BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.
INTRODUCCIÓN Y OBJETIVOS: La colitis ulcerosa (CU) es difícil de tratar, y la terapia estándar no siempre inducen remisión. trasplante de la microbiota fecal (FMT) es un enfoque alternativo que induce la remisión en pequeñas series de pacientes con CU activa. Hemos investigado la seguridad y eficacia en un ensayo aleatorizado y controlado con placebo.
Métodos: Se realizó un estudio paralelo de los pacientes con CU activa sin diarrea infecciosa. Los participantes fueron examinados por sigmoidoscopia flexible al inicio del estudio y luego fueron asignados al azar a los grupos que recibieron FMT (50 ml, a través de un enema de donantes anónimos sanos; n = 38) o placebo (50 ml enema de agua; n = 37) una vez por semana durante 6 semanas. Los pacientes, los médicos y los investigadores estaban cegados a los grupos. El resultado primario fue la remisión de la CU, definida como una puntuación Mayo ≤2 con una puntuación de 0 endoscópica Mayo, en la semana 7. Los pacientes presentó muestras de heces al inicio del estudio y durante cada semana de FMT para el análisis microbioma. El ensayo fue suspendido antes de inutilidad por el Comité de Seguridad de Datos y Vigilancia, pero todos los pacientes que ya están incluidos en el ensayo se les permitió completar el estudio.
RESULTADOS: Setenta pacientes completaron el ensayo (3 abandonaron de entre el grupo placebo y 2 del grupo FMT). Nueve pacientes que recibieron FMT (24%) y 2 que recibieron placebo (5%) estaban en remisión a las 7 semanas (una diferencia estadísticamente significativa del riesgo de 17%; intervalo de confianza del 95%, 2% -33%). No hubo diferencia significativa en los eventos adversos entre los grupos. Siete de los 9 pacientes en remisión después FMT recibió la materia fecal de un solo donante. Tres de los 4 pacientes con CU ≤1 año entraron en remisión, en comparación con 6 de 34 de aquellos con CU> 1 año (p = 0,04, prueba exacta de Fisher). Heces de los pacientes que recibieron FMT tenía una mayor diversidad microbiana, en comparación con la línea base, que la de los pacientes que recibieron el placebo (p = 0,02, prueba de Mann-Whitney).
CONCLUSIONES: FMT induce la remisión en un porcentaje significativamente mayor de pacientes con CU activa que el placebo, sin diferencias en los eventos adversos. donantes y hora de la UC fecal parecen afectar a los resultados. Número ClinicalTrials.gov: NCT01545908.
BACKGROUND & AIMS: Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial.
METHODS: Patients with mild to moderately active UC (n = 50) were assigned to groups that underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control); each transplant was administered via nasoduodenal tube at the start of the study and 3 weeks later. The study was performed at the Academic Medical Center in Amsterdam from June 2011 through May 2014. The composite primary end point was clinical remission (simple clinical colitis activity index scores ≤2) combined with ≥1-point decrease in the Mayo endoscopic score at week 12. Secondary end points were safety and microbiota composition by phylogenetic microarray in fecal samples.
RESULTS: Thirty-seven patients completed the primary end point assessment. In the intention-to-treat analysis, 7 of 23 patients who received fecal transplants from healthy donors (30.4%) and 5 of 25 controls (20.0%) achieved the primary end point (P = .51). In the per-protocol analysis, 7 of 17 patients who received fecal transplants from healthy donors (41.2%) and 5 of 20 controls (25.0%) achieved the primary end point (P = .29). Serious adverse events occurred in 4 patients (2 in the FMT group), but these were not considered to be related to the FMT. At 12 weeks, the microbiota of responders in the FMT group was similar to that of their healthy donors; remission was associated with proportions of Clostridium clusters IV and XIVa.
CONCLUSIONS: In this phase 2 trial, there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received fecal transplants from healthy donors and those who received their own fecal microbiota, which may be due to limited numbers. However, the microbiota of responders had distinct features from that of nonresponders, warranting further study. ClinicalTrials.gov Number: NCT01650038.
