, leading to a higher cumulative dose compared with rCDIs.
If maintenance dosing is required to achieve a sustained benefit in IBD, defined microbiota therapeutics that are independent of donor stool would provide a safer, more scalable option, they added.
So far, five randomized controlled FMT trials using various treatment regimens for patients with mild to moderate ulcerative colitis have been conducted and provide a solid foundation for future trials, the authors wrote. The studies demonstrated clinical remission for 25%-53% of patients at induction phases ranging from 7 to 12 weeks. In two studies, FMT recipients also had higher microbiota diversity.
FMT’s efficacy in Crohn’s disease has been explored less, but two phase 1 trials show promise, the authors noted. In one study, involving patients with mild to moderate Crohn’s disease, clinical remission was achieved in 67% of patients at 8 weeks after FMT, with no significant difference between delivery method, either colonoscopy or gastroscopy. In the other study, involving patients with colonic or ileocolonic Crohn’s disease, steroid-free remission was achieved in 87.5% at week 10 and 50% at week 24 after FMT delivered via colonoscopy.
Targets for Further Research
In general, the clinical outcome of FMT in IBD is likely affected by procedural details, donor characteristics, pretreatment with bowel preparation or antibiotics, drug preparation, dose, frequency, and route of administration, the authors wrote. Just as IBD clinical trials have reached standardization around centralized endoscopic reading and scoring systems, microbiota therapeutics trials would benefit from standardization in these areas. Dosing and strain composition, for instance, will be vital for IBD application.
“For now, there is no significant change to clinical practice,” Grinspan said. “Insights discussed in this investigation will propel the science of IBD medicine into innovative new heights, given that the therapeutic effectiveness of current treatment options for the entire IBD patient population has only seen minimal improvement over the past decade.”
Future studies in IBD should focus on identifying the patient populations most likely to benefit from microbiota therapies, standardizing drug preparation, normalizing the dose across recipients by potency, identifying the minimal dose to maintain remission, exploring the combination of microbiota therapies with existing IBD drugs, and understanding the underlying mechanisms to better integrate strategies and provide options to patients, Grinspan and colleagues wrote.
“In terms of the route of administration, the priority should be on oral formulations to facilitate trial logistics, increase patient adherence and acceptability, and accelerate drug development pipelines,” they added.
‘Next Step’ in Treatment
“While this alternative — or perhaps complementary — approach to current immunotherapies may not be immediately applicable to IBD treatment, it is clearly a next step for treating those patients who failed to completely respond to immune-based therapies,” R. Balfour Sartor, MD, co-director of the Center for Gastrointestinal Biology and Disease at The University of North Carolina at Chapel Hill, told Medscape Medical News.
Sartor, who wasn’t involved with this study, researches IBD management and the mechanisms of microbial and mucosal immune responses.
“In my opinion, modulating the abnormal microbial composition and function of most IBD patients is a very attractive next step to inducing broader and more sustained remissions,” he said. “I believe this approach will require repeated long-term dosing with defined microbial products that avoid the risk of transmitting pathogens and the donor variability of human fecal transplants.”
In addition, clinical trials need to define whether microbial modulation should be used as separate or adjunctive therapy, Sartor said.
“My belief is that this approach will be highly effective as concurrent or sequential therapy combined with immunomodulator or immunosuppressive treatment,” he said. “It will be necessary to identify optimal recipients who will predictably obtain best results by screening patients for their individual microbial profiles and metabolic function. Based on these profiles, various microbial therapies can then be tailored for the best patient outcomes.”
The authors did not report funding for the review. Several authors declared grants, consulting fees, and stock options with various pharmaceutical companies, and two authors have patents related to microbial therapeutics. Sartor reported no relevant disclosures.
Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape Medical News, MDedge, and WebMD.
