This post was written by Thomas Gurry, a Postdoctoral Associate in the Center for Microbiome Informatics and Therapeutics.
Fecal Microbiota Transplantation (FMT) has proven itself to be a highly effective intervention for patients suffering from recurrent Clostridium difficile (C. diff) infection. This success has prompted an explosion of interest in FMT as a potential clinical strategy for combating a number of other chronic conditions likely to involve the human gut microbiota. High on the list of candidate conditions is Inflammatory Bowel Disease (IBD), a chronic inflammatory disorder consisting of two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). While immunosuppressive therapies exist for treating IBD, they do not always result in remission, and patients suffering from severe refractory cases can face colonic resection (in the case of CD) or removal of the entire colon (in the case of UC) as the only remaining options.
Can FMT treat IBD?
In recent years, reports of FMT as a potential treatment for IBD have started to appear. In 2011, Thomas Borody et al. presented an abstract to the American Journal of Gastroenterology in which they described three patients that had been suffering from long-term refractory IBD with a lack of response to standard therapies, yet achieved remission after FMT. A larger study published in Gastroenterology in 2015 by Rossen et al. described a 48 UC patient double-blind randomized clinical trial, where patients assigned to the treatment arm underwent FMT from a total of 15 healthy donors, while patients assigned to the control arm received FMTs from themselves (autologous FMT). However, in this study, no statistically significant difference in clinical and endoscopic remission between the two arms was found.
In a recently published study in the journal Gastroenterology, Moayyedi et al. reported an FMT clinical trial in patients suffering from UC where patients receiving healthy donor FMTs had a statistically significantly higher rate of remission after seven weeks than the placebo arm (which received water instead of an FMT). Of particular interest is the fact that the effect was largely attributable to a single donor (Donor B) among the five healthy donors used for the study. Of the nine patients that achieved remission at seven weeks post-FMT, seven received transplants from Donor B. Although the apparent efficacy of Donor B relative to the other donors was not quite statistically significant (p=0.06), these results suggest that the microbiota of this specific donor’s material had particular properties which are conducive to remission in UC but which were absent in other donors.
New ways to study donor efficacy
This single donor effect opens up a number of fascinating questions: how rare is donor B in the healthy population? Are all effective donors equally effective in all patients? What are the microbial signatures that result in remission in FMT recipients suffering from UC? Is the favorable effect on the immune system attributable to specific bacteria, or specific metabolites? To what extent can this efficacy be encapsulated into a smaller, synthetic community?
In order to answer these questions systematically, we must usher in a new age of FMT trials designed to answer specific questions of this nature. One can determine the efficacy of FMT as a therapy for a given disease by analyzing three associated parameters:
- the ability of ‘good’ donor material in treating the condition
- the frequency of ‘good’ donors in a healthy population
- the extent to which a ‘good’ donor is appropriate for all recipients.
In all of these cases “good” could be in simple opposition to ‘ineffective’, or exist on a more graded spectrum.
In the case of treating C. diff, almost all healthy donors are highly effective in most recipients, marking a favorable extreme on the spectrum of FMT as a therapeutic strategy. In the context of UC, the numbers of patients are too small to allow for robust inference of these parameters from the Rossen and Moayyedi studies, but the data do indicate that UC is markedly different from C. diff, in that the frequency of good donors in the healthy population is low enough that only a single effective donor was reported. However, Donor B was only successful in inducing remission in 39% of patients, compared to 10% in the other donors taken in the aggregate. This suggests that once a good donor for UC is found, it is likely that this donor will only be able to treat a subset of recipients.
Some Final Thoughts
While these results are encouraging, the discovery of statistically significant outcomes in FMT trials will be very challenging due to the many potential combinations of donor and recipients. It will take larger trials to observe an effect in a UC-like condition requiring a specific yet unknown donor-recipient pairing than in a C. diff-like condition for which the efficacy of a good donor is high for all recipients. It remains to be seen whether Donor B’s efficacy at treating UC can be reproduced using donors with alternate microbial compositions, and whether some good donors are quantitatively better than others. More broadly, the donor effect observed in the Moayyedi study highlights the need for more sophisticated FMT trial designs which account for potential donor effects.
Thomas Gurry is a Postdoctoral Associate working in the Center for Microbiome Informatics and Therapeutics. When not studying the clinical data from FMT trials, he ponders ways to make his beard as thick as possible.