Despite promising findings from 2 studies of fecal microbiota transplantation (FMT) in patients with ulcerative colitis, the technology should remain in clinical trials and is not ready for routine practice in patients with inflammatory bowel diseases (IBD), write Ari M. Grinspan and Colleen R. Kelly in an editorial.
The success of FMT in treating Clostridium difficile infection (CDI) has raised the possibility that FMT might be used to treat other diseases associated with alterations in gut microbiota, including IBD. The July issue of Gastroenterology presents findings from the first 2 randomized, controlled studies evaluating the efficacy of FMT in patients with ulcerative colitis.
Paul Moayyedi et al report the results of a randomized, placebo-controlled trial of FMT to induce remission in patients with mild-to-moderate ulcerative colitis. Seventy-five subjects received weekly FMT or placebo (water) via retention enema for 6 weeks. They found that 9 patients who received FMT (24%) and 2 who received placebo (5%) were in remission at week 7. There was no significant difference in adverse events between groups. Interestingly, 7 of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with colitis for less than 1 year entered remission, compared with 6 of the 34 with colitis for more than 1 year. Grinspan and Kelly write that this might mean there is a window of opportunity for treating patients with FMT.
Grinspan and Kelly say that although only cursory microbiome analyses were performed, stool from patients receiving FMT acquired greater microbial diversity, compared with baseline, than that of patients given the placebo.
In the second study, Noortje G. Rossen et al tested the effects of FMT, via nasoduodenal delivery of autologous microbiota (control) or microbiota a healthy donor, in patients with mild to moderately active ulcerative colitis. Two FMTs were performed, 3 weeks apart. In the intention-to-treat analysis, 7/23 patients who received fecal transplants from healthy donors (30.4%) and 5/25 controls (20.0%) achieved the primary end point (clinical remission and ≥1-point decrease in the Mayo endoscopic score at week 12). In the per-protocol analysis, 7/17 patients who received fecal transplants from healthy donors (41.2%) and 5/20 controls (25.0%) achieved the primary end point. However, neither of these differences were statistically significant.
Grinspan and Kelly wrote that the assumed treatment effect (70%) was too high, resulting in a study that was, unfortunately, underpowered to determine whether FMT benefits patients with colitis. Rossen et al found that subjects who entered remission acquired a microbiota profile similar to that of their donors, whereas nonresponders did not.
The editorial states that the findings are valuable because all previous data on the effects of FMT in patients with ulcerative colitis came from case series and cohort studies, limited by small numbers of patients, open-label design, vague FMT protocols, incomplete reporting of IBD-specific data, and poorly defined outcomes.
Grinspan and Kelly wrote that a major limitation on the studies from Moayyedi et al and Rossen et al is that they each overestimated the treatment effect, and were therefore terminated for futility.
Why did 1 study report a positive result and the other a negative result? Grinspan and Kelly explain that Moayyedi et al administered 6 FMT infusions via the lower gastrointestinal route, whereas Rossen et al administered only 2 and via the upper gastrointestinal route. With the upper GI route, the active component of the microbiota might become ineffective by the time it reaches the diseased colon.
The editorial says that there might also be a dose response or a threshold required to alter the intestinal microbiome and reduce inflammation. Furthermore, treatment with anti-tumor necrosis factor was permitted in the study of Moayyedi et al, and subjects receiving the drugs had better outcomes, raising the question as to whether immune factors may have a role in the success of FMT.
Nonetheless, it is clear that FMT is not nearly as effective for patients with IBD as for patients with CDI. IBD is a complicated disease caused by multiple genetic, immunologic, environmental, and microbial factors – although IBD can be characterized by dysbiosis, it is not clear if this is the cause or an effect of the inflammatory process. Grinspan and Kelly say that although FMT can lead to lasting changes in the gut microbiota, manipulating the microbiome may not be an effective strategy for treating IBD.
The editorial adds that although the rate of serious adverse events in both studies was low, IBD flares and infections after FMT have been reported, so larger clinical trials are needed to determine the efficacy and safety of FMT in these patients.
Grinspan and Kelly say that we need more studies to determine the active components of the fecal microbiota, the ideal donor, the ideal recipient, the best mode of delivery, and the best dose. An adequately powered trial will likely require several hundred patients and may not be feasible in the near future.