Fecal Transplantation in Active Ulcerative Colitis?
Andreas Stallmach, Jena
Lancet 2017; 389: 1218–28
Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.
|Paramsothy S1, Kamm MA2, Kaakoush NO3, Walsh AJ4, van den Bogaerde J5, Samuel D6, Leong RWL6, Connor S7, Ng W8, Paramsothy R9, Xuan W10, Lin E11, Mitchell HM12, Borody TJ11|
The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis.
We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4–10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis.
From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1–11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission.
Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor–recipient matching based on microbial profiles.
WHAT SHOULD YOU KNOW ABOUT THIS PAPER
Disturbances of the intestinal microbiota have been linked to the pathogenesis of ulcerative colitis (UC). In active UC microbiota differs from that in healthy subjects and is less diverse (1), (2), (3). As donor microbiota richness and the number of transferred phylotypes have been associated with treatment success in UC (4), this study used a multi-donor approach and a more intense protocol with a higher frequency of fecal microbioma transfer (FMT) applications over an extended period of time to achieve the desired endpoint in patients with UC. Microbial manipulation with faecal microbiota transplantation could offer a new treatment paradigm, beyond immune-based therapies in UC.
Based on the success of FMT in patients with recurrent clostridium difficile infection (CDI) various groups have conmfirmed the therapeutic value of FMT in patients with UC. On this topic, five meta analyses have been published within the last half year (5), (6), (7), (8), (9), which summarize the four controlled studies with that indication. In all meta analyses are positive effects of FMT (odds ratio between 2,89 and 3,6) reported; NNT to reach a remission is about 4, the same magnitude like biologicals in controlled studies. Antibiotic pretreatment may lead to a higher remission rate (54% vs. 25,1%) (6).
How should FMT be performed in patients with active ulcerative colitis ? No standardized approach can be concluded from the different studies. The regimens used are heterogeneous and differ with regards to mode of application (e.g. endoscopic versus enema), frequency (ranging from once to five times per week over 8 weeks), pretreatment (with/without antibiotics) or the transplantate used (from a selected donor to a multidonor approach). The actual study presented here by Paramsothy et al. is based on a multidonor approach with a high frequency of application (overal 40 times). Based on the results achieved as well as on theoretical considerations this concept appears to make sense and it should therefore be pursued further..
Can we recommend the routine use of FMT to treat ulcerative colitis ulcerosa based on these data? Following current understanding (e.g. of German authorities such as the Federal Institute for Drugs and Medical Products, BfArM) FMT is considered a medical treatment. Therefore, preparation and application of dono stool is subject to the respective laws applicable to drugs, depending on the countries situation. The production and performance are within the responsibility of the treating physician who has to be personally involved in the production and application process, and the treatment has to be notified to the local health authorities (10).
How will FMT be developing for the treatment of chronic inflammatory bowel disease (IBD)? Any progress of FMT in treating patients with recurrent CDI will also benefit FMT on IBD. Accordingly, FMT will be developed from endoscopic application to capsule intake using frozen microbioma. An excellent paper by the group of Stefan Schreiber could demonstrate, that not the complete microbioma has to be transferred, but a watery filtrate without bacteria could be sufficient to heal CDI (11). Furthermore, attempts will be undertaken to better select the microbioma of stool donors, to enrich certain positive taxa and reduce negative ones, e.g. Fusobacterium spp. In all likelihood, a recombinant formulation produced in vitro will be established for these indications.
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