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Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet
Gastroenterology, Volume 149, Issue 1, July 2015, Pages 15 - 18
See “Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial,” by Moayyedi P, Surette MG, Kim PT, et al on page 102; “Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis,” by Rossen NG, Fuentes S, van der Spek MJ, et al, on page 110; and “Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook,” by Kelly CR, Kahn S, Kashyap P, et al on page 223.
Podcast interview: www.gastro.org/gastropodcast . Also available on iTunes.
The role of the gut microbiome in human disease and inflammation has gained international attention over the past decade. The success of fecal microbiota transplantation (FMT) in treating Clostridium difficile infections (CDI) has raised the possibility that FMT may be beneficial in other diseases associated with alterations in gut microbiota, or dysbiosis. 1 Excitement around the possibility of FMT for inflammatory bowel disease (IBD) among patients and clinicians has grown rapidly, as anecdotal reports and small case series have suggested that FMT may have a beneficial effect.2 and 3 A recent metaanalysis showed that FMT in IBD is variable in efficacy with beneficial effects seemingly limited to patients with Crohn’s disease and the pediatric population. 4 In this issue of Gastroenterology, the first 2 randomized, controlled studies evaluating the efficacy of FMT in ulcerative colitis (UC) are presented.5 and 6
Moayyedi et al report the results of a randomized, placebo-controlled trial using FMT to induce remission in patients with mild-to-moderate UC. Seventy-five subjects received weekly FMT or placebo (water) via retention enema for 6 weeks. Investigators and recipients were blinded to the treatment allocation. The primary endpoint was remission, defined as Mayo Score of <3 with an endoscopic subscore of 0 at week 7. Six donors were used in this study, with the majority of subjects receiving FMT from 2 donors (A and B). The data safety and monitoring board (DSMB) recommended discontinuing the study at interim analysis because of futility in reaching the primary efficacy endpoint. The authors presented interim data at an international conference in May 2014, reporting a negative study. 7 With the addition of 22 subjects already enrolled, this study attained significance for the primary end point of remission. Each of these additional subjects had received active FMT from a single donor: “donor B.” Overall, the authors found that subjects who received FMT achieved remission significantly more than those receiving placebo (9/38 [24%] vs 2/37 [5%]; P = .03). Although only cursory microbiome analyses were performed, it seems that patients who received active FMT developed an increase in microbial diversity compared with those who received placebo.
In the study reported by Rossen et al, 50 patients, also with mild to moderately active UC, were treated with either donor stool or autologous FMT (infusion of their own stool as placebo) delivered via nasoduodenal tube at baseline and again 3 weeks later. Only 37 completed assessment for the primary endpoint—clinical remission combined with a ≥1-point decrease in the Mayo endoscopic score at week 12. There was no difference in clinical and endoscopic remission between the 2 groups in either the intention-to-treat or per-protocol analyses. This study was also terminated at interim analysis by the DSMB because of futility. The assumed treatment effect (70%) was too high, resulting in a study that was, unfortunately, underpowered to test the hypothesis that FMT is beneficial in UC. The authors did show that subjects who responded favorably to FMT shifted to develop a microbiota profile similar to their respective donors, whereas nonresponders did not shift.
These 2 studies make valuable contributions to the existing literature. Both represent an improvement compared with previous case series and cohort studies that were limited by small numbers of patients, open-label design, vague FMT protocols, incomplete reporting of IBD-specific data, and poorly defined outcomes. A major limitation on the studies from Moayyedi et al and Rossen et al is that they both dramatically overestimated the treatment effect of FMT for UC. Because of this error, the studies were terminated by their respective DSMB owing to futility.
Why was 1 study positive and the other negative? There were several major differences between these 2 trials ( Table 1 ). Moayyedi et al administered 6 FMT infusions via the lower gastrointestinal (GI) route, whereas Rossen et al administered only 2 and via the upper GI route. The upper GI route might render the active constituent of FMT ineffective by the time it reaches the diseased colon. It is also possible that there is a dose response or a threshold required for engraftment to be attained to alter effectively the gut microbiome and the downstream inflammatory cascade. Furthermore, treatment with anti-tumor necrosis factor was permitted in 1 study (Moayyedi et al) and not the other, and those subjects on immunosuppression did better, raising the question as to whether immune factors may have a role in successful FMT induction. These uncertainties make our ignorance clear; we still do not understand the active component of FMT. Is it a bacteria or bacterial metabolite, or is it the interaction between microbial and host factors?
|Characteristic||Moayyedi et al 5||Rossen et al 6|
|Study design||Double-blind, randomized (1:1), controlled||Double-blind, randomized (1:1), controlled|
|Study population||Adult patients with mild to moderate UC||Adult patients with mild to moderate UC|
|Sample size calculation||130||80|
|Subjects randomized (n)||75||50|
|Completing therapy (n)||70||37|
|Anti-TNF permitted?||Yes, at stable doses for ≥12 weeks||No|
|Route of FMT delivery||Retention enema||Nasoduodenal tube|
|Donor stool||6 volunteers, fresh or frozen||15 donors, fresh|
|Dose schedule||Weekly for 6 weeks||2 doses (0 and 3 weeks)|
|Primary endpoint||Remission (Mayo score ≤2 with an endoscopic score of 0) at week 7.||Remission (simple clinical colitis activity score ≤2) combined with ≥1-point decrease in Mayo endoscopic score at week 12|
|Subjects who achieved the primary endpoint||9/38 (24%) treated with FMT vs 2/37 (5%) controls (P = .03)||7/23 (30.4%) treated with FMT vs 5/25 (20%) controls (P = .51)|
|Microbiome analyses||Yes; increased diversity in FMT treated subjects compared with the control group.||Yes; increased diversity of responders in both groups. FMT treated group developed similar microbiota profile to respective donor.|
FMT, fecal microbiota transplantation; TNF, tumor necrosis factor; UC, ulcerative colitis.
The results from Moayyedi et al suggest that FMT is a heterogeneous treatment, and the effect may be donor dependent. Although donor B’s impact seemed to sway the results of this study, it is important to note that use of stool from this donor did not attain significance versus placebo in achieving remission (P = .06). It is intriguing to suggest that 1 person’s stool may be more effective than another, but this study was not designed or powered to make that conclusion. The microbiota of this donor was enriched in members of the Lachnospiraceae family and the Ruminococcus genus, a similar profile to another donor in this study associated with FMT success. Previous studies have revealed that certain bacterial taxa, including Lachnospiraceae, are depleted in IBD. 8 However, the small size of this study does not permit meaningful analyses of subgroups by donor or elucidate mechanisms of effect. Further investigation is required before we can say whether donor B has “the right stuff.”
It is clear that FMT is not nearly as effective in IBD as it is in CDI. CDI occurs as a result of marked disruption of the indigenous gut microbiota by antibiotics. 9 Treatment with FMT results in high cure rates for recurrent CDI, regardless of recipient, donor, or delivery method.10 and 11 Unlike CDI, IBD is a complicated disease with a complex pathologic interplay between genetic, immunologic, environmental, and microbial factors. IBD may be characterized by dysbiosis, but it is unclear if this is a cause or an effect of the underlying inflammatory process. Although FMT can lead to lasting changes in the gut microbiota that correlate with treatment as seen in CDI, 12 manipulating the microbiome may not be an effective strategy for treating IBD. Interestingly, although numbers are small, the data from Moayyedi et al suggest that newly diagnosed UC patients may have the best outcomes with FMT. Is there a window of opportunity to treat patients with FMT after diagnosis?
If FMT can make some IBD patients better, could it make others worse? Although the rate of serious adverse events in both of these studies was low, IBD flares and infections after FMT have been described,13, 14, and 15 and larger clinical trials to establish both efficacy and safety are critical before FMT can be considered ready for prime time. Although these 2 trials provide interesting data, we need more studies to establish the active ingredient or ingredients in FMT, 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. The availability of stable, encapsulated formulations and frozen banked donor material will facilitate these studies.
We have been treating our IBD patients with immunomodulation for several decades. Perhaps microbial modulation via FMT is another treatment strategy, but we are not there just yet. Based on the current data, FMT should remain in clinical trials and not clinical practice. There are 5 randomized, controlled trials of FMT in UC that are registered on clinicaltrials.gov that hopefully will shed additional light on the subject ( NCT02291523 , NCT02330653 , NCT02390726 , NCT01896635 , and NCT02335281 ).
- 1 L.P. Smits, K.E. Bouter, W.M. de Vos, et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013;145:946-953 Crossref
- 2 S. Kunde, A. Pham, S. Bonczyk, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr. 2013;56:597-601 Crossref
- 3 T.J. Borody, E.F. Warren, S. Leis, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003;37:42-47 Crossref
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- 6 N.G. Rossen, S. Fuentes, M.J. van der Spek, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149:110-118
- 7 P. Moayyedi, M. Surette, W. Wolfe, et al. A randomized, placebo controlled trial of fecal microbiota therapy in active ulcerative colitis. Gastroenterology. 2014;146(Suppl 1):S159
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- 10 E. van Nood, A. Vrieze, M. Nieuwdorp, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407-415 Crossref
- 11 G. Cammarota, G. Ianiro, A. Gasbarrini. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol. 2014;48:693-702
- 12 A. Weingarden, A. Gonzalez, Y. Vazquez-Baeza. Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. Microbiome. 2015;3:10
- 13 L.M. De Leon, J.B. Watson, C.R. Kelly. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11:1036-1038 Crossref
- 14 C. Kelly, C. Ihunnah, M. Fischer, et al. Fecal microbiota transplant for treatment of Clostridium difficile in immunocompromised patients. Am J Gastroenterol. 2014;109:1065-1071
- 15 E.L. Hohmann, A.N. Ananthakrishnan, V. Deshpande. Case records of the Massachusetts General Hospital. Case 25-2014. A 37-year-old man with ulcerative colitis and bloody diarrhea. N Engl J Med. 2014;371:668-675
Department of Medicine, The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
Department of Medicine, Lifespan Women’s Medicine Collaborative, The Miriam Hospital, Alpert Medical School of Brown University, Providence, Rhode Island
∗ Reprint requests Address requests for reprints to: Ari M. Grinspan, MD, Assistant Professor of Medicine, The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
Conflicts of interest These authors disclose the following: Dr Grinspan received research support from SUCCESS (Sinai Ulcerative Colitis Clinical, Experimental and System Studies). Dr Kelly served as a consultant and site investigator for Seres Health and received research support from Assembly Biosciences.
© 2015 AGA Institute, Published by Elsevier B.V.