OBJECTIVES: To study the role of faecal microbiota transplantation [FMT] in maintenance of remission in ulcerative colitis [UC].
METHODS: In this pilot study, patients with UC in clinical remission achieved after multi-session FMT were randomly allocated to either maintenance FMT or placebo colonoscopic infusion every 8 weeks, for 48 weeks. The standard of care [SOC] therapy was continued in all patients. The primary endpoint was maintenance of steroid-free clinical remission [Mayo score ≤2, all subscores ≤1] at Week 48. Secondary endpoints were achievement of endoscopic remission [endoscopic Mayo score 0] and histological remission [Nancy grade 0, 1] at Week 48.
RESULTS: In all, 61 patients in clinical remission were randomised to receive either FMT [n = 31] or placebo [n = 30]. The primary outcome was achieved in 27/31 [87.1%] patients allocated FMT versus 20/30 [66.7%] patients assigned placebo [p = 0.111]. Secondary endpoints of endoscopic remission (FMT: 18/31 [58.1%] versus placebo: 8/30 [26.7%], p = 0.026) and histological remission (FMT: 14/31 [45.2%] versus placebo: 5/30 [16.7%], p = 0. 033) were achieved in a significantly higher number of patients with FMT. Three patients receiving FMT [9.7%] and 8 patients on placebo [26.7%] relapsed. There were no serious adverse events necessitating discontinuation in patients on FMT; one patient who relapsed on placebo required colectomy.
CONCLUSIONS: Maintenance FMT in patients who are in clinical remission may help sustain clinical, endoscopic and histological remission in patients with UC.
IMPORTANCE: High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.
OBJECTIVE: To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.
DESIGN, SETTING, AND PARTICIPANTS: A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.
INTERVENTIONS: Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.
MAIN OUTCOMES AND MEASURES: The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.
RESULTS: Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.
CONCLUSIONS AND RELEVANCE: 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. Further research is needed to assess longer-term maintenance of remission and safety.
TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12613000236796.
INTRODUCTION Fecal microbiota transplantation (FMT) has shown promise in treating ulcerative colitis (UC); however, the characteristics of an ideal stool donor are unknown. Butyrate, a short-chain fatty acid (SCFA), may modulate UC remission. We investigated the safety, efficacy and the translational impact of FMT capsules (FMTc) in active UC using rationally selected donors high in butyrate. METHODS A double blind, randomized, placebo-control pilot trial was conducted in patients with mild to moderate UC (Mayo Score 4-10) utilizing FMT by colonoscopy (50g stool) followed by daily FMTc (0.375g stool). The placebo arm received sham FMT and daily placebo capsules. All subjects were pre-treated with a 7-days of antibiotics. FMT material was derived from 2 healthy donors with high stool butyrate. Adverse events (AEs), histologic activity, endoscopic score, clinical response, and inflammatory markers were monitored. Exploratory endpoints included measurements of stool butyrate and other SCFAs (gas chromatography), mucosal serotonin transporter (SERT) and tryptophan hydroxylase 1 (TPH1) mRNA by qPCR. RESULTS Fifteen patients met initial eligibility criteria and were randomized to the FMT (n=7) or placebo (n=8) arm. Baseline patient characteristics were similar between FMT (mean age=39yrs, female=3, baseline Mayo score=4.6) and placebo (mean age=49yrs, female=4, baseline Mayo score=4.4) arms. After baseline colonoscopy, 3 participants were excluded due to a lack of endoscopic disease activity. Overall, there were no statistically significant differences in AEs and no serious AE related to FMT. At week 12, histologic inflammation decreased in 4/6 (66%) subjects in the FMT arm vs. 1/6 (16.6%) the placebo arm. Histologic remission (lack of neutrophils) was achieved in 3 (50%) FMT vs. 0 placebo subjects. Endoscopic response (decrease in Mayo subscore > 1 or UCEIS > 2) was achieved in 3/7 (43%) FMT vs. 0/8 (0%) placebo. Endoscopic Mayo score and IBDQ bowel symptoms were superior in the FMT arm at week 12 (p=0.05) and week 18 (p=0.05). Clinical remission (Mayo score < 3) or response (>3 point reduction in Mayo Score) was achieved in 2/7 (29%) and 2/7 (29%) vs. 1/8 (13%) and 0/8 (0%) in FMT compared to placebo. Fecal lactoferrin was positive in 50% FMT subjects vs. 100% of placebo subjects at week 18. Stool SCFAs initially increased in the FMT (acetate, propionate in 4/4; butyrate, valerate in 3/4) vs. placebo arm (butyrate, acetate, propionate in 1/3; valerate in 0/3). TPH1 and SERT were lower in subjects compared to healthy controls; FMT did not affect levels from baseline. CONCLUSION To our knowledge, this is the first report of FMT capsules in the treatment of UC. These data suggest that FMTc are safe and potentially decrease histologic, endoscopic and clinical evidence of disease. These effects may be related to changes in SCFA production. [Figure Presented]
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.
To study the role of faecal microbiota transplantation [FMT] in maintenance of remission in ulcerative colitis [UC].
METHODS:
In this pilot study, patients with UC in clinical remission achieved after multi-session FMT were randomly allocated to either maintenance FMT or placebo colonoscopic infusion every 8 weeks, for 48 weeks. The standard of care [SOC] therapy was continued in all patients. The primary endpoint was maintenance of steroid-free clinical remission [Mayo score ≤2, all subscores ≤1] at Week 48. Secondary endpoints were achievement of endoscopic remission [endoscopic Mayo score 0] and histological remission [Nancy grade 0, 1] at Week 48.
RESULTS:
In all, 61 patients in clinical remission were randomised to receive either FMT [n = 31] or placebo [n = 30]. The primary outcome was achieved in 27/31 [87.1%] patients allocated FMT versus 20/30 [66.7%] patients assigned placebo [p = 0.111]. Secondary endpoints of endoscopic remission (
FMT:
18/31 [58.1%] versus placebo: 8/30 [26.7%], p = 0.026) and histological remission (
FMT:
14/31 [45.2%] versus placebo: 5/30 [16.7%], p = 0. 033) were achieved in a significantly higher number of patients with FMT. Three patients receiving FMT [9.7%] and 8 patients on placebo [26.7%] relapsed. There were no serious adverse events necessitating discontinuation in patients on FMT; one patient who relapsed on placebo required colectomy.
CONCLUSIONS:
Maintenance FMT in patients who are in clinical remission may help sustain clinical, endoscopic and histological remission in patients with UC.
