Donor Fecal Transplant Improves Colitis in Randomized Trial

Ricki Lewis, PhD

January 15, 2019

Anaerobically-processed fecal microbiota transplantation (FMT) from donors helped about one third of patients with ulcerative colitis (UC) in a small, randomized, double-blind clinical trial, according to findings published online today in JAMA.

Fecal transplant is FDA approved in the United States to treat only recurrent or refractory Clostridium difficile infection. Most treatments for UC target the immune response, and not the colonic microbiome.

Three prior trials have assessed efficacy of FMT to treat UC, with mixed results. The studies used aerobic conditions for stool preparation and delivered large microbial populations. However, because most species in the colonic microbiome are obligate anaerobes, oxygen exposure during preparation could be killing the very species that quell the inflammation of UC.

Therefore, Samuel P. Costello, MBBS, of the Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, Australia, and colleagues investigated whether they could induce short-term UC remission using anaerobic preparations of pooled donor fecal material.

The researchers treated 73 adults with mild to moderate UC at three tertiary referral centers between June 2013 and June 2016. The patients were evaluated at 8 weeks and followed annually until June 2017. Thirty-eight participants received anaerobically prepared pooled donor FMT and 35 received their own prepared stool.

The treatment was introduced using colonoscopy, followed with two enemas in a 7-day period. The patients in the control group had the option to receive autologous treatment open-label following unblinding after the 8th week, and were then followed for a year.

To assess outcomes, the authors used the Mayo score, which combines endoscopic and clinical markers and ranges from 0 to 12, where 0 is no disease and 12 is severe disease. The primary outcome was steroid-free remission with a Mayo score of 2 or less with an endoscopic Mayo score of 1 or less at week 8 and reassessment at 12 months.

Twelve of the 38 (32%) participants receiving donor FMT went into remission as did 3 of the 35 (9%) receiving autologous FMT (odds ratio [OR], 5.0; 95% confidence interval [CI], 1.2 - 20.1; P = .03). Five of the 12 participants (42%) responding to donor FMT remained in remission at 12 months.

Three serious adverse events occurred in the donor FMT group (worsening colitis, C difficile infection requiring colectomy, and pneumonia) and two in the autologous FMT group (worsening colitis).

Compared with those in the autologous group, more patients in the donor FMT group had a clinical response at 8 weeks, defined as a ≥3-point reduction in total Mayo score (55% vs 23%; OR, 4.3; 95% CI, 1.5 - 11.9; P = .007). They were also more likely to have clinical remission, defined as a Simple Clinical Colitis Activity Index score ≤2 (47% vs 17%; OR, 4.5; 95% CI, 1.5 - 13.5, P = .01).

In addition, at 8 weeks, 11% of patients receiving donor FMT had steroid-free endoscopic remission, defined as a Mayo score of <1, compared to none in the control group. All but one of the patients in the control group opted to receive donor FMT in the open-label part of the trial.

At 12 months, flexible sigmoidoscopy data was available for 26 of 38 (68%) patients in the donor FMT group and revealed that 11 (42%) were in clinical and endoscopic remission.

Patient acceptability was high for both groups, both before the one-week course of FMT (65 of 69 participants [94%]) and at the 12-month mark (57 of 60 [95%]).

The researchers conclude, "In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks."

The study was "hypothesis generating," the researchers write, and further investigation will be necessary to assess whether the increased microbial diversity in the pooled donor material, and the exclusion of oxygen in the preparation, facilitated remission. The 10 most abundant bacteria and one archaeal species with increased abundance were anaerobic, and the team singled out Anaerofilum pentosovorans and Bacteroides coprophilus as "strongly associated with disease improvement following" donor FMT.

"Pooling stool from multiple donors serves to increase the bacterial diversity of the product and the chances that material from a donor with optimal composition of bacteria in the stool will be included," Colleen R. Kelly, MD, of Brown University, Providence, Rhode Island, and Ashwin N. Ananthakrishnan, MD, of Harvard Medical School, Boston, Massachusetts, write in an accompanying editorial.

Because the microbial diversity waned by year’s end, Kelly and Ananthakrishnan suggest that "future studies should incorporate microbiome analyses at additional time points to determine how frequently FMT may need to be administered to maintain effects."

Limitations of the study include the observational design after 8 weeks and loss of some patients to follow-up.

The study was funded by the National Health and Medical Research Council and the Gutsy Foundation. Costello has received grants from the National Health and Medical Research Council and Gutsy Foundation, as well as fees from Janssen, Shire, Ferring, Microbiotica, and Pfizer. Coauthors reported one or more financial relationships with one or more of the following companies: Abbvie, Janssen, Gilead, Abbott, Allergan, Bayer, Celgene, Ferring, Hospira, Merck Sharp & Dohme, Nestle, Orphan, Pfizer, Shire, Takeda, and Vifor. Kelly was a site investigator of a clinical trial for Finch Therapeutics and served on the advisory board for Openbiome. Ananthakrishnan received grant support from the Crohn's and Colitis Foundation, National Institutes of Health, Chleck family Foundation, and Pfizer, and served on the advisory board for Gilead.

JAMA. Published online January 15, 2019. Abstract, Editorial

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