CME Author: Zeena Nackerdien
Study Authors: Samuel P. Costello, Patrick A. Hughes et al; and Colleen R. Kelly and Ashwin N. Ananthakrishnan.
Target Audience and Goal Statement: Gastroenterologists, infectious disease specialists, and internists
The goal was to assess the efficacy of a short duration of treatment with fecal microbiota transplantation (FMT) in inducing remission of ulcerative colitis (UC) using anaerobically prepared stool.
- Can a short duration of FMT using an anaerobically prepared pooled stool suspension induce remission in active UC?
- Is it possible to achieve efficacy in UC using low-intensity (i.e., fewer doses of) FMT?
Study Synopsis and Perspective:
Colonic mucosal inflammation at the interface between the luminal contents and the mucosal immune system is a hallmark of the inflammatory bowel disease (IBD) ulcerative colitis (UC). Compared within the general population, UC is linked to a risk of colectomy and a higher risk of colorectal cancer. While the colonic microbiome has been linked to UC pathogenesis, most treatments have focused on the immune response rather than the luminal microbiome.
Samuel B. Costello, MBBS, of Queen Elizabeth Hospital in Woodville, South Australia, and colleagues, explained in their new study that based on evidence from the literature, variable efficacies have been observed among patients with active UC treated with high-intensity, aerobically prepared FMT regimens. The authors hypothesized that since oxygen-sensitive organisms/metabolites, of which colonic microorganisms are prime examples, may be reduced or lost during FMT preparation, a low-intensity regimen with anaerobically prepared FMT might enhance microbial viability.
In the randomized, controlled, double-blind clinical trial conducted from 2013 to 2016, the researchers assessed 133 UC patients for eligibility across three Australian tertiary referral centers. A total of 38 patients were randomized to a donor FMT (dFMT) group and 35 to an autologous FMT (aFMT) to assess the efficacy of FMT to induce disease remission at 8 weeks using anaerobically prepared stool.
Since oxygen-sensitive organisms and their metabolites were thought to be important for the beneficial clinical effects of dFMT, the latter intervention represented stool samples that were pooled from three to four highly screened donors and prepared under anaerobic conditions. Patients received the interventions via colonoscopy, followed by two enemas over 1 week. The researchers offered open-label therapy to aFMT participants at the end of 8 weeks and patients were followed for up for 1 year.
Steroid-free remission of UC (total Mayo score ≤2 with an endoscopic Mayo score ≤1 at week 8) served as the primary endpoint and was reassessed at 12 months. Secondary endpoints included adverse events (AEs).
A total of 69 of the 73 randomized patients (95%) completed the trial (mean age of 39, with 33 [45%] of the total women). Primary outcomes were achieved in 12 of the 38 participants receiving pooled dFMT versus three of the 35 participants who received aFMT. The secondary outcome of clinical response — i.e., ≥3-point reduction in total Mayo score at week 8 and 12 months, was achieved in more dFMT-treated (55%) than aFMT-treated patients (23%).
There were three serious AEs in the dFMT group (one case of worsening colitis, one case of C. difficile colitis requiring colectomy, and one case of pneumonia) and two serious AEs in the aFMT group (both worsening colitis). Remission was maintained at 12 months in 42% of participants who achieved steroid-free remission of UC at week 8 following dFMT.
All of the organisms most strongly associated with a positive treatment response in the study were anaerobes (10 bacteria and the archaea Methanobrevibacter smithii), the researchers reported. Increased microorganism abundance remained relatively stable from weeks 4 and 8, but variability in abundance was noted for many of the organisms by 12 months. Elevated abundance of Anaerofilum pentosovorans and Bacteroides coprophilus species was strongly associated with disease improvement following dFMT.
Regarding the mechanism of action, the researchers said, “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,” although 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 the treatment groups at weeks 4 or 8, and SCFA concentrations were not associated with any observed dFMT treatment effect, Costello and co-authors noted.
Besides the inherent limitations of an observational crossover study design, the lack of a prespecified antibiotic “washout” period may have led to bias in the initial microbiome assessment, the authors noted. Due to statistical power limitations, secondary outcomes, including safety, and results from subgroup analysis should be considered exploratory, the team added. Other study limitations included the fact that there was no central video reading of colonoscopies. Moreover, stool handling was not done under completely anaerobic conditions outside of the anaerobic chamber.
Source Reference: JAMA 2019; 321(2):156-164
Editorial: JAMA 2019; 321(2): 151-152
Study Highlights: Explanation of Findings
Safety profiles for adults with mild to moderate UC who were randomized to receive dFMT (n=38) or aFMT (n=35) were acceptable, and at 8 weeks, 32% of dFMT-treated patients achieved the primary outcome of steroid-free remission versus 9% of aFMT-treated patients. Several patients who achieved remission at 8 weeks (42%) maintained that remission at 12 months.
Unlike drugs, use of FMT is complicated by batch-to-batch variations in microorganisms, which make it difficult to establish an exact dosage, noted Colleen R. Kelly, MD, of Brown University in Providence, Rhode Island, and Ashwin N. Ananthakrishnan, MD, MPH, of Massachusetts General Hospital and Harvard University in Boston, writing in an accompanying editorial. They said that efficacy >90% could be achieved with a single FMT for C. difficile infection — a major source of morbidity and mortality for hospitalized patients.
Addition of FMT also offered better outcomes in recurrent C. difficile infection. But prior studies involving UC cases and the delivery of the intervention by enema differed in that as many as 40 doses of FMT (high-intensity treatment) had to be administered to demonstrate beneficial clinical effects, the editorialists noted. One such study of active UC achieved steroid-free clinical remission with endoscopic remission or response in 27% of patients allocated multi-donor, intensive-dosing FMT versus 8% who received placebo colonic infusion.
“High-intensity FMT did not appear to be more effective than a low-intensity FMT regimen” based on the current results, Kelly and Ananthakrishnan said.
Regarding the durability of effects on the gut microbiome of the recipient after FMT, bacterial diversity rose up to 8 weeks, but was lost by 12 months, suggesting, the editorialists said, that an appropriate interval between FMT may lie somewhere between these two time points. In addition, maintenance therapy might be necessary, as evidence from the literature had shown that durability of donor bacterial strains after FMT was limited in patients with IBD and in immunocompromised patients, Kelly and Ananthakrishnan said.
To date, all four randomized clinical trials, including this one, demonstrated rates of remission between 24% and 32% in FMT-treated UC patients, which represented an advance over the 9% and 17% respective remission rates reported for the approved biologics, adalimumab and vedolizumab; however, trials involving biologics enrolled patients with greater disease severity.
The editorialists hypothesized that manipulation of the microbiome in UC would likely be most effective when used in combination with agents that target the immune dysfunction underlying the disorder. Furthermore, this exploratory trial has unleashed more questions that should be investigated in larger trials — for example, FMT delivery methods, mechanisms of action, long-term durability of effects, and whether FMT has a role as monotherapy or adjunct treatment in mild or severe UC.
Kelly and Ananthakrishnan said that it is possible to imagine that therapeutic manipulation of intestinal microbiota by full-spectrum FMT or a targeted approach using synthetic cultured consortia of bacterial species might one day be a component of UC treatment. Regulatory agencies should therefore provide a reasonable pathway for approval of microbial-based therapeutics, the editorial stated.