TY - JOUR
AU - Singh Pannu,, Anmol
AB - Abstract 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. Inflammatory bowel disease, clinical remission, endoscopic remission, histological remission, faecal microbiota transplantation 1. Introduction Ulcerative colitis [UC] is a chronic and progressive inflammatory disease with a relapsing and remitting course.1 Conventionally, induction of remission in patients with UC is achieved with 5-aminosalicylates [5-ASAs], corticosteroids, and biologics. Subsequently, these patients are maintained on 5-ASAs, thiopurines, or biologics. However, 5-ASAs have modest efficacy, and corticosteroids and thiopurines have substantial adverse events with long-term use.2–5 In addition to this, annual relapse rates of up to 25–40% have been reported despite use of optimal doses of 5-ASAs and/or thiopurines.5–12 Biologics [infliximab, adalimumab, and vedolizumab] are approved for induction and maintenance of remission.13–15 Though efficacious, these agents are expensive, can cause potentially serious adverse events, and despite use of these drugs, less than half of the patients maintain remission and up to one-fifth of patients with inflammatory bowel disease [IBD] may require surgical interventions.16–18 Therefore, newer treatment strategies are being evaluated for the induction and maintenance of remission in patients with active UC. Faecal microbiota transplantation [FMT] is emerging as a novel therapy for UC as it targets gut microbial dysbiosis, which in addition to the host’s genetic susceptibility and immune response, contributes to the pathogenesis of UC.19 Transplantation of faecal matter from a healthy individual to a patient with active UC has been proposed to correct dysbiosis-mediated immunological disturbances by inhibiting Th1 differentiation, activity of T cells, leukocyte adhesion, and production of inflammatory mediators.19 Several studies have reported the efficacy of FMT for the induction of remission in patients with active UC.20–23 However, except for a small series of three paediatric patients with UC where 22–30 treatments with FMT aided withdrawal of immunotherapy [infliximab, 6-mercaptopurine, and steroids],24 the role of FMT as a maintenance therapy in patients who have achieved clinical remission on this therapy has not been reported so far. 2. Materials and Methods 2.1. Study design This was a pilot randomised study conducted in the Department of Gastroenterology, Dayanand Medical College and Hospital, a tertiary care hospital in northern India. The study was approved by the Institutional Review Board and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all subjects. The study was registered with Clinical Trials Registry-India [CTRI/2018/02/012148]. 2.2. Study population Since September 2015, patients with active UC [Mayo score 4–10] who were being treated with standard of care therapy [5-ASAs, corticosteroids, and thiopurines] have been offered FMT as an add-on therapy. Those with proctitis [E1 disease] and on topical 5-ASAs were excluded. Patients who consented underwent seven sessions of FMT via a colonoscopic route for induction of remission [Supplementary Figure 1, available as Supplementary data at ECCO-JCC online]. These patients have been analysed in part and have been reported.25 Patients who achieved clinical remission [defined as Mayo score ≤2, with each subscore ≤1] with FMT and were on stable medication regimens [5-ASA and azathioprine for 6 months] were eligible for this study. Eligible patients who consented were then randomised in a 1:1 ratio according to a computer-generated randomisation list, to receive either FMT or placebo by a colonoscopic route every 8 weeks,for a further 48 weeks. The standard of care, i.e. 5-ASA with/without azathioprine, in a stable dose [5-ASA 4-4.8 g/day, azathioprine 2 mg/kg/day] was continued in all patients. 2.3. Intervention The interventions [colonoscopic infusion of FMT or placebo] were scheduled at Weeks 0, 8, 16, 24, 32, 40, and 48. Both patients and treating physicians were blinded to the nature of intervention done. Bowel preparation was done with polyethylene glycol lavage, a night before the procedure. Ileocolonoscopy was performed under conscious sedation by two endoscopists [VMe, YG] and the slurry [faecal slurry or placebo] was administered into the ileum and/or caecum. A single donor was used for all the patients. He was a healthy, unrelated, voluntary individual aged 32 years, with no personal or family history of UC or any other autoimmune disease. He was screened by stool microscopy and culture for common detectable enteric pathogens [Salmonella, Shigella, Campylobacter, Vibrio cholera, Entamoeba coli, Clostridium difficile, Giardia lamblia, and Cryptosporidium] and also for antibodies against hepatitis A, C, and E, hepatitis B surface antigen [HBsAg], syphilis, and human immunodeficiency virus [HIV]. In order to ensure an uninterrupted supply of faecal slurry, stool samples of the donor were stored at -80⁰C in a stool bank and used after thawing, in case the fresh stool sample was either not available or not suitable for processing. The faecal slurry was prepared from freshly passed stools by the donor on the morning of the procedure. These stool samples were inspected visually on the day of procedure and only those with Bristol stool score 3 or 4 were used. The sample [100 g] was diluted with preservative-free normal saline [200 ml] and homogenised using a blender [Stomacher® 400 Circulator, Seward, UK, at 230 rpm for 1 min] till it reached a liquid consistency. This slurry was filtered to remove the particulate matter, filled into four syringes [50 ml each] and used within 1 h of preparation or 6 h of passage of stools. Preservative-free normal saline with added food grade colour was used as placebo. Post FMT, recipients were encouraged to retain the slurry for 4–6 h. All patients were followed up during each session of intervention for disease activity and clinical outcomes, slurry retention time, and adverse events. 2.4. Clinical outcomes The clinical status and laboratory and endoscopic findings were recorded at each visit, or earlier in case of worsening of symptoms. Disease activity was assessed by Mayo Score at each visit. Histological disease activity was assessed using the Nancy Index at Week 48, by a blinded pathologist [VN].26 The worst site of inflammation was assessed using the Mayo endoscopic subscore and a blinded review, and consensus scoring of endoscopic images [photographs] was done by two gastroenterologists [AjS, RM]. 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. Clinical relapse was defined as worsening of diarrhoea, need for any treatment escalation [defined as the need for increasing the dose of ongoing drugs, including topical medication, or any drug changes] to induce remission, hospitalisation, or colectomy. All patients who relapsed on treatment and those who were lost to follow-up were considered as treatment failures. Adverse events like fever, abdominal pain or distension, nausea, vomiting, anorexia, worsening of diarrhoea, perianal or rectal pain, flatulence, borborygmi, bloating, constipation, urinary tract infection, respiratory tract infection, etc. were recorded at each visit. In addition, all patients were advised to inform about any post-FMT adverse events either by telephone or by visiting the outpatient department. A serious adverse event was defined as any untoward medical occurrence after enrolment into the study, resulting in inpatient hospitalisation or prolongation of hospitalisation, which was life-threatening or resulted in death of the patient. 2.5. Statistical analysis An intention-to-treat analysis was done and included all patients who underwent one session of FMT after initial clinical remission. Data were described in terms of frequencies [number of cases] and relative frequencies [percentages], as appropriate. Normally distributed continuous data were expressed as mean (±standard deviation [SD]). Subjects [FMT] were compared with the controls [placebo]. The clinical response in both groups was compared at 48 weeks by using an unpaired Student’s t test and a chi square test for continuous and categorical variables, respectively. SPSS Statistics v21.0 was used for statistical analysis. Using the standard α = 0.05 cut off, p <0.05 was considered as statistically significant. 3. Results Between September 2015 and June 2017, 128 consecutive patients with active UC were offered FMT as an add-on therapy, of whom 112 patients consented for the same. Clinical remission with FMT [seven sessions] was achieved in 65/112 patients [58%] [Supplementary Figure 1]. Eight weeks after the last session of FMT in induction phase, the patients in remission were then offered maintenance therapy with FMT. Four patients refused to consent for the same; the remaining 61 patients were randomly allocated to receive either FMT [n = 31] or placebo [n = 30], in addition to the standard of care therapies, every 8 weeks [Figure 1]. The baseline characteristics of both groups were similar, except for a higher erythrocyte sedimentation rate [ESR] in the FMT group [Table 1]. None of the patients was on maintenance biologics during the study. Ileocolonoscopy was performed under conscious sedation and faecal slurry delivered into ileum/caecum. The mean slurry retention times [hours] were 4.51 ± 0.4 and 4.64 ± 0.70, respectively, for patients on FMT and placebo infusion. Table 1. Baseline characteristics of the enrolled population FMT [n = 31] Placebo [n = 30] p-value Mean age [years] 33 ± 12.4 34.6 ± 12.3 0.622 Males [n] [%] 22 [70.9] 22 [73.3] 0.837 Non-smokers [n] [%] 28 [90.3] 26 [86.7] 0.654 Disease extent  Left-sided colitis 25 [80.6] 22 [73.3] 0.49  Extensive colitis 6 [19.4] 8 [26.7] Disease duration [mean ± SD] [years] 4.1 ± 2.9 4.5 ± 3.5 0.658 Number of relapses in past 1 [0–5] 1 [0–5] Median [range] 0.592 Concomitant medications [n][%]  5-ASA 31 [100] 30 [100]  AZA/6-MP 19 [61.3] 16 [53.3] 0.53 Previous exposure to biologics  Infliximab 5 [16.1] 3 [10] 0.48  Adalimumab biosimilar 2 [6.5] 4 [13.3] 0.37 Mean CRP [mg/L] 5.1 ± 2.1 4.5 ± 1.9 0.224 Mean ESR [mm/1st h] 15.8 ± 6.8 12.3 ± 4.5 0.020 Mean Mayo Score 1.9 ± 0.3 1.8 ± 0.4 0.297 Mean Endoscopic Mayo Score 0.9 ± 0.3 0.8 ± 0.4 0.685 FMT [n = 31] Placebo [n = 30] p-value Mean age [years] 33 ± 12.4 34.6 ± 12.3 0.622 Males [n] [%] 22 [70.9] 22 [73.3] 0.837 Non-smokers [n] [%] 28 [90.3] 26 [86.7] 0.654 Disease extent  Left-sided colitis 25 [80.6] 22 [73.3] 0.49  Extensive colitis 6 [19.4] 8 [26.7] Disease duration [mean ± SD] [years] 4.1 ± 2.9 4.5 ± 3.5 0.658 Number of relapses in past 1 [0–5] 1 [0–5] Median [range] 0.592 Concomitant medications [n][%]  5-ASA 31 [100] 30 [100]  AZA/6-MP 19 [61.3] 16 [53.3] 0.53 Previous exposure to biologics  Infliximab 5 [16.1] 3 [10] 0.48  Adalimumab biosimilar 2 [6.5] 4 [13.3] 0.37 Mean CRP [mg/L] 5.1 ± 2.1 4.5 ± 1.9 0.224 Mean ESR [mm/1st h] 15.8 ± 6.8 12.3 ± 4.5 0.020 Mean Mayo Score 1.9 ± 0.3 1.8 ± 0.4 0.297 Mean Endoscopic Mayo Score 0.9 ± 0.3 0.8 ± 0.4 0.685 SD, standard deviation; 5-ASA, 5-aminosalicylates; 6-MP, 6-mercaptopurine; AZA, azathiopurine; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FMT, faecal microbiota transplantation. Open in new tab Table 1. Baseline characteristics of the enrolled population FMT [n = 31] Placebo [n = 30] p-value Mean age [years] 33 ± 12.4 34.6 ± 12.3 0.622 Males [n] [%] 22 [70.9] 22 [73.3] 0.837 Non-smokers [n] [%] 28 [90.3] 26 [86.7] 0.654 Disease extent  Left-sided colitis 25 [80.6] 22 [73.3] 0.49  Extensive colitis 6 [19.4] 8 [26.7] Disease duration [mean ± SD] [years] 4.1 ± 2.9 4.5 ± 3.5 0.658 Number of relapses in past 1 [0–5] 1 [0–5] Median [range] 0.592 Concomitant medications [n][%]  5-ASA 31 [100] 30 [100]  AZA/6-MP 19 [61.3] 16 [53.3] 0.53 Previous exposure to biologics  Infliximab 5 [16.1] 3 [10] 0.48  Adalimumab biosimilar 2 [6.5] 4 [13.3] 0.37 Mean CRP [mg/L] 5.1 ± 2.1 4.5 ± 1.9 0.224 Mean ESR [mm/1st h] 15.8 ± 6.8 12.3 ± 4.5 0.020 Mean Mayo Score 1.9 ± 0.3 1.8 ± 0.4 0.297 Mean Endoscopic Mayo Score 0.9 ± 0.3 0.8 ± 0.4 0.685 FMT [n = 31] Placebo [n = 30] p-value Mean age [years] 33 ± 12.4 34.6 ± 12.3 0.622 Males [n] [%] 22 [70.9] 22 [73.3] 0.837 Non-smokers [n] [%] 28 [90.3] 26 [86.7] 0.654 Disease extent  Left-sided colitis 25 [80.6] 22 [73.3] 0.49  Extensive colitis 6 [19.4] 8 [26.7] Disease duration [mean ± SD] [years] 4.1 ± 2.9 4.5 ± 3.5 0.658 Number of relapses in past 1 [0–5] 1 [0–5] Median [range] 0.592 Concomitant medications [n][%]  5-ASA 31 [100] 30 [100]  AZA/6-MP 19 [61.3] 16 [53.3] 0.53 Previous exposure to biologics  Infliximab 5 [16.1] 3 [10] 0.48  Adalimumab biosimilar 2 [6.5] 4 [13.3] 0.37 Mean CRP [mg/L] 5.1 ± 2.1 4.5 ± 1.9 0.224 Mean ESR [mm/1st h] 15.8 ± 6.8 12.3 ± 4.5 0.020 Mean Mayo Score 1.9 ± 0.3 1.8 ± 0.4 0.297 Mean Endoscopic Mayo Score 0.9 ± 0.3 0.8 ± 0.4 0.685 SD, standard deviation; 5-ASA, 5-aminosalicylates; 6-MP, 6-mercaptopurine; AZA, azathiopurine; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FMT, faecal microbiota transplantation. Open in new tab Figure 1. Open in new tabDownload slide Flow diagram of patients included in the study. FMT, faecal microbiota transplantation; SOC, standard of care therapy; UC, ulcerative colitis. Figure 1. Open in new tabDownload slide Flow diagram of patients included in the study. FMT, faecal microbiota transplantation; SOC, standard of care therapy; UC, ulcerative colitis. The primary outcome of maintenance of clinical remission at 48 weeks was achieved in 27/31 [87.1%] patients allocated FMT versus 20/30 [66.7%] patients assigned placebo (Yates corrected chi square = 2.54, p = 0.111 [Figure 2, Table 2]). Secondary endpoints of endoscopic remission (18/31 [58.1%] with FMT versus 8/30 [26.7%] with placebo), [Yates corrected chi square = 4.93, p = 0.026] and histological remission (14/31 [45.2%] with FMT versus 5/30 [16.7%] with placebo) [Yates corrected chi square = 4.52, p = 0.033] were achieved in a significantly higher number of patients with FMT [Figure 2, Table 2]. Inflammatory markers (ESR and C-reactive protein [CRP]) were both significantly higher in the placebo arm at Week 48 [Table 2]. Table 2 Outcome measures comparing faecal microbiota transplantation with placebo for maintenance of remission at Week 48. Outcome Measure FMT Placebo p-value Clinical remission 27/31 20/30 0.111 Endoscopic remission 18/31 8/30 0.026 Histological remission 14/31 5/30 0.033 ESR [mm/h] [mean ± std. dev] 10.1 ± 2.8 20.5 [5.3] <0.001 CRP [mg/L] [mean ± std. dev] 4.5 ± 1.9 7.2 [2.5] <0.001 Serious adverse events 0 0 — Outcome Measure FMT Placebo p-value Clinical remission 27/31 20/30 0.111 Endoscopic remission 18/31 8/30 0.026 Histological remission 14/31 5/30 0.033 ESR [mm/h] [mean ± std. dev] 10.1 ± 2.8 20.5 [5.3] <0.001 CRP [mg/L] [mean ± std. dev] 4.5 ± 1.9 7.2 [2.5] <0.001 Serious adverse events 0 0 — FMT, faecal microbiota transplantation; CRP: C-reactive protein, ESR: erythrocyte sedimentation rate Open in new tab Table 2 Outcome measures comparing faecal microbiota transplantation with placebo for maintenance of remission at Week 48. Outcome Measure FMT Placebo p-value Clinical remission 27/31 20/30 0.111 Endoscopic remission 18/31 8/30 0.026 Histological remission 14/31 5/30 0.033 ESR [mm/h] [mean ± std. dev] 10.1 ± 2.8 20.5 [5.3] <0.001 CRP [mg/L] [mean ± std. dev] 4.5 ± 1.9 7.2 [2.5] <0.001 Serious adverse events 0 0 — Outcome Measure FMT Placebo p-value Clinical remission 27/31 20/30 0.111 Endoscopic remission 18/31 8/30 0.026 Histological remission 14/31 5/30 0.033 ESR [mm/h] [mean ± std. dev] 10.1 ± 2.8 20.5 [5.3] <0.001 CRP [mg/L] [mean ± std. dev] 4.5 ± 1.9 7.2 [2.5] <0.001 Serious adverse events 0 0 — FMT, faecal microbiota transplantation; CRP: C-reactive protein, ESR: erythrocyte sedimentation rate Open in new tab Figure 2. Open in new tabDownload slide Bar graph showing clinical outcomes of patients. FMT, faecal microbiota transplantation; SOC, standard of care therapy. Figure 2. Open in new tabDownload slide Bar graph showing clinical outcomes of patients. FMT, faecal microbiota transplantation; SOC, standard of care therapy. Of the 61 patients in clinical remission, only nine were in endoscopic remission [FMT: n = 4, placebo: n = 5] at the start of the study [Week 0]. At 48 weeks, addition of FMT to standard of care resulted in maintenance of endoscopic remission in all four patients, and 14 additional patients achieved endoscopic mucosal healing [before and after treatment, Yates corrected chi square = 11.91, p <0.001]. On the other hand, in the placebo group, all five patients maintained endoscopic remission and three more patients achieved endoscopic mucosal healing[before and after treatment, Yates corrected chi square = 0.398, p = 0.538]. Three patients receiving FMT [9.7%] and eight patients on placebo [26.7%] relapsed [Yates corrected chi square = 1.94, p = 0.164]. The likelihood of a relapse was higher in the placebo group (risk ratio: 2.6 [0.9–7.3, p = 0.07]). A majority of the relapses [FMT: 2/3; placebo: 8/8] were noted after Week 24. All relapses were treated with steroids along with the standard of care. One patient on FMT discontinued therapy as he was asymptomatic and refused repeated interventions. There were no serious adverse events necessitating discontinuation of treatment in patients on FMT [Table 3]. One patient relapsed on placebo and did not respond to steroids, thus requiring colectomy. Another patient in the placebo group died of myocardial infarction [unrelated to FMT]. Table 3 Adverse events experienced by the patients and controls during the study period. Time Week 0 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Adverse events FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo Fevera 1 0 1 0 1 1 0 0 0 0 0 0 0 0 Transient abdominal pain/ distension 2 2 2 2 2 2 1 1 1 0 1 1 1 0 Nausea/ vomiting 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Transient worsening of diarrhoeab 1 0 1 1 1 1 0 0 1 1 0 0 0 0 Perianal or rectal pain 1 1 0 1 0 0 0 0 0 0 0 0 0 0 Flatulance 2 1 2 2 1 1 1 0 0 0 0 1 0 0 Others 0 0 0 0 0 0 0 0 0 0 0 1 0 0 Time Week 0 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Adverse events FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo Fevera 1 0 1 0 1 1 0 0 0 0 0 0 0 0 Transient abdominal pain/ distension 2 2 2 2 2 2 1 1 1 0 1 1 1 0 Nausea/ vomiting 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Transient worsening of diarrhoeab 1 0 1 1 1 1 0 0 1 1 0 0 0 0 Perianal or rectal pain 1 1 0 1 0 0 0 0 0 0 0 0 0 0 Flatulance 2 1 2 2 1 1 1 0 0 0 0 1 0 0 Others 0 0 0 0 0 0 0 0 0 0 0 1 0 0 FMT, faecal microbiota transplantation. aFever was low-grade and self-limiting in all patients. bManaged conservatively, no antibiotics or probiotics were given. Open in new tab Table 3 Adverse events experienced by the patients and controls during the study period. Time Week 0 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Adverse events FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo Fevera 1 0 1 0 1 1 0 0 0 0 0 0 0 0 Transient abdominal pain/ distension 2 2 2 2 2 2 1 1 1 0 1 1 1 0 Nausea/ vomiting 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Transient worsening of diarrhoeab 1 0 1 1 1 1 0 0 1 1 0 0 0 0 Perianal or rectal pain 1 1 0 1 0 0 0 0 0 0 0 0 0 0 Flatulance 2 1 2 2 1 1 1 0 0 0 0 1 0 0 Others 0 0 0 0 0 0 0 0 0 0 0 1 0 0 Time Week 0 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Adverse events FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo FMT Placebo Fevera 1 0 1 0 1 1 0 0 0 0 0 0 0 0 Transient abdominal pain/ distension 2 2 2 2 2 2 1 1 1 0 1 1 1 0 Nausea/ vomiting 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Transient worsening of diarrhoeab 1 0 1 1 1 1 0 0 1 1 0 0 0 0 Perianal or rectal pain 1 1 0 1 0 0 0 0 0 0 0 0 0 0 Flatulance 2 1 2 2 1 1 1 0 0 0 0 1 0 0 Others 0 0 0 0 0 0 0 0 0 0 0 1 0 0 FMT, faecal microbiota transplantation. aFever was low-grade and self-limiting in all patients. bManaged conservatively, no antibiotics or probiotics were given. Open in new tab 4. Discussion Faecal microbiota transplant is a novel therapeutic tool in UC. Three of the four randomised controlled trials [RCTs] to date, along with several case series, suggest its efficacy for inducing remission in active UC.20–23,27–33 Ours is a pilot study to assess the role of FMT in maintenance of remission in patients with UC. A trend towards a higher rate of maintenance of steroid-free clinical remission was noted with addition of FMT to SOC, though this did not achieve statistical significance. However, the pre-specified secondary endpoints of both endoscopic and histological remission were statistically superior in patients receiving FMT as compared with those receiving placebo. FMT is a robust method of manipulation of gut microbiota, which has emerged as a potential therapy for patients with UC, after its success in treatment of Clostridium difficile infection.34It has been shown to increase the diversity of the faecal bacterial populations in the recipients,35,36and this donor microbiota engraftment may result in long-lasting response in patients with Clostridium difficile infection.37 An early study on the use of FMT for active UC suggested that it was efficacious and achieved long-term [1–13 years] clinical, endoscopic, and histological remission.38 Subsequent case series and reports showed mixed results, and none showed a sustained long-term benefit with a limited duration of FMT.39–41 Our study suggests that FMT-induced remission is not sustained; more patients in the placebo group suffered relapses, though the difference was not statistically significant. Our protocol of sustaining clinical remission with 8-weekly FMT was found to be effective. The therapeutic goal of treatment in IBD has evolved from mere control of symptoms [i.e. resolution of diarrhea and control of rectal bleeding] to achievement of deep remission. In UC, there is no validated definition of deep remission; however, it has been defined as achievement of both clinical and endoscopic mucosal healing.42 Once deep remission is achieved, the risk of relapse, hospitalisation, development of colorectal malignancy, and need for colectomy is reduced.43,44 We observed that 52/61 [85.2%] of our patients [FMT: 27/31, placebo:25/30] in clinical remission still had an inflamed mucosa on endoscopy [Mayo endoscopic score 1] at baseline. With continuation of FMT, at 48 weeks all the patients in endoscopic remission initially at Week 0 maintained the same, and an additional 14 patients [45.2%] in the FMT group and three patients [10%] in placebo group achieved endoscopic mucosal healing. Thus, a total of 18/31 [58.1%] patients achieved endoscopic mucosal healing with FMT at 48 weeks, as compared with 8/30 [26.7%] with placebo, and this was significantly higher than the pre-treatment status. Unlike what can occur with thiopurines and biologics, maintenance therapy with FMT in this small pilot study was associated with few adverse events, none of which was serious to warrant discontinuation. In patients with UC in clinical and endoscopic remission, histological activity is an independent risk factor for clinical relapse and thus histological remission is now being considered as an endpoint in clinical trials and a treatment goal in clinical practice in patients with UC.45–47 There are very few studies assessing the rates of histological healing with conventional therapies in UC; 5-ASA compounds can improve histology in 30–60% of the patients, but only 10–30% achieve histological remission.48–51 A study on 32 refractory active UC patients maintained on azathioprine showed 78% histological remission, but 90% of these patients relapsed within a median duration of 4 years.52 Biologics have also shown significant reduction in the histological score [67%] but histological remission was noted in only one-third of the patients.53 In our study, among patients maintained on FMT, histological remission was achieved in 45.2% which was statistically greater than among those on placebo [6.7%]. Thus, FMT seems to be an effective therapy for maintenance of long-term remission in UC patients. The positive outcomes achieved in our study could be attributed to various factors. First, we used a colonoscopic route for administration of faecal slurry into the ileum. Of the four RCTs on FMT in UC published so far, those with a colonic or rectal instillation of faecal slurry23,54 have shown better response compared with the upper gastrointestinal [GI] route of administration.21 It has been hypothesised that instillation of the faecal slurry in the upper GI tract may not be effective, as gastric acid can destroy Bacteroides and Firmicutes.55 Furthermore, the microbial uptake may be better when faecal samples are administered by colonoscopy, as inflammation in UC starts in rectum and proceeds proximally and dysbiosis is expected to be more in inflamed areas than in the non-inflamed areas.56 In addition to this, colonoscopic administration ensured a directly observed therapy [as opposed to home enemas] and larger volumes of donor faeces could be administered, with a good retention time. Another factor which may have resulted in positive results was pre-FMT bowel preparation. The role of bowel preparation in published literature is controversial. However, an adequate bowel preparation before the procedure may help in successful colonisation of donor microbiota in the recipient by clearing the pro-inflammatory bacteria before the introduction of new flora.57 In addition, it has additional benefits of adequate mucosal assessment during each session. However, bowel preparation with polyethylene glycol may itself cause changes in microbiome and thus produce results not attributable to FMT alone.58 Our study had a few limitations. The power achieved with the current sample size was 49%. To achieve power of 80%, an alpha error of 5%, and assuming similar outcomes, the sample size required is 80 in each arm. It was difficult to attain this sample size at a single centre; however, our pilot study was randomised and had a control group, which imparts strength to the same. Though the colonoscopic route is more efficacious than an upper GI administration as already discussed, repeated procedures with previous preparation may not be accepted by many patients. Using oral encapsulated FMT with a colonic release may increase the acceptance of FMT for maintenance of remission over longer periods of time.59 The data for maintenance of remission is for 48 weeks only, and microbiome analysis of the patients and donors has not been done yet. However, despite these limitations, there certainly is a signal that FMT for maintenance of remission in UC may be effective and larger multicentre studies with an adequate sample size, long-term follow-up, and detailed microbiome analysis of the patients and donors may be planned in future to substantiate the same. To conclude, addition of FMT to the standard of care may aid in maintenance of steroid-free clinical remission in a larger number of patients. It also enhances the achievement of endoscopic and histological remission. Larger multicentre studies with a longer follow-up and data on serial changes in histology and microbiome are needed to establish FMT as a treatment option for maintenance of remission. Funding None. Conflict of Interest The authors declare no conflicts of interest. Author Contributions AjS: concept and design; collection, analysis, and interpretation of the data; drafting of the article; critical revision of the article for important intellectual content; final approval of the article. RM: concept and design; collection, analysis, and interpretation of the data; drafting of the article; critical revision of the article for important intellectual content; final approval of the article. ArS: collection, analysis, and interpretation of the data; drafting of the article; critical revision of the article for important intellectual content; final approval of the article. VMi: concept and design; analysis and interpretation of the data; drafting of the article; critical revision of the article for important intellectual content; final approval of the article. VMe: analysis and interpretation of the data; critical revision of the article for important intellectual content; final approval of the article. VN: data analysis; critical revision of the article for important intellectual content; final approval of the article. TS: data analysis; critical revision of the article for important intellectual content; final approval of the article. ASP: data collection; critical revision of the article for important intellectual content; final approval of the article. References 1. Kornbluth A , Sachar DB ; Practice Parameters Committee of the American College of Gastroenterology . Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee . Am J Gastroenterol 2010 ; 105 : 501 – 23; quiz 524 . 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TI - Role of Faecal Microbiota Transplantation for Maintenance of Remission in Patients With Ulcerative Colitis: A Pilot Study
JO - Journal of Crohn's and Colitis
DO - 10.1093/ecco-jcc/jjz060
DA - 2019-09-27
UR - https://www.deepdyve.com/lp/oxford-university-press/role-of-faecal-microbiota-transplantation-for-maintenance-of-remission-0MTmZFiuQr
SP - 1311
VL - 13
IS - 10
DP - DeepDyve
ER -