One-week treatment with anaerobically prepared pooled donor fecal microbiota transplantation (dFMT) led to more than three times the likelihood of remission at 8 weeks versus autologous counterpart (aFMT) in active mild-to-moderate ulcerative colitis (UC), Australian researchers found.
In the small, randomized trial, the primary outcome — defined as steroid-free remission of UC at week 8 — was achieved in 32% (12 of 38 participants) receiving pooled dFMT compared with 9% (three of 35) receiving aFMT, for a difference of 23% (95% CI 4%-42%) and an odds ratio of 5.0 (95% CI 1.2-20.1, P=0.03), according to Samuel B. Costello, MBBS, of the Queen Elizabeth Hospital in Woodville, South Australia.
Furthermore, five of 12 dFMT participants (42%) who achieved remission at week 8 maintained remission at 12 months, they reported in JAMA.
FMT has demonstrated variable efficacy in treating active UC in three randomized clinical trials using aerobically prepared stool suspensions with relatively high treatment intensities, the authors noted.
The current study, conducted at three centers from June 2013 to June 2016, randomized 73 adult patients and followed them until June 2017. More than half the cohort was male, and the median age was 38.5 in the dFMT arm and 35 in the aFMT arm.
Patients were randomized in blinded fashion to receive either anaerobically prepared pooled dFMT (n=38) or autologous FMT (n=35) via colonoscopy followed by two FMT enemas over 7 days. At 8 weeks, 0pen-label dFMT therapy was made available to aFMT arm.
The primary outcome was steroid-free remission at 8 weeks, defined as a total Mayo score of ≤2 (range 0-12) with an endoscopic Mayo score of ≤1 (range 0-3).
In secondary outcomes, clinical response was also observed in more participants receiving dFMT than aFMT: 21 of 38 (55%) versus eight of 35 (23%), for a difference of 32% (OR 4.3, 95% CI 1.5-11.9, P=0.007). Clinical remission was also greater at 47% versus 17%, for a difference of 30%.
Steroid-free endoscopic remission occurred in four of 38 participants (11%) receiving dFMT versus none of 35 receiving aFMT (95% CI –1 to 27, P=0 12). At 8 weeks, 34 of 35 aFMT participants (97%) crossed over to dFMT. At 8 weeks, the mean total Mayo score decreased in both groups but more so with dFMT: aFMT –1.2 (95% CI –1.9 to–0.5) and dFMT –3.5 (95% CI –4.3 to –2.7).
As to dFMT’s mechanism of action, “It is plausible that the treatment effect of dFMT resulted from the acquisition of metabolic functional capacity from donor microorganisms and was not driven by a primary immunological effect,” the authors wrote, adding that dedicated studies are required to validate the findings.
In other measures, metabolomic change from baseline in stool concentrations of butyrate and other short-chain fatty acids (SCFAs) was not significantly different between treatment groups at weeks 4 or 8, and SCFA concentrations were not associated with any observed dFMT treatment effect. Safety was similar in both arms, with three serious adverse events in the dFMT group and two in the aFMT group.
In an accompanying editorial, Colleen R. Kelly, MD, of Brown University in Providence, Rhode Island, and Ashwin N. Ananthakrishnan, MD, MPH, of Harvard University in Boston, noted that the four published randomized trials of FMT for UC have demonstrated similar rates of remission ranging from 24% to 32%. In comparison, UC trials of the biologics adalimumab (Humira) and vedolizumab (Entyvio) have shown efficacy rates of just 9% and 17%, respectively, albeit in cohorts with greater disease severity.
Another important finding of the current study is that low-intensity FMT may be as effective as high-intensity FMT since positive results emerged with only three doses versus the more than 40 doses in some previous research. For example, in a 2017 study, separate researchers reported on the efficacy of dFMT over placebo with an intensive regime of a single colonoscopic delivery to the right colon, followed by enemas 5 days per week for 8 weeks.
Kelly and Ananthakrishnan also surmised that since the increased bacterial diversity seen with FMT at 8 weeks was lost by 1 year, the appropriate interval for FMT administration may lie somewhere between these two points, and maintenance therapy is probably necessary.
“Future studies should incorporate microbiome analyses at additional time points to determine how frequently FMT may need to be administered to maintain effects,” they wrote. They also cautioned that restoring microbial diversity may not be the only factor, and that a more nuanced alteration in the microbial composition determines therapy response.
Despite FMT’s promise, this approach poses problems versus drug therapy, in that, exact dosage is difficult to determine and microorganisms vary widely from batch to batch, the editorialists noted.
Ultimately, broad microbial restoration via FMT is effective in only a third of UC patients, a proportion that parallels the efficacy of systemic immunosuppression. “Rather than stand-alone therapy, manipulation of the microbiome in UC is likely to be most effective when used in combination with agents, such as immunomodulators and biologics, which target the immune dysregulation underlying the disorder,” they wrote.
Study limitations included its open-label crossover phase after 8 weeks and incomplete outcome ascertainment, making 12-month findings observational only. Furthermore, there was significant loss of follow-up by 12 months. Also, the study’s limited power with the associated risk of type 1 error necessitated considering secondary outcome and subgroup analyses as exploratory only, and the study was not powered to assess safety.
In addition, there was no central video reading of colonoscopies, and also no prespecified antibiotic washout period before entry, leading to possible bias in initial microbiome assessment of patients taking antibiotics. Moreover, stool handling was not done under completely anaerobic conditions outside of the anaerobic chamber.
The study was funded by the National Health and Medical Research Council and the Gutsy Foundation.
Costello disclosed relevant relationships with Janssen, Shire, Ferring, Microbiotica, and Pfizer. Co-authors disclosed multiple relevant relationships with industry including AbbVie, Shire, Janssen, Ferring, Takeda, Abbott, Allergan, Bayer, Celgene, Hospira, Merck Sharp & Dohme, Nestle, Orphan, Pfizer, and Vifor.
Kelly disclosed relevant relationships with Finch Therapeutics and OpenBiome. Ananthakrishnan disclosed a relevant relationship with Gilead.