Costello SP, Hughes PA, Waters O, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA. 2019;321(2):156-164.
To assess the ability of a short course of anaerobically prepared, rectally delivered multi-donor fecal microbiota transplant (FMT) to induce and maintain steroid-free remission in patients with active ulcerative colitis compared to placebo FMT (aerobically prepared autologous stool).
Randomized, double-blind placebo-controlled trial
The study included 73 adults (mean age 39; 45% women) with mild to moderately active ulcerative colitis.
Study Medication and Dosage
Participants received polyethylene glycol bowel prep the evening prior to FMT. The next day they received one colonoscopic administration of 200 mL of anaerobically prepared, multi-donor FMT (intervention) or aerobically prepared autologous stool (placebo). Participants were given loperamide 2 mg by mouth before the procedure.
Within the next week they received two 100 mL retention enemas of either the intervention or placebo.
The primary outcome was steroid-free remission of ulcerative colitis (defined as total Mayo score ≤2 with an endoscopic Mayo score of ≤1) at 8 weeks.
Secondary outcomes included:
- Steroid-free remission at 12 months
- Clinical response (≥3 reduction in Mayo score) at 8 weeks and 12 months
- Clinical remission (Simple Clinical Colitis Activity Index ≤2 at 8 weeks and 12 months)
- Endoscopic remission (Mayo score <1 at week 8 and 12 months)
- Microbiome (by 16SrRNA) and fecal short chain fatty acid (SCFA) concentrations at baseline and weeks 4, 8, and 52
- Adverse events
- Lamina propria mononuclear cell (LPMC) analysis of biopsied tissue at baseline and week 8
- Patient perception and acceptability of FMT
There was statistically significant better outcome at 8 weeks in the intervention group vs the placebo: 32% of the intervention group vs 9% of the placebo group achieved the primary endpoint of steroid-free remission with endoscopic remission (difference 23%; 95% confidence interval [CI]: 4%-42%; P=0.03) at 8 weeks.
Of those in the intervention group who achieved remission at 8 weeks, 42% were still in remission at 12 months. We aren’t able to compare this to the placebo group, since members of the placebo group were offered the intervention following the 8-week primary endpoint.
I think the real take-home of this study for clinicians at this time is not to marvel at the potential benefits of the anaerobic preparation but to note that the safety and efficacy of rectally administered FMT for ulcerative colitis is confirmed yet again.
Clinical response (difference 32; 95% CI: 10%-54%; P=0.007) and clinical remission (difference 30%; 95% CI: 7%-51%; P=0.01) were both significantly higher in the intervention group.
Microbial diversity significantly increased in the intervention group at weeks 4 and 8, due mostly to an increased abundance of anaerobes. Specifically, increased abundance of the obligate anaerobes Anaerofilum pentosovorans and Bacteroides coprophilus was strongly associated with disease improvement.
There were no significant differences in SCFAs, adverse events, or LPMC analyses between the 2 groups.
At 12 months, 95% of participants thought that 1-week induction therapy with FMT would be acceptable to patients with ulcerative colitis.
Fecal microbiota transplant is not approved for any use in the United States. Clinician use of FMT outside of clinical trials is tolerated by the US Food and Drug Administration (FDA) via “enforcement discretion” only when used for patients with Clostridium difficile (“C diff”) infections not responding to standard therapies (recurrent C difficile infection [rCDI]).1 FDA guidelines do not permit clinicians to prepare or administer FMT for patients with ulcerative colitis, unless they also have rCDI.
Many patients with ulcerative colitis want to use FMT. As early as 2013, surveys have indicated that “despite reporting satisfactory to excellent disease control with their treatments, the vast majority of patients with ulcerative colitis are interested in or willing to consider FMT.”2 They are not waiting around for clinicians to get permission; ulcerative colitis patients are simply doing FMT at home, because it is easy, and it appears that it is remarkably safe and can be quite effective at inducing and perhaps maintaining remission in patients with ulcerative colitis.
The first case study of FMT for ulcerative colitis was published in the Lancet in 1989,3 and there have been 3 peer-reviewed randomized controlled trials (RCTs) of FMT for inflammatory bowel disease (IBD) published prior to the paper being reviewed here:
- Rossen at al gave 2 doses of nasoduodenal tube-administered FMT over 3 weeks and did not find significant benefit for the FMT group.4
- Moayyedi et al gave 6 doses of enema-administered FMT over 6 weeks and found a statistically significant 19% increase over placebo in their primary outcome: clinical and endoscopic remission.5
- Paramsothy et al gave 1 colonoscopic dose, then 40 enema-administered doses of FMT over 8 weeks and also found a statistically significant 19% increase over placebo in their primary outcome: steroid-free clinical remission with endoscopic remission or response.6
Moayyedi and Paramsothy’s intervention groups reached remission 19% more often than their placebo groups, but in the current study under review (Costello et al) the intervention group reached remission 23% more often than the placebo group, a superior response to treatment, despite fewer doses of FMT. Possible explanations for this could include that Moayyedi, Paramsothy, and many clinicians have been over-dosing, or because Costello’s anaerobic preparation is superior. Moayyedi’s single-donor, enema-only administration approach is unlikely to have been responsible for the possibly reduced benefit, since Paramsothy, like Costello, used multidonor FMT with initial colonoscopic administration.
Costello et al may be suggesting a new FMT preparation protocol that could lead to remission in a slightly higher percentage of FMT recipients. I think the real take-home of this study for clinicians at this time is not to marvel at the potential benefits of the anaerobic preparation but to note that the safety and efficacy of rectally administered FMT for ulcerative colitis is confirmed yet again. In all 3 RCTs of rectally administered FMT published so far, it appears about 20% of people with ulcerative colitis enter clinical remission with endoscopic healing who would not have otherwise done so, and about 5%-10% have clinical remission or response who would not have otherwise.
For comparison’s sake, biologic therapies, which are an ongoing therapy, cost thousands of dollars per month in the United States and appear to induce remission in only 15% of people who would have otherwise not experienced remission.7
Our patients are doing FMT at home, and they want our support. While intervening or applying FMT in office is not recommended, practitioners should have knowledge of the barriers to safe, effective home FMT for ulcerative colitis. These include:
- Lack of eligible donor
- Need for donor screening
- Unfamiliarity with logistic protocols
- Lack of medical monitoring
At this time in the United States, if our patients don’t have an eligible donor in their friend or family community, the patient can go to an FMT clinic in a jurisdiction in which FMT for ulcerative colitis is permitted, including clinics in the United Kingdom, Bahamas, Mexico, and Australia.
However, if they do have a potential donor, we can assist in donor screening, logistic protocols, and medical monitoring of their condition as they undergo home FMT, as well as providing care using other modalities, of course. Instructions for self-administering FMT at home have been in peer-reviewed publications since 2010.8
One note regarding safety: in June 2019, FDA reported a death in 1 of 2 immunocompromised patients who had contracted extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli (E coli) from an FMT donor, and began to require that any FMT used in clinical trials come from donors who have been screened for multi-drug resistant organisms (MDROs) with proper history questions and stool tests.9
This additional testing is an important requirement for investigational FMT, or any FMT that is used with immunocompromised patients. For context, there have been published papers on FMT in immunocompromised populations since 2014.10 All of the trials and reviews to date, including the most recent ones in February11 and March12 2019, have concluded that FMT appears to be acceptably safe for use in immunocompromised populations. It also appears to be equally effective in the immunocompromised and the immunocompetent populations. On a final note, FMT has been given to patients already colonized with MDROs to successfully decolonize them, even when donors have not been screened for MDROs,13 and even when the patients are immunocompromised.14
FDA is exceedingly unlikely to approve whole-stool FMT for any use. If and when FDA approves an FMT-similar microbiological product for rCDI that can be used off-label for ulcerative colitis, or approves an FMT-similar for ulcerative colitis, our ulcerative colitis patients may stop using whole-stool home FMT. Until that time, FDA applies the precautionary principle “better safe than sorry,” and does not allow clinicians to prepare or administer FMT for patient use. Some of our patients, however, will invoke the proactionary principle: “better well than wondering.”