Abstract

Background Faecal microbiota transplantation [FMT] has been investigated as a potential treatment for inflammatory bowel disease [IBD]. We thus performed a systematic review and meta-analysis assessing the effectiveness and safety of FMT in IBD. Methods A systematic review was conducted until January 2017. Studies were excluded if patients had co-infection or data were pooled across disease subtypes (ulcerative colitis [UC], Crohn’s disease [CD], pouchitis). Clinical remission was established as the primary outcome. Pooled effect sizes and 95% confidence intervals were obtained using the random effects model. Results In all, 53 studies were included [41 in UC, 11 in CD, 4 in pouchitis]. Overall, 36% [201/555] of UC, 50.5% [42/83] of CD, and 21.5% [5/23] of pouchitis patients achieved clinical remission. Among cohort studies, the pooled proportion achieving clinical remission was 33% (95% confidence interval [CI] = 23%–43%] for UC and 52% [95% CI = 31%–72%] for CD, both with moderate risk of heterogeneity. For four RCTs in UC, significant benefit in clinical remission (pooled odds ratios [[P-OR] = 2.89, 95% CI = 1.36–6.13, p = 0.006) with moderate heterogeneity [Cochran’s Q, p = 0.188; I2 = 37%] was noted. Sub-analyses suggest remission in UC improved with increased number of FMT infusions and lower gastrointestinal tract administration. Most adverse events were transient gastrointestinal complaints. Microbiota analysis was performed in 24 studies, with many identifying increased diversity and a shift in recipient microbiota profile towards the donor post-FMT. Conclusions FMT appears effective in UC remission induction, but long-term durability and safety remain unclear. Additional well-designed controlled studies of FMT in IBD are needed, especially in CD and pouchitis.

1. Introduction

Faecal microbiota transplantation [FMT] has revolutionised the field of microbial therapeutics. It has proven extremely effective in the treatment of Clostridium difficile infection [CDI],1,2 and is considered to have potential in other conditions where disturbances in the enteric microbiota are implicated in disease pathogenesis, such as the inflammatory bowel diseases [IBD].3 Although FMT is a simple therapy in practice that was first described in Western medical literature over 50 years ago,4 and proposed as a treatment strategy for IBD over 25 years ago,5 it is only in recent years that there has been an exponential growth in patient, media, and research interest.6 The initial systematic review on the role of FMT in IBD published in 2012 consisted of only nine retrospective reports, deemed of insufficient quality to perform meta-analysis.7 Within 2 years, an updated systematic review identified 18 studies, including nine cohort studies of FMT in IBD on which a meta-analysis was performed.8 Since then, the number of available studies has again more than doubled, including the publication of the first four randomised controlled trials [RCTs] of FMT in ulcerative colitis [UC].9–12

In this latest systematic review and meta-analysis, we summarise the available literature and evaluate the efficacy of FMT in the various IBD subtypes of UC, Crohn’s disease [CD], and pouchitis, by performing meta-analyses on the associated prospective studies.

2. Methods

2.1. Search strategy

A systematic review was conducted in accordance with the PRISMA,13 Cochrane,14 and MOOSE15 guidelines. We searched five electronic databases [Pubmed, Medline, Cochrane, Biomed Central, and Embase] from inception to the January 4, 2017 using search terms as previously described7 [Table A1, available as Supplementary data at ECCO-JCC online]. No language limits or any other advance features were used. Major conference proceedings from 2011–2016 were searched to identify abstract publications, including: Digestive Diseases Week [DDW], European Crohn’s and Colitis Organisation [ECCO; including 2017], United European Gastroenterology Week [UEGW], American College of Gastroenterology [ACG], and Advances in IBD [AIBD]. References from previous review articles were also searched to identify studies that may have been missed by the above-mentioned searches. The clinicaltrials.gov registry was also searched.

2.2. Study selection criteria

2.2.1. Inclusion criteria

Articles were included in this systematic review if they reported on clinical efficacy and/or safety of FMT in inflammatory bowel disease in human subjects. FMT was defined as the infusion of faeces-derived matter and bacteria from a healthy individual[s] into a recipient. Case reports, case series, cohort studies, and RCTs were all included [full text or abstract publications]. For the meta-analyses, however, only cohort studies and RCTs were included.

2.2.2. Exclusion criteria

Studies were excluded if data for particular IBD subtypes [UC, CD, pouchitis] were pooled and not individually reported, due to inherent differences between these conditions. Studies were also excluded if they only included patients who had co-infection with Clostridium difficile or other pathogens, or if data on non-infected IBD patients were not individually reported or able to be extracted. In addition, studies reporting duplicate data were excluded.

2.2.3. Outcome measures

Efficacy of FMT in IBD was assessed as clinical remission [primary outcome] or clinical response as defined by the respective study authors [Tables 1–5]. Where possible, endoscopic [mucosal healing] and histologic data were also extracted. Safety was assessed using reported adverse event and serious adverse event data.

Table 1. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up Case report Bennet et al., 19895 1 Severe, steroid refractory NR Enema NR Multiple [not further specified] NR Yes

[regimen not specified] NR 1 - NR 1 6 months Case report Borody

et al., 198919 1 NR NR NR NR NR NR NR NR 1 - 1 1 3 months Case report Borody et al., 201120 1 Chronic relapsing UC NR NR NR NR NR NR NR 0 1 NR NR 12 years Case report Hohmann et al., 201421 1 Moderate Wife & 10-month old child NR NR 4 Fresh No No 0 0 0 0 NR Case report Vandenplas et al., 201522 1

[paediatric] Severe Related [first 4 infusions: age-related niece, last 3 infusions: older brother] Colonoscopy first 2 infusions, nasoduodenal. next 5 infusions 100 g stool in 100 ml 7 [interval not specified] Fresh No NR 1 - NR 1 6 months Case report Seth et al., 201623 1 Moderate [Mayo 9] Unrelated [brother-in- law] Colonoscopy 200 g stool in 350 ml saline 3 [every 2 weeks] Fresh No Yes 1

[Mayo 0, withdrawal of all medications] - 1

[Mayo 0, withdrawal of all medications] 1 8 months Case report Kumagai et al., 201624 1 [paediatric] Severe [PUCAI 85] Related [mother] Enema x 2, then nasoduodenal x 4 60 g stool in 250 ml saline 6 [over 10 days] Fresh No NR 0

[required colectomy] 0 0 0 3 months Case report Ni et al., 201625 1 Moderately steroid- dependent [Mayo 9] Related [father] Percutaneous endoscopic caecostomy 100 g stool in 250 ml saline > 50 [daily for 1 month then 2 x week for 3 months] Fresh No Yes 1 [Mayo 0] - 1 [Mayo 0] NR 12 months Case report Shimzu et al., 201626 1

[paediatric] Severe steroid dependent Related [father] Colonoscopy x 1 then enemas Stool diluted in 250 ml saline 16 [daily for first 5 days, then every 2–4 weeks over 10 months] Fresh No Yes 1

[PUCAI 0] - 0 0 10 months Case series Borody et al., 200127 3 Active colitis, severe symptoms NR Enema Stool diluted in 200 ml infusion 5

[daily for 5 days] Fresh Vancomycin 500mg bd, metronidazole 400 mg bd, rifampicin 150 mg bd for 7–15 days NR 3/3 [100%] - 3/3 [100%] NR 8–16 months Case series Borody et al., 200328 6 Active, not further specified Recipient- identified [related & unrelated] Enema 200-300 g stool in 200-300 ml saline 5, [daily for 5 days] Fresh Vancomycin 500 mg bd + metronidazole 400 mg bd + rifampicin 150 mg bd for 7–10 days Yes 6/6 [100%] - 6/6 [100%] 6/6 [100%] 1–13 years Case series Borody et al., 201229 62 Active, not further specified NR NR NR NR NR NR NR 42/62 [68%] [0–1 on modified Powell- Tuck index] 57/62 [92%] [> 2-point drop in Powell- Tuck index] 12/21 [57%] 12/21 [57%] NR Case series Shah et al., 201230 16 NR NR NR NR NR NR NR NR NR 8/16 [50%] [avoid surgery or medications] NR NR NR Case series Brandt et al.,

201331 11 NR NR NR NR NR NR NR NR NR [safety study] NR NR NR Mean 14.7 months [range 7–31] Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up Case report Bennet et al., 19895 1 Severe, steroid refractory NR Enema NR Multiple [not further specified] NR Yes

[regimen not specified] NR 1 - NR 1 6 months Case report Borody

et al., 198919 1 NR NR NR NR NR NR NR NR 1 - 1 1 3 months Case report Borody et al., 201120 1 Chronic relapsing UC NR NR NR NR NR NR NR 0 1 NR NR 12 years Case report Hohmann et al., 201421 1 Moderate Wife & 10-month old child NR NR 4 Fresh No No 0 0 0 0 NR Case report Vandenplas et al., 201522 1

[paediatric] Severe Related [first 4 infusions: age-related niece, last 3 infusions: older brother] Colonoscopy first 2 infusions, nasoduodenal. next 5 infusions 100 g stool in 100 ml 7 [interval not specified] Fresh No NR 1 - NR 1 6 months Case report Seth et al., 201623 1 Moderate [Mayo 9] Unrelated [brother-in- law] Colonoscopy 200 g stool in 350 ml saline 3 [every 2 weeks] Fresh No Yes 1

[Mayo 0, withdrawal of all medications] - 1

[Mayo 0, withdrawal of all medications] 1 8 months Case report Kumagai et al., 201624 1 [paediatric] Severe [PUCAI 85] Related [mother] Enema x 2, then nasoduodenal x 4 60 g stool in 250 ml saline 6 [over 10 days] Fresh No NR 0

[required colectomy] 0 0 0 3 months Case report Ni et al., 201625 1 Moderately steroid- dependent [Mayo 9] Related [father] Percutaneous endoscopic caecostomy 100 g stool in 250 ml saline > 50 [daily for 1 month then 2 x week for 3 months] Fresh No Yes 1 [Mayo 0] - 1 [Mayo 0] NR 12 months Case report Shimzu et al., 201626 1

[paediatric] Severe steroid dependent Related [father] Colonoscopy x 1 then enemas Stool diluted in 250 ml saline 16 [daily for first 5 days, then every 2–4 weeks over 10 months] Fresh No Yes 1

[PUCAI 0] - 0 0 10 months Case series Borody et al., 200127 3 Active colitis, severe symptoms NR Enema Stool diluted in 200 ml infusion 5

[daily for 5 days] Fresh Vancomycin 500mg bd, metronidazole 400 mg bd, rifampicin 150 mg bd for 7–15 days NR 3/3 [100%] - 3/3 [100%] NR 8–16 months Case series Borody et al., 200328 6 Active, not further specified Recipient- identified [related & unrelated] Enema 200-300 g stool in 200-300 ml saline 5, [daily for 5 days] Fresh Vancomycin 500 mg bd + metronidazole 400 mg bd + rifampicin 150 mg bd for 7–10 days Yes 6/6 [100%] - 6/6 [100%] 6/6 [100%] 1–13 years Case series Borody et al., 201229 62 Active, not further specified NR NR NR NR NR NR NR 42/62 [68%] [0–1 on modified Powell- Tuck index] 57/62 [92%] [> 2-point drop in Powell- Tuck index] 12/21 [57%] 12/21 [57%] NR Case series Shah et al., 201230 16 NR NR NR NR NR NR NR NR NR 8/16 [50%] [avoid surgery or medications] NR NR NR Case series Brandt et al.,

201331 11 NR NR NR NR NR NR NR NR NR [safety study] NR NR NR Mean 14.7 months [range 7–31] View Large

Table 1. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up Case report Bennet et al., 19895 1 Severe, steroid refractory NR Enema NR Multiple [not further specified] NR Yes

[regimen not specified] NR 1 - NR 1 6 months Case report Borody

et al., 198919 1 NR NR NR NR NR NR NR NR 1 - 1 1 3 months Case report Borody et al., 201120 1 Chronic relapsing UC NR NR NR NR NR NR NR 0 1 NR NR 12 years Case report Hohmann et al., 201421 1 Moderate Wife & 10-month old child NR NR 4 Fresh No No 0 0 0 0 NR Case report Vandenplas et al., 201522 1

[paediatric] Severe Related [first 4 infusions: age-related niece, last 3 infusions: older brother] Colonoscopy first 2 infusions, nasoduodenal. next 5 infusions 100 g stool in 100 ml 7 [interval not specified] Fresh No NR 1 - NR 1 6 months Case report Seth et al., 201623 1 Moderate [Mayo 9] Unrelated [brother-in- law] Colonoscopy 200 g stool in 350 ml saline 3 [every 2 weeks] Fresh No Yes 1

[Mayo 0, withdrawal of all medications] - 1

[Mayo 0, withdrawal of all medications] 1 8 months Case report Kumagai et al., 201624 1 [paediatric] Severe [PUCAI 85] Related [mother] Enema x 2, then nasoduodenal x 4 60 g stool in 250 ml saline 6 [over 10 days] Fresh No NR 0

[required colectomy] 0 0 0 3 months Case report Ni et al., 201625 1 Moderately steroid- dependent [Mayo 9] Related [father] Percutaneous endoscopic caecostomy 100 g stool in 250 ml saline > 50 [daily for 1 month then 2 x week for 3 months] Fresh No Yes 1 [Mayo 0] - 1 [Mayo 0] NR 12 months Case report Shimzu et al., 201626 1

[paediatric] Severe steroid dependent Related [father] Colonoscopy x 1 then enemas Stool diluted in 250 ml saline 16 [daily for first 5 days, then every 2–4 weeks over 10 months] Fresh No Yes 1

[PUCAI 0] - 0 0 10 months Case series Borody et al., 200127 3 Active colitis, severe symptoms NR Enema Stool diluted in 200 ml infusion 5

[daily for 5 days] Fresh Vancomycin 500mg bd, metronidazole 400 mg bd, rifampicin 150 mg bd for 7–15 days NR 3/3 [100%] - 3/3 [100%] NR 8–16 months Case series Borody et al., 200328 6 Active, not further specified Recipient- identified [related & unrelated] Enema 200-300 g stool in 200-300 ml saline 5, [daily for 5 days] Fresh Vancomycin 500 mg bd + metronidazole 400 mg bd + rifampicin 150 mg bd for 7–10 days Yes 6/6 [100%] - 6/6 [100%] 6/6 [100%] 1–13 years Case series Borody et al., 201229 62 Active, not further specified NR NR NR NR NR NR NR 42/62 [68%] [0–1 on modified Powell- Tuck index] 57/62 [92%] [> 2-point drop in Powell- Tuck index] 12/21 [57%] 12/21 [57%] NR Case series Shah et al., 201230 16 NR NR NR NR NR NR NR NR NR 8/16 [50%] [avoid surgery or medications] NR NR NR Case series Brandt et al.,

201331 11 NR NR NR NR NR NR NR NR NR [safety study] NR NR NR Mean 14.7 months [range 7–31] Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up Case report Bennet et al., 19895 1 Severe, steroid refractory NR Enema NR Multiple [not further specified] NR Yes

[regimen not specified] NR 1 - NR 1 6 months Case report Borody

et al., 198919 1 NR NR NR NR NR NR NR NR 1 - 1 1 3 months Case report Borody et al., 201120 1 Chronic relapsing UC NR NR NR NR NR NR NR 0 1 NR NR 12 years Case report Hohmann et al., 201421 1 Moderate Wife & 10-month old child NR NR 4 Fresh No No 0 0 0 0 NR Case report Vandenplas et al., 201522 1

[paediatric] Severe Related [first 4 infusions: age-related niece, last 3 infusions: older brother] Colonoscopy first 2 infusions, nasoduodenal. next 5 infusions 100 g stool in 100 ml 7 [interval not specified] Fresh No NR 1 - NR 1 6 months Case report Seth et al., 201623 1 Moderate [Mayo 9] Unrelated [brother-in- law] Colonoscopy 200 g stool in 350 ml saline 3 [every 2 weeks] Fresh No Yes 1

[Mayo 0, withdrawal of all medications] - 1

[Mayo 0, withdrawal of all medications] 1 8 months Case report Kumagai et al., 201624 1 [paediatric] Severe [PUCAI 85] Related [mother] Enema x 2, then nasoduodenal x 4 60 g stool in 250 ml saline 6 [over 10 days] Fresh No NR 0

[required colectomy] 0 0 0 3 months Case report Ni et al., 201625 1 Moderately steroid- dependent [Mayo 9] Related [father] Percutaneous endoscopic caecostomy 100 g stool in 250 ml saline > 50 [daily for 1 month then 2 x week for 3 months] Fresh No Yes 1 [Mayo 0] - 1 [Mayo 0] NR 12 months Case report Shimzu et al., 201626 1

[paediatric] Severe steroid dependent Related [father] Colonoscopy x 1 then enemas Stool diluted in 250 ml saline 16 [daily for first 5 days, then every 2–4 weeks over 10 months] Fresh No Yes 1

[PUCAI 0] - 0 0 10 months Case series Borody et al., 200127 3 Active colitis, severe symptoms NR Enema Stool diluted in 200 ml infusion 5

[daily for 5 days] Fresh Vancomycin 500mg bd, metronidazole 400 mg bd, rifampicin 150 mg bd for 7–15 days NR 3/3 [100%] - 3/3 [100%] NR 8–16 months Case series Borody et al., 200328 6 Active, not further specified Recipient- identified [related & unrelated] Enema 200-300 g stool in 200-300 ml saline 5, [daily for 5 days] Fresh Vancomycin 500 mg bd + metronidazole 400 mg bd + rifampicin 150 mg bd for 7–10 days Yes 6/6 [100%] - 6/6 [100%] 6/6 [100%] 1–13 years Case series Borody et al., 201229 62 Active, not further specified NR NR NR NR NR NR NR 42/62 [68%] [0–1 on modified Powell- Tuck index] 57/62 [92%] [> 2-point drop in Powell- Tuck index] 12/21 [57%] 12/21 [57%] NR Case series Shah et al., 201230 16 NR NR NR NR NR NR NR NR NR 8/16 [50%] [avoid surgery or medications] NR NR NR Case series Brandt et al.,

201331 11 NR NR NR NR NR NR NR NR NR [safety study] NR NR NR Mean 14.7 months [range 7–31] View Large

Table 2. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow Up NOS Total Cohort Angelberger et al., 201332 5 Moderate- severe [Mayo ≥ 6] Recipient- identified but first degree- relatives excluded Nasojejunal & enema combined Median 24 g stool in 250 ml saline for nasojejunal infusion, median 20 g stool in 100 ml saline for enema 3 [daily for 3 days] Fresh Metronidazole 500 mg bd and probiotic [Yomogi or Omnibiotic] for 5–10 days before FMT Yes 0 [Mayo ≤ 2, no subscore > 1] 1/5 [20%] [Mayo drop ≥ 3 and ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR 12

weeks 5 Cohort Kump et al., 201333 6 Moderate- severe [Mayo 8–11] Unrelated Colonoscopy [TI + colon] 100-150 g stool in 200-350 ml Single Fresh No Yes 0 [Mayo ≤ 2] 2/6 [33%] [Mayo drop ≥ 3] NR NR 3

months 5 Cohort Kunde et al., 201334 10 [paediatric] Mild- moderate [PUCAI 15–65] Recipient- identified [related & unrelated] Enema Average 90 g stool [range 70-113 g] in 4 x 60 ml saline 5

[daily for 5 days] Fresh No No 3/9 [33%] at 1 and 4 weeks [PUCAI < 10] 7/9 [78%] at 1 Week 6/9 [67%] at 1 month [PUCAI drop > 15] NR NR 4

weeks 6 Cohort Cui et al., 201535 15 [data on 14] Moderate- severe [Montreal]

Steroid- dependent Recipient- identified [related & unrelated] Midgut through gastroscope 150-200 ml infusion 1–2, [1 week apart] NR No NR 4/14 [29%] [Montreal 0] 8/14 [57%] [Montreal improvement ≥ 1] & discontinuation of steroids NR NR > 3 months 5 Cohort Damman et al., 201536 7 Mild- moderate [UCDAI 3–10] Recipient- identified [1 related, rest unrelated] Colonoscopy 175–290 ml of stool mixture [1 g stool:2-3 ml

saline] Single Fresh No Yes 1/7 [14%] at 4 weeks [UCDAI ≤ 2 & no subscore > 1] 1/7 [14%] at 4 weeks [UCDAI drop ≥ 3] NR 1/7 [14%]

at 4 weeks 3 months 6 Cohort Karolewska- Bochenek et al., 201537 4 [paediatric] Moderate- severe Unrelated Gastroscopy 50 ml infusion 8 [daily first 5 days, alternate days in second week] NR No NR 0 4/4 [100%] NR NR 4

weeks 4 Cohort Kellermayer et al., 201538 3 [paediatric] Immunotherapy-dependent but controlled mucosal disease at study commencement [Mayo 0–1] Unrelated Colonoscopy followed by enemas 50 g stool in 250 ml saline; 60–250 ml delivered 22–30 [daily for fortnight, thrice weekly for fortnight, then weekly for 6–12 weeks] Frozen No Yes 3/3 [100%] - 3/3 [100%] 3/3 [100%] 3

months 3 Cohort Kump et al., 201539 17, 10 controls [triple antibiotic therapy] Chronic active NR Colonoscopy [initially right colon, then left colon on subsequent infusions] NR 5 [fortnightly infusions] NR Triple therapy [not specified] for 10 days Yes FMT: 4/17 [24%], control: 0 [Mayo ≤ 2] FMT: 10/17 [59%], control: 2/10 [20%] [Mayo drop ≥ 3] NR NR 90

days 6 Cohort Scaldaferri et al., 201540 8, 7 controls Mild-moderate [partial Mayo ≥ 4, endoscopic Mayo ≥ 1] Recipient- identified NR 200 ml of faecal slurry 3 [interval not specified] NR Not specified Yes FMT: 3/8 [38%], control: 2/7 [29%] [partial Mayo ≤ 2, all subscores ≤ 1] FMT: 4/8 [50%], control:

2/7 [29%] [partial Mayo drop ≥ 2] 33% [Mayo 0 at Week 6] NR 12

weeks 7 Cohort Suskind et al., 201541 4 [paediatric] Mild-moderate [PUCAI] NR Nasogastric 30 g stool in 100 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes 0 [PUCAI < 10] 0 NR NR 12

weeks 6 Cohort Vermeire et al., 201642 8 Moderate- severe; refractory, failed immunotherapy and anti-TNF Unrelated & related Nasogastric 3, rectal tube 5 200 g stool in 400 ml 2 [daily for 2 days] Fresh No Yes 2/8 [25%] NR 2/8 [25%] [Mayo endoscopy subscore ≤ 1] NR 8

weeks 5 Cohort Wei et al., 201543 11 Mild- moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 8/11 [73%] [Mayo < 2] NR NR NR 4

weeks 4 Cohort Ren et al., 201544 7 Severe [Mayo ≥ 10] Relatives or healthy volunteers Gastroscopy or colonoscopy or combined gastroscopy & colonoscopy Gastroscopy, 100-200 ml; colonoscopy, 200-300 ml 1–3 infusions [5 pts x 1, 1 pt x 2, 1 pt x 3] Fresh No No 5/7 [71%] [Day 30] [partial Mayo ≤ 2, subscores ≤ 1] 7/7 [100%] [partial Mayo drop ≥ 3 or 30% drop] NR NR median 90 days, range 30–210 days 5 Cohort Karakan et al., 201645 14 Steroid- dependent or non-responsive NR Colonoscopy NR 1–6 [interval not specified] NR NR Yes 6/14 [43%] 11/14 [78.5%] NR NR 3–18 months 4 Cohort Goyal et al., 201646 12 [paediatric] Mild- moderate [PUCAI < 65] Recipient- identified [related & unrelated] Both gastroscopy/ jejunoscopy [20-30 ml] and colonoscopy [200-250 ml] in TI/caecum 150 g stool in 250 ml saline Single Fresh Metronidazole/ vancomycin for 5 days, ceasing 48 before FMT Yes 0 [PUCAI < 10] 2/12 [17%] [PUCAI drop ≥ 15] NR NR 6 months 6 Cohort Laszlo et al., 201647 4 Moderate- severe Related [family member] Colonoscopy 150 ml faecal suspension diluted in 400-425 ml saline Single Fresh No Yes 4/4 [100%] - 2/4 [50%] NR 5 months 5 Cohort [RCT for pectin, FMT in both arms] Wei et al., 201648 20 [10 FMT alone; 10 FMT + 5 days oral pectin] Mild-moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 500 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 7/20 [35%] [3/10 FMT, 4/10 FMT + pectin] [Mayo ≤ 2] 13/20 [65%] [7/10 FMT, 6/10 FMT + pectin] [Mayo drop > 30%, 1 point drop in tarry stools or increase > 16 points in IBDQ] NR NR 12 weeks 5 Cohort [data from ongoing RCT] Pai et al., 201649 2 [paediatric] Active Unrelated Enemas NR 12 [biweekly for 6 weeks] Frozen NR NR 0 0 NR NR NR 7 Cohort Jacob et al., 201650 20 Active [Mayo ≥ 3, endoscopic subscore ≥ 1] Unrelated multidonor [2-donor concentrate] Colonoscopy [TI + right colon] 120 ml infusion Single Frozen No Yes 3/20 [15%] [Mayo ≤ 2, no subscore > 1] 7/20 [35%] [Mayo drop ≥ 3 and bleeding subscore ≤ 1] 2/20 [10%] [Mayo endoscopy subscore 0] NR 4 weeks 6 Cohort Nishida et al., 201651 41 Mild- moderate [Mayo 3–9, endoscopic subscore ≥ 1] Related [family member] Colonoscopy [caecum] 150-200 g stool in 500 ml saline Single Fresh No Yes 0 [Mayo ≤ 2, no subscore > 1] 11/41 [27%] [Mayo drop ≥ 3 and/or Mayo clinical score drop ≥ 2 with rectal bleeding subscore decrease ≥ 1] NR NR 8 weeks 6 Cohort Zhang et al., 201652 19 Moderate- severe [Mayo ≥ 6] NR Midgut through gastroscope 150-200 ml infusion Single Fresh No NR 2/19 [11%] [Mayo ≤2, no subscore > 1] 11/19 [58%] [Mayo drop ≥ 3 or ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR ≥ 3 months 5 Cohort Grewal et al., 201653 17 Moderate- severe, steroid- dependent NR NR NR 7 [2 infusions 2 weeks apart, then 5 infusions every 4 weeks] NR NR NR 15/17 [88%] [Week 4] 10/17 [59%] at 1 year with steroid cessation NR NR NR 12 months 5 Cohort [open- label extension cohort of RCT placebo arm] Paramsothy et al.,

201711 37 Mild-moderate [Mayo 4–10] Unrelated multidonor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline 40 [5/week for 8 weeks] Frozen No No 17/37 [46%] [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] NR 8/37 [22%] [steroid- free Mayo endoscopy subscore 0] NR 8 weeks post FMT [total 16 weeks] 5 Cohort Ishikawa et al., 201754 17, 19 controls [triple antibiotic therapy] Active [Lichtiger Clinical Activity Index ≥ 5 or endoscopic Mayo subscore ≥ 1] Recipient- identified [related & unrelated] Colonoscopy 150-250 g stool in 350-500 ml saline Single Fresh Amoxycillin 1500 mg, fosfomycin 3000 mg, metronidazole 750 mg daily for 2 weeks till 2 days before FMT Yes FMT: 9/17 [53%], control: 3/19 [16%] [CAI ≤ 3] FMT: 14/17 [82%], control: 13/19 [68%] [CAI < 10 & drop ≥ 3] NR NR 4

weeks 9 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow Up NOS Total Cohort Angelberger et al., 201332 5 Moderate- severe [Mayo ≥ 6] Recipient- identified but first degree- relatives excluded Nasojejunal & enema combined Median 24 g stool in 250 ml saline for nasojejunal infusion, median 20 g stool in 100 ml saline for enema 3 [daily for 3 days] Fresh Metronidazole 500 mg bd and probiotic [Yomogi or Omnibiotic] for 5–10 days before FMT Yes 0 [Mayo ≤ 2, no subscore > 1] 1/5 [20%] [Mayo drop ≥ 3 and ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR 12

weeks 5 Cohort Kump et al., 201333 6 Moderate- severe [Mayo 8–11] Unrelated Colonoscopy [TI + colon] 100-150 g stool in 200-350 ml Single Fresh No Yes 0 [Mayo ≤ 2] 2/6 [33%] [Mayo drop ≥ 3] NR NR 3

months 5 Cohort Kunde et al., 201334 10 [paediatric] Mild- moderate [PUCAI 15–65] Recipient- identified [related & unrelated] Enema Average 90 g stool [range 70-113 g] in 4 x 60 ml saline 5

[daily for 5 days] Fresh No No 3/9 [33%] at 1 and 4 weeks [PUCAI < 10] 7/9 [78%] at 1 Week 6/9 [67%] at 1 month [PUCAI drop > 15] NR NR 4

weeks 6 Cohort Cui et al., 201535 15 [data on 14] Moderate- severe [Montreal]

Steroid- dependent Recipient- identified [related & unrelated] Midgut through gastroscope 150-200 ml infusion 1–2, [1 week apart] NR No NR 4/14 [29%] [Montreal 0] 8/14 [57%] [Montreal improvement ≥ 1] & discontinuation of steroids NR NR > 3 months 5 Cohort Damman et al., 201536 7 Mild- moderate [UCDAI 3–10] Recipient- identified [1 related, rest unrelated] Colonoscopy 175–290 ml of stool mixture [1 g stool:2-3 ml

saline] Single Fresh No Yes 1/7 [14%] at 4 weeks [UCDAI ≤ 2 & no subscore > 1] 1/7 [14%] at 4 weeks [UCDAI drop ≥ 3] NR 1/7 [14%]

at 4 weeks 3 months 6 Cohort Karolewska- Bochenek et al., 201537 4 [paediatric] Moderate- severe Unrelated Gastroscopy 50 ml infusion 8 [daily first 5 days, alternate days in second week] NR No NR 0 4/4 [100%] NR NR 4

weeks 4 Cohort Kellermayer et al., 201538 3 [paediatric] Immunotherapy-dependent but controlled mucosal disease at study commencement [Mayo 0–1] Unrelated Colonoscopy followed by enemas 50 g stool in 250 ml saline; 60–250 ml delivered 22–30 [daily for fortnight, thrice weekly for fortnight, then weekly for 6–12 weeks] Frozen No Yes 3/3 [100%] - 3/3 [100%] 3/3 [100%] 3

months 3 Cohort Kump et al., 201539 17, 10 controls [triple antibiotic therapy] Chronic active NR Colonoscopy [initially right colon, then left colon on subsequent infusions] NR 5 [fortnightly infusions] NR Triple therapy [not specified] for 10 days Yes FMT: 4/17 [24%], control: 0 [Mayo ≤ 2] FMT: 10/17 [59%], control: 2/10 [20%] [Mayo drop ≥ 3] NR NR 90

days 6 Cohort Scaldaferri et al., 201540 8, 7 controls Mild-moderate [partial Mayo ≥ 4, endoscopic Mayo ≥ 1] Recipient- identified NR 200 ml of faecal slurry 3 [interval not specified] NR Not specified Yes FMT: 3/8 [38%], control: 2/7 [29%] [partial Mayo ≤ 2, all subscores ≤ 1] FMT: 4/8 [50%], control:

2/7 [29%] [partial Mayo drop ≥ 2] 33% [Mayo 0 at Week 6] NR 12

weeks 7 Cohort Suskind et al., 201541 4 [paediatric] Mild-moderate [PUCAI] NR Nasogastric 30 g stool in 100 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes 0 [PUCAI < 10] 0 NR NR 12

weeks 6 Cohort Vermeire et al., 201642 8 Moderate- severe; refractory, failed immunotherapy and anti-TNF Unrelated & related Nasogastric 3, rectal tube 5 200 g stool in 400 ml 2 [daily for 2 days] Fresh No Yes 2/8 [25%] NR 2/8 [25%] [Mayo endoscopy subscore ≤ 1] NR 8

weeks 5 Cohort Wei et al., 201543 11 Mild- moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 8/11 [73%] [Mayo < 2] NR NR NR 4

weeks 4 Cohort Ren et al., 201544 7 Severe [Mayo ≥ 10] Relatives or healthy volunteers Gastroscopy or colonoscopy or combined gastroscopy & colonoscopy Gastroscopy, 100-200 ml; colonoscopy, 200-300 ml 1–3 infusions [5 pts x 1, 1 pt x 2, 1 pt x 3] Fresh No No 5/7 [71%] [Day 30] [partial Mayo ≤ 2, subscores ≤ 1] 7/7 [100%] [partial Mayo drop ≥ 3 or 30% drop] NR NR median 90 days, range 30–210 days 5 Cohort Karakan et al., 201645 14 Steroid- dependent or non-responsive NR Colonoscopy NR 1–6 [interval not specified] NR NR Yes 6/14 [43%] 11/14 [78.5%] NR NR 3–18 months 4 Cohort Goyal et al., 201646 12 [paediatric] Mild- moderate [PUCAI < 65] Recipient- identified [related & unrelated] Both gastroscopy/ jejunoscopy [20-30 ml] and colonoscopy [200-250 ml] in TI/caecum 150 g stool in 250 ml saline Single Fresh Metronidazole/ vancomycin for 5 days, ceasing 48 before FMT Yes 0 [PUCAI < 10] 2/12 [17%] [PUCAI drop ≥ 15] NR NR 6 months 6 Cohort Laszlo et al., 201647 4 Moderate- severe Related [family member] Colonoscopy 150 ml faecal suspension diluted in 400-425 ml saline Single Fresh No Yes 4/4 [100%] - 2/4 [50%] NR 5 months 5 Cohort [RCT for pectin, FMT in both arms] Wei et al., 201648 20 [10 FMT alone; 10 FMT + 5 days oral pectin] Mild-moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 500 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 7/20 [35%] [3/10 FMT, 4/10 FMT + pectin] [Mayo ≤ 2] 13/20 [65%] [7/10 FMT, 6/10 FMT + pectin] [Mayo drop > 30%, 1 point drop in tarry stools or increase > 16 points in IBDQ] NR NR 12 weeks 5 Cohort [data from ongoing RCT] Pai et al., 201649 2 [paediatric] Active Unrelated Enemas NR 12 [biweekly for 6 weeks] Frozen NR NR 0 0 NR NR NR 7 Cohort Jacob et al., 201650 20 Active [Mayo ≥ 3, endoscopic subscore ≥ 1] Unrelated multidonor [2-donor concentrate] Colonoscopy [TI + right colon] 120 ml infusion Single Frozen No Yes 3/20 [15%] [Mayo ≤ 2, no subscore > 1] 7/20 [35%] [Mayo drop ≥ 3 and bleeding subscore ≤ 1] 2/20 [10%] [Mayo endoscopy subscore 0] NR 4 weeks 6 Cohort Nishida et al., 201651 41 Mild- moderate [Mayo 3–9, endoscopic subscore ≥ 1] Related [family member] Colonoscopy [caecum] 150-200 g stool in 500 ml saline Single Fresh No Yes 0 [Mayo ≤ 2, no subscore > 1] 11/41 [27%] [Mayo drop ≥ 3 and/or Mayo clinical score drop ≥ 2 with rectal bleeding subscore decrease ≥ 1] NR NR 8 weeks 6 Cohort Zhang et al., 201652 19 Moderate- severe [Mayo ≥ 6] NR Midgut through gastroscope 150-200 ml infusion Single Fresh No NR 2/19 [11%] [Mayo ≤2, no subscore > 1] 11/19 [58%] [Mayo drop ≥ 3 or ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR ≥ 3 months 5 Cohort Grewal et al., 201653 17 Moderate- severe, steroid- dependent NR NR NR 7 [2 infusions 2 weeks apart, then 5 infusions every 4 weeks] NR NR NR 15/17 [88%] [Week 4] 10/17 [59%] at 1 year with steroid cessation NR NR NR 12 months 5 Cohort [open- label extension cohort of RCT placebo arm] Paramsothy et al.,

201711 37 Mild-moderate [Mayo 4–10] Unrelated multidonor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline 40 [5/week for 8 weeks] Frozen No No 17/37 [46%] [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] NR 8/37 [22%] [steroid- free Mayo endoscopy subscore 0] NR 8 weeks post FMT [total 16 weeks] 5 Cohort Ishikawa et al., 201754 17, 19 controls [triple antibiotic therapy] Active [Lichtiger Clinical Activity Index ≥ 5 or endoscopic Mayo subscore ≥ 1] Recipient- identified [related & unrelated] Colonoscopy 150-250 g stool in 350-500 ml saline Single Fresh Amoxycillin 1500 mg, fosfomycin 3000 mg, metronidazole 750 mg daily for 2 weeks till 2 days before FMT Yes FMT: 9/17 [53%], control: 3/19 [16%] [CAI ≤ 3] FMT: 14/17 [82%], control: 13/19 [68%] [CAI < 10 & drop ≥ 3] NR NR 4

weeks 9 View Large

Table 2. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow Up NOS Total Cohort Angelberger et al., 201332 5 Moderate- severe [Mayo ≥ 6] Recipient- identified but first degree- relatives excluded Nasojejunal & enema combined Median 24 g stool in 250 ml saline for nasojejunal infusion, median 20 g stool in 100 ml saline for enema 3 [daily for 3 days] Fresh Metronidazole 500 mg bd and probiotic [Yomogi or Omnibiotic] for 5–10 days before FMT Yes 0 [Mayo ≤ 2, no subscore > 1] 1/5 [20%] [Mayo drop ≥ 3 and ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR 12

weeks 5 Cohort Kump et al., 201333 6 Moderate- severe [Mayo 8–11] Unrelated Colonoscopy [TI + colon] 100-150 g stool in 200-350 ml Single Fresh No Yes 0 [Mayo ≤ 2] 2/6 [33%] [Mayo drop ≥ 3] NR NR 3

months 5 Cohort Kunde et al., 201334 10 [paediatric] Mild- moderate [PUCAI 15–65] Recipient- identified [related & unrelated] Enema Average 90 g stool [range 70-113 g] in 4 x 60 ml saline 5

[daily for 5 days] Fresh No No 3/9 [33%] at 1 and 4 weeks [PUCAI < 10] 7/9 [78%] at 1 Week 6/9 [67%] at 1 month [PUCAI drop > 15] NR NR 4

weeks 6 Cohort Cui et al., 201535 15 [data on 14] Moderate- severe [Montreal]

Steroid- dependent Recipient- identified [related & unrelated] Midgut through gastroscope 150-200 ml infusion 1–2, [1 week apart] NR No NR 4/14 [29%] [Montreal 0] 8/14 [57%] [Montreal improvement ≥ 1] & discontinuation of steroids NR NR > 3 months 5 Cohort Damman et al., 201536 7 Mild- moderate [UCDAI 3–10] Recipient- identified [1 related, rest unrelated] Colonoscopy 175–290 ml of stool mixture [1 g stool:2-3 ml

saline] Single Fresh No Yes 1/7 [14%] at 4 weeks [UCDAI ≤ 2 & no subscore > 1] 1/7 [14%] at 4 weeks [UCDAI drop ≥ 3] NR 1/7 [14%]

at 4 weeks 3 months 6 Cohort Karolewska- Bochenek et al., 201537 4 [paediatric] Moderate- severe Unrelated Gastroscopy 50 ml infusion 8 [daily first 5 days, alternate days in second week] NR No NR 0 4/4 [100%] NR NR 4

weeks 4 Cohort Kellermayer et al., 201538 3 [paediatric] Immunotherapy-dependent but controlled mucosal disease at study commencement [Mayo 0–1] Unrelated Colonoscopy followed by enemas 50 g stool in 250 ml saline; 60–250 ml delivered 22–30 [daily for fortnight, thrice weekly for fortnight, then weekly for 6–12 weeks] Frozen No Yes 3/3 [100%] - 3/3 [100%] 3/3 [100%] 3

months 3 Cohort Kump et al., 201539 17, 10 controls [triple antibiotic therapy] Chronic active NR Colonoscopy [initially right colon, then left colon on subsequent infusions] NR 5 [fortnightly infusions] NR Triple therapy [not specified] for 10 days Yes FMT: 4/17 [24%], control: 0 [Mayo ≤ 2] FMT: 10/17 [59%], control: 2/10 [20%] [Mayo drop ≥ 3] NR NR 90

days 6 Cohort Scaldaferri et al., 201540 8, 7 controls Mild-moderate [partial Mayo ≥ 4, endoscopic Mayo ≥ 1] Recipient- identified NR 200 ml of faecal slurry 3 [interval not specified] NR Not specified Yes FMT: 3/8 [38%], control: 2/7 [29%] [partial Mayo ≤ 2, all subscores ≤ 1] FMT: 4/8 [50%], control:

2/7 [29%] [partial Mayo drop ≥ 2] 33% [Mayo 0 at Week 6] NR 12

weeks 7 Cohort Suskind et al., 201541 4 [paediatric] Mild-moderate [PUCAI] NR Nasogastric 30 g stool in 100 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes 0 [PUCAI < 10] 0 NR NR 12

weeks 6 Cohort Vermeire et al., 201642 8 Moderate- severe; refractory, failed immunotherapy and anti-TNF Unrelated & related Nasogastric 3, rectal tube 5 200 g stool in 400 ml 2 [daily for 2 days] Fresh No Yes 2/8 [25%] NR 2/8 [25%] [Mayo endoscopy subscore ≤ 1] NR 8

weeks 5 Cohort Wei et al., 201543 11 Mild- moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 8/11 [73%] [Mayo < 2] NR NR NR 4

weeks 4 Cohort Ren et al., 201544 7 Severe [Mayo ≥ 10] Relatives or healthy volunteers Gastroscopy or colonoscopy or combined gastroscopy & colonoscopy Gastroscopy, 100-200 ml; colonoscopy, 200-300 ml 1–3 infusions [5 pts x 1, 1 pt x 2, 1 pt x 3] Fresh No No 5/7 [71%] [Day 30] [partial Mayo ≤ 2, subscores ≤ 1] 7/7 [100%] [partial Mayo drop ≥ 3 or 30% drop] NR NR median 90 days, range 30–210 days 5 Cohort Karakan et al., 201645 14 Steroid- dependent or non-responsive NR Colonoscopy NR 1–6 [interval not specified] NR NR Yes 6/14 [43%] 11/14 [78.5%] NR NR 3–18 months 4 Cohort Goyal et al., 201646 12 [paediatric] Mild- moderate [PUCAI < 65] Recipient- identified [related & unrelated] Both gastroscopy/ jejunoscopy [20-30 ml] and colonoscopy [200-250 ml] in TI/caecum 150 g stool in 250 ml saline Single Fresh Metronidazole/ vancomycin for 5 days, ceasing 48 before FMT Yes 0 [PUCAI < 10] 2/12 [17%] [PUCAI drop ≥ 15] NR NR 6 months 6 Cohort Laszlo et al., 201647 4 Moderate- severe Related [family member] Colonoscopy 150 ml faecal suspension diluted in 400-425 ml saline Single Fresh No Yes 4/4 [100%] - 2/4 [50%] NR 5 months 5 Cohort [RCT for pectin, FMT in both arms] Wei et al., 201648 20 [10 FMT alone; 10 FMT + 5 days oral pectin] Mild-moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 500 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 7/20 [35%] [3/10 FMT, 4/10 FMT + pectin] [Mayo ≤ 2] 13/20 [65%] [7/10 FMT, 6/10 FMT + pectin] [Mayo drop > 30%, 1 point drop in tarry stools or increase > 16 points in IBDQ] NR NR 12 weeks 5 Cohort [data from ongoing RCT] Pai et al., 201649 2 [paediatric] Active Unrelated Enemas NR 12 [biweekly for 6 weeks] Frozen NR NR 0 0 NR NR NR 7 Cohort Jacob et al., 201650 20 Active [Mayo ≥ 3, endoscopic subscore ≥ 1] Unrelated multidonor [2-donor concentrate] Colonoscopy [TI + right colon] 120 ml infusion Single Frozen No Yes 3/20 [15%] [Mayo ≤ 2, no subscore > 1] 7/20 [35%] [Mayo drop ≥ 3 and bleeding subscore ≤ 1] 2/20 [10%] [Mayo endoscopy subscore 0] NR 4 weeks 6 Cohort Nishida et al., 201651 41 Mild- moderate [Mayo 3–9, endoscopic subscore ≥ 1] Related [family member] Colonoscopy [caecum] 150-200 g stool in 500 ml saline Single Fresh No Yes 0 [Mayo ≤ 2, no subscore > 1] 11/41 [27%] [Mayo drop ≥ 3 and/or Mayo clinical score drop ≥ 2 with rectal bleeding subscore decrease ≥ 1] NR NR 8 weeks 6 Cohort Zhang et al., 201652 19 Moderate- severe [Mayo ≥ 6] NR Midgut through gastroscope 150-200 ml infusion Single Fresh No NR 2/19 [11%] [Mayo ≤2, no subscore > 1] 11/19 [58%] [Mayo drop ≥ 3 or ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR ≥ 3 months 5 Cohort Grewal et al., 201653 17 Moderate- severe, steroid- dependent NR NR NR 7 [2 infusions 2 weeks apart, then 5 infusions every 4 weeks] NR NR NR 15/17 [88%] [Week 4] 10/17 [59%] at 1 year with steroid cessation NR NR NR 12 months 5 Cohort [open- label extension cohort of RCT placebo arm] Paramsothy et al.,

201711 37 Mild-moderate [Mayo 4–10] Unrelated multidonor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline 40 [5/week for 8 weeks] Frozen No No 17/37 [46%] [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] NR 8/37 [22%] [steroid- free Mayo endoscopy subscore 0] NR 8 weeks post FMT [total 16 weeks] 5 Cohort Ishikawa et al., 201754 17, 19 controls [triple antibiotic therapy] Active [Lichtiger Clinical Activity Index ≥ 5 or endoscopic Mayo subscore ≥ 1] Recipient- identified [related & unrelated] Colonoscopy 150-250 g stool in 350-500 ml saline Single Fresh Amoxycillin 1500 mg, fosfomycin 3000 mg, metronidazole 750 mg daily for 2 weeks till 2 days before FMT Yes FMT: 9/17 [53%], control: 3/19 [16%] [CAI ≤ 3] FMT: 14/17 [82%], control: 13/19 [68%] [CAI < 10 & drop ≥ 3] NR NR 4

weeks 9 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow Up NOS Total Cohort Angelberger et al., 201332 5 Moderate- severe [Mayo ≥ 6] Recipient- identified but first degree- relatives excluded Nasojejunal & enema combined Median 24 g stool in 250 ml saline for nasojejunal infusion, median 20 g stool in 100 ml saline for enema 3 [daily for 3 days] Fresh Metronidazole 500 mg bd and probiotic [Yomogi or Omnibiotic] for 5–10 days before FMT Yes 0 [Mayo ≤ 2, no subscore > 1] 1/5 [20%] [Mayo drop ≥ 3 and ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR 12

weeks 5 Cohort Kump et al., 201333 6 Moderate- severe [Mayo 8–11] Unrelated Colonoscopy [TI + colon] 100-150 g stool in 200-350 ml Single Fresh No Yes 0 [Mayo ≤ 2] 2/6 [33%] [Mayo drop ≥ 3] NR NR 3

months 5 Cohort Kunde et al., 201334 10 [paediatric] Mild- moderate [PUCAI 15–65] Recipient- identified [related & unrelated] Enema Average 90 g stool [range 70-113 g] in 4 x 60 ml saline 5

[daily for 5 days] Fresh No No 3/9 [33%] at 1 and 4 weeks [PUCAI < 10] 7/9 [78%] at 1 Week 6/9 [67%] at 1 month [PUCAI drop > 15] NR NR 4

weeks 6 Cohort Cui et al., 201535 15 [data on 14] Moderate- severe [Montreal]

Steroid- dependent Recipient- identified [related & unrelated] Midgut through gastroscope 150-200 ml infusion 1–2, [1 week apart] NR No NR 4/14 [29%] [Montreal 0] 8/14 [57%] [Montreal improvement ≥ 1] & discontinuation of steroids NR NR > 3 months 5 Cohort Damman et al., 201536 7 Mild- moderate [UCDAI 3–10] Recipient- identified [1 related, rest unrelated] Colonoscopy 175–290 ml of stool mixture [1 g stool:2-3 ml

saline] Single Fresh No Yes 1/7 [14%] at 4 weeks [UCDAI ≤ 2 & no subscore > 1] 1/7 [14%] at 4 weeks [UCDAI drop ≥ 3] NR 1/7 [14%]

at 4 weeks 3 months 6 Cohort Karolewska- Bochenek et al., 201537 4 [paediatric] Moderate- severe Unrelated Gastroscopy 50 ml infusion 8 [daily first 5 days, alternate days in second week] NR No NR 0 4/4 [100%] NR NR 4

weeks 4 Cohort Kellermayer et al., 201538 3 [paediatric] Immunotherapy-dependent but controlled mucosal disease at study commencement [Mayo 0–1] Unrelated Colonoscopy followed by enemas 50 g stool in 250 ml saline; 60–250 ml delivered 22–30 [daily for fortnight, thrice weekly for fortnight, then weekly for 6–12 weeks] Frozen No Yes 3/3 [100%] - 3/3 [100%] 3/3 [100%] 3

months 3 Cohort Kump et al., 201539 17, 10 controls [triple antibiotic therapy] Chronic active NR Colonoscopy [initially right colon, then left colon on subsequent infusions] NR 5 [fortnightly infusions] NR Triple therapy [not specified] for 10 days Yes FMT: 4/17 [24%], control: 0 [Mayo ≤ 2] FMT: 10/17 [59%], control: 2/10 [20%] [Mayo drop ≥ 3] NR NR 90

days 6 Cohort Scaldaferri et al., 201540 8, 7 controls Mild-moderate [partial Mayo ≥ 4, endoscopic Mayo ≥ 1] Recipient- identified NR 200 ml of faecal slurry 3 [interval not specified] NR Not specified Yes FMT: 3/8 [38%], control: 2/7 [29%] [partial Mayo ≤ 2, all subscores ≤ 1] FMT: 4/8 [50%], control:

2/7 [29%] [partial Mayo drop ≥ 2] 33% [Mayo 0 at Week 6] NR 12

weeks 7 Cohort Suskind et al., 201541 4 [paediatric] Mild-moderate [PUCAI] NR Nasogastric 30 g stool in 100 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes 0 [PUCAI < 10] 0 NR NR 12

weeks 6 Cohort Vermeire et al., 201642 8 Moderate- severe; refractory, failed immunotherapy and anti-TNF Unrelated & related Nasogastric 3, rectal tube 5 200 g stool in 400 ml 2 [daily for 2 days] Fresh No Yes 2/8 [25%] NR 2/8 [25%] [Mayo endoscopy subscore ≤ 1] NR 8

weeks 5 Cohort Wei et al., 201543 11 Mild- moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 8/11 [73%] [Mayo < 2] NR NR NR 4

weeks 4 Cohort Ren et al., 201544 7 Severe [Mayo ≥ 10] Relatives or healthy volunteers Gastroscopy or colonoscopy or combined gastroscopy & colonoscopy Gastroscopy, 100-200 ml; colonoscopy, 200-300 ml 1–3 infusions [5 pts x 1, 1 pt x 2, 1 pt x 3] Fresh No No 5/7 [71%] [Day 30] [partial Mayo ≤ 2, subscores ≤ 1] 7/7 [100%] [partial Mayo drop ≥ 3 or 30% drop] NR NR median 90 days, range 30–210 days 5 Cohort Karakan et al., 201645 14 Steroid- dependent or non-responsive NR Colonoscopy NR 1–6 [interval not specified] NR NR Yes 6/14 [43%] 11/14 [78.5%] NR NR 3–18 months 4 Cohort Goyal et al., 201646 12 [paediatric] Mild- moderate [PUCAI < 65] Recipient- identified [related & unrelated] Both gastroscopy/ jejunoscopy [20-30 ml] and colonoscopy [200-250 ml] in TI/caecum 150 g stool in 250 ml saline Single Fresh Metronidazole/ vancomycin for 5 days, ceasing 48 before FMT Yes 0 [PUCAI < 10] 2/12 [17%] [PUCAI drop ≥ 15] NR NR 6 months 6 Cohort Laszlo et al., 201647 4 Moderate- severe Related [family member] Colonoscopy 150 ml faecal suspension diluted in 400-425 ml saline Single Fresh No Yes 4/4 [100%] - 2/4 [50%] NR 5 months 5 Cohort [RCT for pectin, FMT in both arms] Wei et al., 201648 20 [10 FMT alone; 10 FMT + 5 days oral pectin] Mild-moderate [Mayo 2–10] Unrelated Colonoscopy 60 g stool in 500 ml saline Single Fresh Vancomycin 500 mg bd for 3 days before FMT Yes 7/20 [35%] [3/10 FMT, 4/10 FMT + pectin] [Mayo ≤ 2] 13/20 [65%] [7/10 FMT, 6/10 FMT + pectin] [Mayo drop > 30%, 1 point drop in tarry stools or increase > 16 points in IBDQ] NR NR 12 weeks 5 Cohort [data from ongoing RCT] Pai et al., 201649 2 [paediatric] Active Unrelated Enemas NR 12 [biweekly for 6 weeks] Frozen NR NR 0 0 NR NR NR 7 Cohort Jacob et al., 201650 20 Active [Mayo ≥ 3, endoscopic subscore ≥ 1] Unrelated multidonor [2-donor concentrate] Colonoscopy [TI + right colon] 120 ml infusion Single Frozen No Yes 3/20 [15%] [Mayo ≤ 2, no subscore > 1] 7/20 [35%] [Mayo drop ≥ 3 and bleeding subscore ≤ 1] 2/20 [10%] [Mayo endoscopy subscore 0] NR 4 weeks 6 Cohort Nishida et al., 201651 41 Mild- moderate [Mayo 3–9, endoscopic subscore ≥ 1] Related [family member] Colonoscopy [caecum] 150-200 g stool in 500 ml saline Single Fresh No Yes 0 [Mayo ≤ 2, no subscore > 1] 11/41 [27%] [Mayo drop ≥ 3 and/or Mayo clinical score drop ≥ 2 with rectal bleeding subscore decrease ≥ 1] NR NR 8 weeks 6 Cohort Zhang et al., 201652 19 Moderate- severe [Mayo ≥ 6] NR Midgut through gastroscope 150-200 ml infusion Single Fresh No NR 2/19 [11%] [Mayo ≤2, no subscore > 1] 11/19 [58%] [Mayo drop ≥ 3 or ≥ 30%, along with drop in bleeding subscore ≥ 1 or bleeding subscore ≤ 1] NR NR ≥ 3 months 5 Cohort Grewal et al., 201653 17 Moderate- severe, steroid- dependent NR NR NR 7 [2 infusions 2 weeks apart, then 5 infusions every 4 weeks] NR NR NR 15/17 [88%] [Week 4] 10/17 [59%] at 1 year with steroid cessation NR NR NR 12 months 5 Cohort [open- label extension cohort of RCT placebo arm] Paramsothy et al.,

201711 37 Mild-moderate [Mayo 4–10] Unrelated multidonor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline 40 [5/week for 8 weeks] Frozen No No 17/37 [46%] [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] NR 8/37 [22%] [steroid- free Mayo endoscopy subscore 0] NR 8 weeks post FMT [total 16 weeks] 5 Cohort Ishikawa et al., 201754 17, 19 controls [triple antibiotic therapy] Active [Lichtiger Clinical Activity Index ≥ 5 or endoscopic Mayo subscore ≥ 1] Recipient- identified [related & unrelated] Colonoscopy 150-250 g stool in 350-500 ml saline Single Fresh Amoxycillin 1500 mg, fosfomycin 3000 mg, metronidazole 750 mg daily for 2 weeks till 2 days before FMT Yes FMT: 9/17 [53%], control: 3/19 [16%] [CAI ≤ 3] FMT: 14/17 [82%], control: 13/19 [68%] [CAI < 10 & drop ≥ 3] NR NR 4

weeks 9 View Large

Table 3. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre- antibiotic Bowel lavage Primary endpoint Clinical remission Clinical response Endoscopic remission Endoscopic response Histologic remission Follow- up DBRCT Moayeddi et al., 20159 75: 38 FMT, 37 controls Mild- severe, [Mayo 4–12] Unrelated Enema 50g stool in 50 ml infusion 6 [weekly] Frozen 21, fresh 15, combination fresh & frozen 1 No No Clinical and endoscopic remission Mayo < 3 with endoscopic Mayo 0 9/38 [24%] vs 2/37 [5%], p = 0.03 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo < 3] 15/38 [39%] vs 9/37 [24%], p = 0.16 [Mayo drop ≥ 3] 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo endoscopy subscore 0] NR 7 FMT, 1 placebo 7 weeks DBRCT Rossen et al., 201510 48: 23 FMT, 25 control autologous stool Mild- moderate [SCCAI 4–11] Unrelated & related Nasoduodenal Minimum 60 g stool in 500 ml 2 [3 weeks apart] Fresh No Yes Clinical remission and endoscopic improvement SCCAI ≤ 2 in combination with ≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid], 7/23 [30%] vs 5/25 [20%], p = 0.51 7/23 [30%] vs 8/25 [32%], p = NS [SCCAI ≤ 2] 11/23 [48%] vs 13/25 [52%], p = NS [SCCAI drop ≥ 1.5] NR 8/23 [35%] vs 9/25 [36%], p = NS (≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid]) NR 12 weeks DBRCT Paramsothy et al., 201711 81: 41 FMT, 40 controls Mild- moderate [Mayo 4–10] Unrelated multi- donor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline infusion 40 [5/week for 8 weeks] Frozen No Yes Steroid-free clinical remission and endoscopic improvement, Mayo ≤ 2, all subscores ≤ 1, ≥ 1 point drop in endoscopy subscore, off steroids 11/41 [27%] vs 3/40 [8%], p = 0.02 18/41 [44%] vs 8/40 [20%], p = 0.02 [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] 22/41 [54%] vs 9/40 [23%], p = 0.01 [steroid- free drop in combined Mayo subscore for bleeding & stool frequency of ≥ 3 or 50%] 5/41 [12%] vs 3/40 [8%], p = NS [steroid- free Mayo endoscopy subscore 0] 13/41 [32%] vs 4/40 [10%], p = 0.02 [steroid- free Mayo endoscopy subscore ≤ 1 with drop ≥ 1] NR 8 weeks post FMT [total 16 weeks] DBRCT Costello et al., 201712 73: 38 FMT, 35 control autologous stools Mild- moderate [Mayo 3–10] Unrelated multi- donor [3–4 donors/ infusion] Colonoscopy followed by enemas NR 3 [3/week] Frozen No Yes Steroid-free remission, Mayo ≤ 2, endoscopic subscore ≤ 1, off steroids 12/38 [32%] vs 3/35 [9%], p = 0.02 19/38 [50%] vs 6/35 [17%], p < 0.01 [steroid-free SCCAI ≤ 2] 21/38 [55%] vs 7/35 [20%], p < 0.01 [steroid- free Mayo drop ≥ 3] 21/38 [55%] vs 6/35 [17%], p < 0.01 [steroid- free Mayo endoscopy subscore ≤ 1] NR NR 8 weeks Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre- antibiotic Bowel lavage Primary endpoint Clinical remission Clinical response Endoscopic remission Endoscopic response Histologic remission Follow- up DBRCT Moayeddi et al., 20159 75: 38 FMT, 37 controls Mild- severe, [Mayo 4–12] Unrelated Enema 50g stool in 50 ml infusion 6 [weekly] Frozen 21, fresh 15, combination fresh & frozen 1 No No Clinical and endoscopic remission Mayo < 3 with endoscopic Mayo 0 9/38 [24%] vs 2/37 [5%], p = 0.03 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo < 3] 15/38 [39%] vs 9/37 [24%], p = 0.16 [Mayo drop ≥ 3] 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo endoscopy subscore 0] NR 7 FMT, 1 placebo 7 weeks DBRCT Rossen et al., 201510 48: 23 FMT, 25 control autologous stool Mild- moderate [SCCAI 4–11] Unrelated & related Nasoduodenal Minimum 60 g stool in 500 ml 2 [3 weeks apart] Fresh No Yes Clinical remission and endoscopic improvement SCCAI ≤ 2 in combination with ≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid], 7/23 [30%] vs 5/25 [20%], p = 0.51 7/23 [30%] vs 8/25 [32%], p = NS [SCCAI ≤ 2] 11/23 [48%] vs 13/25 [52%], p = NS [SCCAI drop ≥ 1.5] NR 8/23 [35%] vs 9/25 [36%], p = NS (≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid]) NR 12 weeks DBRCT Paramsothy et al., 201711 81: 41 FMT, 40 controls Mild- moderate [Mayo 4–10] Unrelated multi- donor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline infusion 40 [5/week for 8 weeks] Frozen No Yes Steroid-free clinical remission and endoscopic improvement, Mayo ≤ 2, all subscores ≤ 1, ≥ 1 point drop in endoscopy subscore, off steroids 11/41 [27%] vs 3/40 [8%], p = 0.02 18/41 [44%] vs 8/40 [20%], p = 0.02 [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] 22/41 [54%] vs 9/40 [23%], p = 0.01 [steroid- free drop in combined Mayo subscore for bleeding & stool frequency of ≥ 3 or 50%] 5/41 [12%] vs 3/40 [8%], p = NS [steroid- free Mayo endoscopy subscore 0] 13/41 [32%] vs 4/40 [10%], p = 0.02 [steroid- free Mayo endoscopy subscore ≤ 1 with drop ≥ 1] NR 8 weeks post FMT [total 16 weeks] DBRCT Costello et al., 201712 73: 38 FMT, 35 control autologous stools Mild- moderate [Mayo 3–10] Unrelated multi- donor [3–4 donors/ infusion] Colonoscopy followed by enemas NR 3 [3/week] Frozen No Yes Steroid-free remission, Mayo ≤ 2, endoscopic subscore ≤ 1, off steroids 12/38 [32%] vs 3/35 [9%], p = 0.02 19/38 [50%] vs 6/35 [17%], p < 0.01 [steroid-free SCCAI ≤ 2] 21/38 [55%] vs 7/35 [20%], p < 0.01 [steroid- free Mayo drop ≥ 3] 21/38 [55%] vs 6/35 [17%], p < 0.01 [steroid- free Mayo endoscopy subscore ≤ 1] NR NR 8 weeks View Large

Table 3. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre- antibiotic Bowel lavage Primary endpoint Clinical remission Clinical response Endoscopic remission Endoscopic response Histologic remission Follow- up DBRCT Moayeddi et al., 20159 75: 38 FMT, 37 controls Mild- severe, [Mayo 4–12] Unrelated Enema 50g stool in 50 ml infusion 6 [weekly] Frozen 21, fresh 15, combination fresh & frozen 1 No No Clinical and endoscopic remission Mayo < 3 with endoscopic Mayo 0 9/38 [24%] vs 2/37 [5%], p = 0.03 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo < 3] 15/38 [39%] vs 9/37 [24%], p = 0.16 [Mayo drop ≥ 3] 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo endoscopy subscore 0] NR 7 FMT, 1 placebo 7 weeks DBRCT Rossen et al., 201510 48: 23 FMT, 25 control autologous stool Mild- moderate [SCCAI 4–11] Unrelated & related Nasoduodenal Minimum 60 g stool in 500 ml 2 [3 weeks apart] Fresh No Yes Clinical remission and endoscopic improvement SCCAI ≤ 2 in combination with ≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid], 7/23 [30%] vs 5/25 [20%], p = 0.51 7/23 [30%] vs 8/25 [32%], p = NS [SCCAI ≤ 2] 11/23 [48%] vs 13/25 [52%], p = NS [SCCAI drop ≥ 1.5] NR 8/23 [35%] vs 9/25 [36%], p = NS (≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid]) NR 12 weeks DBRCT Paramsothy et al., 201711 81: 41 FMT, 40 controls Mild- moderate [Mayo 4–10] Unrelated multi- donor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline infusion 40 [5/week for 8 weeks] Frozen No Yes Steroid-free clinical remission and endoscopic improvement, Mayo ≤ 2, all subscores ≤ 1, ≥ 1 point drop in endoscopy subscore, off steroids 11/41 [27%] vs 3/40 [8%], p = 0.02 18/41 [44%] vs 8/40 [20%], p = 0.02 [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] 22/41 [54%] vs 9/40 [23%], p = 0.01 [steroid- free drop in combined Mayo subscore for bleeding & stool frequency of ≥ 3 or 50%] 5/41 [12%] vs 3/40 [8%], p = NS [steroid- free Mayo endoscopy subscore 0] 13/41 [32%] vs 4/40 [10%], p = 0.02 [steroid- free Mayo endoscopy subscore ≤ 1 with drop ≥ 1] NR 8 weeks post FMT [total 16 weeks] DBRCT Costello et al., 201712 73: 38 FMT, 35 control autologous stools Mild- moderate [Mayo 3–10] Unrelated multi- donor [3–4 donors/ infusion] Colonoscopy followed by enemas NR 3 [3/week] Frozen No Yes Steroid-free remission, Mayo ≤ 2, endoscopic subscore ≤ 1, off steroids 12/38 [32%] vs 3/35 [9%], p = 0.02 19/38 [50%] vs 6/35 [17%], p < 0.01 [steroid-free SCCAI ≤ 2] 21/38 [55%] vs 7/35 [20%], p < 0.01 [steroid- free Mayo drop ≥ 3] 21/38 [55%] vs 6/35 [17%], p < 0.01 [steroid- free Mayo endoscopy subscore ≤ 1] NR NR 8 weeks Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre- antibiotic Bowel lavage Primary endpoint Clinical remission Clinical response Endoscopic remission Endoscopic response Histologic remission Follow- up DBRCT Moayeddi et al., 20159 75: 38 FMT, 37 controls Mild- severe, [Mayo 4–12] Unrelated Enema 50g stool in 50 ml infusion 6 [weekly] Frozen 21, fresh 15, combination fresh & frozen 1 No No Clinical and endoscopic remission Mayo < 3 with endoscopic Mayo 0 9/38 [24%] vs 2/37 [5%], p = 0.03 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo < 3] 15/38 [39%] vs 9/37 [24%], p = 0.16 [Mayo drop ≥ 3] 9/38 [24%] vs 2/37 [5%], p = 0.03 [Mayo endoscopy subscore 0] NR 7 FMT, 1 placebo 7 weeks DBRCT Rossen et al., 201510 48: 23 FMT, 25 control autologous stool Mild- moderate [SCCAI 4–11] Unrelated & related Nasoduodenal Minimum 60 g stool in 500 ml 2 [3 weeks apart] Fresh No Yes Clinical remission and endoscopic improvement SCCAI ≤ 2 in combination with ≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid], 7/23 [30%] vs 5/25 [20%], p = 0.51 7/23 [30%] vs 8/25 [32%], p = NS [SCCAI ≤ 2] 11/23 [48%] vs 13/25 [52%], p = NS [SCCAI drop ≥ 1.5] NR 8/23 [35%] vs 9/25 [36%], p = NS (≥ 1 point drop in combined Mayo endoscopic score [rectum & sigmoid]) NR 12 weeks DBRCT Paramsothy et al., 201711 81: 41 FMT, 40 controls Mild- moderate [Mayo 4–10] Unrelated multi- donor [3–7 donors/ infusion] Colonoscopy followed by enemas 37.5 g stool in 150 ml saline infusion 40 [5/week for 8 weeks] Frozen No Yes Steroid-free clinical remission and endoscopic improvement, Mayo ≤ 2, all subscores ≤ 1, ≥ 1 point drop in endoscopy subscore, off steroids 11/41 [27%] vs 3/40 [8%], p = 0.02 18/41 [44%] vs 8/40 [20%], p = 0.02 [steroid- free Mayo subscore ≤ 1 for bleeding & stool frequency combined] 22/41 [54%] vs 9/40 [23%], p = 0.01 [steroid- free drop in combined Mayo subscore for bleeding & stool frequency of ≥ 3 or 50%] 5/41 [12%] vs 3/40 [8%], p = NS [steroid- free Mayo endoscopy subscore 0] 13/41 [32%] vs 4/40 [10%], p = 0.02 [steroid- free Mayo endoscopy subscore ≤ 1 with drop ≥ 1] NR 8 weeks post FMT [total 16 weeks] DBRCT Costello et al., 201712 73: 38 FMT, 35 control autologous stools Mild- moderate [Mayo 3–10] Unrelated multi- donor [3–4 donors/ infusion] Colonoscopy followed by enemas NR 3 [3/week] Frozen No Yes Steroid-free remission, Mayo ≤ 2, endoscopic subscore ≤ 1, off steroids 12/38 [32%] vs 3/35 [9%], p = 0.02 19/38 [50%] vs 6/35 [17%], p < 0.01 [steroid-free SCCAI ≤ 2] 21/38 [55%] vs 7/35 [20%], p < 0.01 [steroid- free Mayo drop ≥ 3] 21/38 [55%] vs 6/35 [17%], p < 0.01 [steroid- free Mayo endoscopy subscore ≤ 1] NR NR 8 weeks View Large

Table 4. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up NOS total Case report Borody et al., 198919 1 NR NR NR NR NR NR NR NR 1 - NR NR 4 months - Case report Swaminath et al., 201455 1 Patchy colitis, severe from 11 to 22 cm Partner Enema NR 5 [daily for 5 days] Fresh NR NR 0 [worsening of colitis symptoms with FMT] 0 [worsening of colitis symptoms with FMT] NR NR 3 weeks, near resolution of bleeding and diarrhoea with topical 5-ASA - Case report Gordon et al., 201456 1 Severe, HBI 30 partner NR NR Daily, number not specified Fresh Vancomycin for previous Clostridium difficile infection NR 0 1 [HBI drop 30 to 7] NR NR Relapse at 6 months, commenced azathioprine - Case report Kao et al., 201457 1 Moderate-severe,

HBI 12 Unrelated Colonoscopy 400 ml of 1:4 stool: saline Single Fresh 7-day course of ciprofloxacin & metronidazole till 2 days before FMT Yes 1 [HBI 0] - 1 complete mucosal healing 1 4 weeks - Cohort Kahn et al., 201458 8 Active, HBI > 6 Unrelated Colonoscopy NR Single NR NR Yes NR [safety study] NR NR NR 1 week 4 Cohort Cui et al., 201559 30 Moderate- severe, HBI > 6 Unrelated & related Midgut through gastroscope 150-200 ml infusion Single Fresh or frozen No yes 23/30 [76.7%] [HBI < 5] 26/30 [86.7%] [HBI drop > 3] NR NR 6–15 months 4 Cohort Suskind et al., 201560 9 [paediatric] Mild- moderate [PCDAI 10–29] Related [parent] Nasogastric 30 g stool in 100-200 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes Week 2: 7/9 [78%], Weeks 6 & 12: 5/9 [56%] [PCDAI < 10] NR NR NR 12 weeks 6 Cohort Vermeire et al., 201642 6 Moderate- severe Unrelated & related Nasogastric 200 g stool in 400 ml saline 2 [daily for 2 days] Fresh No Yes 0 NR 0 NR 8 weeks 5 Cohort Wei et al., 201543 3 Active, CDAI 150–400 Unrelated Nasogastric [2] colonoscopy [1] 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days beforeFMT Yes 0 Mean CDAI drop from 345 to 135 NR NR 4 weeks 5 Cohort Vaughn et al., 201661 19 Active, HBI ≥ 5 Unrelated Colonoscopy 50 g stool in 250 ml solution Single Frozen No Yes 10/19 [53%] [HBI < 5 at Week 4] 11/19 [58%] [HBI drop ≥ 3 at Week 4] NR NR 26 weeks 6 Cohort Goyal et al., 201646 4 [paediatric] Mild- moderate, PCDAI < 40 Recipient- identified [related & unrelated] Both duodenoscopy and jejunoscopy [20–30 ml] and colonoscopy [200-250 ml] 150 g stool in 250 ml saline Single Fresh Metronidazole/vancomycin for 5 days, ceasing 48 h before FMT yes 2/4 [50%] PCDAI < 10 or | normalisation of lactoferrin/ calprotectin 3/4 [75%] PCDAI drop ≥ 12.5 NR NR 6 months 4 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up NOS total Case report Borody et al., 198919 1 NR NR NR NR NR NR NR NR 1 - NR NR 4 months - Case report Swaminath et al., 201455 1 Patchy colitis, severe from 11 to 22 cm Partner Enema NR 5 [daily for 5 days] Fresh NR NR 0 [worsening of colitis symptoms with FMT] 0 [worsening of colitis symptoms with FMT] NR NR 3 weeks, near resolution of bleeding and diarrhoea with topical 5-ASA - Case report Gordon et al., 201456 1 Severe, HBI 30 partner NR NR Daily, number not specified Fresh Vancomycin for previous Clostridium difficile infection NR 0 1 [HBI drop 30 to 7] NR NR Relapse at 6 months, commenced azathioprine - Case report Kao et al., 201457 1 Moderate-severe,

HBI 12 Unrelated Colonoscopy 400 ml of 1:4 stool: saline Single Fresh 7-day course of ciprofloxacin & metronidazole till 2 days before FMT Yes 1 [HBI 0] - 1 complete mucosal healing 1 4 weeks - Cohort Kahn et al., 201458 8 Active, HBI > 6 Unrelated Colonoscopy NR Single NR NR Yes NR [safety study] NR NR NR 1 week 4 Cohort Cui et al., 201559 30 Moderate- severe, HBI > 6 Unrelated & related Midgut through gastroscope 150-200 ml infusion Single Fresh or frozen No yes 23/30 [76.7%] [HBI < 5] 26/30 [86.7%] [HBI drop > 3] NR NR 6–15 months 4 Cohort Suskind et al., 201560 9 [paediatric] Mild- moderate [PCDAI 10–29] Related [parent] Nasogastric 30 g stool in 100-200 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes Week 2: 7/9 [78%], Weeks 6 & 12: 5/9 [56%] [PCDAI < 10] NR NR NR 12 weeks 6 Cohort Vermeire et al., 201642 6 Moderate- severe Unrelated & related Nasogastric 200 g stool in 400 ml saline 2 [daily for 2 days] Fresh No Yes 0 NR 0 NR 8 weeks 5 Cohort Wei et al., 201543 3 Active, CDAI 150–400 Unrelated Nasogastric [2] colonoscopy [1] 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days beforeFMT Yes 0 Mean CDAI drop from 345 to 135 NR NR 4 weeks 5 Cohort Vaughn et al., 201661 19 Active, HBI ≥ 5 Unrelated Colonoscopy 50 g stool in 250 ml solution Single Frozen No Yes 10/19 [53%] [HBI < 5 at Week 4] 11/19 [58%] [HBI drop ≥ 3 at Week 4] NR NR 26 weeks 6 Cohort Goyal et al., 201646 4 [paediatric] Mild- moderate, PCDAI < 40 Recipient- identified [related & unrelated] Both duodenoscopy and jejunoscopy [20–30 ml] and colonoscopy [200-250 ml] 150 g stool in 250 ml saline Single Fresh Metronidazole/vancomycin for 5 days, ceasing 48 h before FMT yes 2/4 [50%] PCDAI < 10 or | normalisation of lactoferrin/ calprotectin 3/4 [75%] PCDAI drop ≥ 12.5 NR NR 6 months 4 View Large

Table 4. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up NOS total Case report Borody et al., 198919 1 NR NR NR NR NR NR NR NR 1 - NR NR 4 months - Case report Swaminath et al., 201455 1 Patchy colitis, severe from 11 to 22 cm Partner Enema NR 5 [daily for 5 days] Fresh NR NR 0 [worsening of colitis symptoms with FMT] 0 [worsening of colitis symptoms with FMT] NR NR 3 weeks, near resolution of bleeding and diarrhoea with topical 5-ASA - Case report Gordon et al., 201456 1 Severe, HBI 30 partner NR NR Daily, number not specified Fresh Vancomycin for previous Clostridium difficile infection NR 0 1 [HBI drop 30 to 7] NR NR Relapse at 6 months, commenced azathioprine - Case report Kao et al., 201457 1 Moderate-severe,

HBI 12 Unrelated Colonoscopy 400 ml of 1:4 stool: saline Single Fresh 7-day course of ciprofloxacin & metronidazole till 2 days before FMT Yes 1 [HBI 0] - 1 complete mucosal healing 1 4 weeks - Cohort Kahn et al., 201458 8 Active, HBI > 6 Unrelated Colonoscopy NR Single NR NR Yes NR [safety study] NR NR NR 1 week 4 Cohort Cui et al., 201559 30 Moderate- severe, HBI > 6 Unrelated & related Midgut through gastroscope 150-200 ml infusion Single Fresh or frozen No yes 23/30 [76.7%] [HBI < 5] 26/30 [86.7%] [HBI drop > 3] NR NR 6–15 months 4 Cohort Suskind et al., 201560 9 [paediatric] Mild- moderate [PCDAI 10–29] Related [parent] Nasogastric 30 g stool in 100-200 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes Week 2: 7/9 [78%], Weeks 6 & 12: 5/9 [56%] [PCDAI < 10] NR NR NR 12 weeks 6 Cohort Vermeire et al., 201642 6 Moderate- severe Unrelated & related Nasogastric 200 g stool in 400 ml saline 2 [daily for 2 days] Fresh No Yes 0 NR 0 NR 8 weeks 5 Cohort Wei et al., 201543 3 Active, CDAI 150–400 Unrelated Nasogastric [2] colonoscopy [1] 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days beforeFMT Yes 0 Mean CDAI drop from 345 to 135 NR NR 4 weeks 5 Cohort Vaughn et al., 201661 19 Active, HBI ≥ 5 Unrelated Colonoscopy 50 g stool in 250 ml solution Single Frozen No Yes 10/19 [53%] [HBI < 5 at Week 4] 11/19 [58%] [HBI drop ≥ 3 at Week 4] NR NR 26 weeks 6 Cohort Goyal et al., 201646 4 [paediatric] Mild- moderate, PCDAI < 40 Recipient- identified [related & unrelated] Both duodenoscopy and jejunoscopy [20–30 ml] and colonoscopy [200-250 ml] 150 g stool in 250 ml saline Single Fresh Metronidazole/vancomycin for 5 days, ceasing 48 h before FMT yes 2/4 [50%] PCDAI < 10 or | normalisation of lactoferrin/ calprotectin 3/4 [75%] PCDAI drop ≥ 12.5 NR NR 6 months 4 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic remission Histologic remission Follow-up NOS total Case report Borody et al., 198919 1 NR NR NR NR NR NR NR NR 1 - NR NR 4 months - Case report Swaminath et al., 201455 1 Patchy colitis, severe from 11 to 22 cm Partner Enema NR 5 [daily for 5 days] Fresh NR NR 0 [worsening of colitis symptoms with FMT] 0 [worsening of colitis symptoms with FMT] NR NR 3 weeks, near resolution of bleeding and diarrhoea with topical 5-ASA - Case report Gordon et al., 201456 1 Severe, HBI 30 partner NR NR Daily, number not specified Fresh Vancomycin for previous Clostridium difficile infection NR 0 1 [HBI drop 30 to 7] NR NR Relapse at 6 months, commenced azathioprine - Case report Kao et al., 201457 1 Moderate-severe,

HBI 12 Unrelated Colonoscopy 400 ml of 1:4 stool: saline Single Fresh 7-day course of ciprofloxacin & metronidazole till 2 days before FMT Yes 1 [HBI 0] - 1 complete mucosal healing 1 4 weeks - Cohort Kahn et al., 201458 8 Active, HBI > 6 Unrelated Colonoscopy NR Single NR NR Yes NR [safety study] NR NR NR 1 week 4 Cohort Cui et al., 201559 30 Moderate- severe, HBI > 6 Unrelated & related Midgut through gastroscope 150-200 ml infusion Single Fresh or frozen No yes 23/30 [76.7%] [HBI < 5] 26/30 [86.7%] [HBI drop > 3] NR NR 6–15 months 4 Cohort Suskind et al., 201560 9 [paediatric] Mild- moderate [PCDAI 10–29] Related [parent] Nasogastric 30 g stool in 100-200 ml saline Single Fresh Rifaximin 200 mg tds for 3 days, omeprazole day before and day of FMT Yes Week 2: 7/9 [78%], Weeks 6 & 12: 5/9 [56%] [PCDAI < 10] NR NR NR 12 weeks 6 Cohort Vermeire et al., 201642 6 Moderate- severe Unrelated & related Nasogastric 200 g stool in 400 ml saline 2 [daily for 2 days] Fresh No Yes 0 NR 0 NR 8 weeks 5 Cohort Wei et al., 201543 3 Active, CDAI 150–400 Unrelated Nasogastric [2] colonoscopy [1] 60 g stool in 350 ml saline Single Fresh Vancomycin 500 mg bd for 3 days beforeFMT Yes 0 Mean CDAI drop from 345 to 135 NR NR 4 weeks 5 Cohort Vaughn et al., 201661 19 Active, HBI ≥ 5 Unrelated Colonoscopy 50 g stool in 250 ml solution Single Frozen No Yes 10/19 [53%] [HBI < 5 at Week 4] 11/19 [58%] [HBI drop ≥ 3 at Week 4] NR NR 26 weeks 6 Cohort Goyal et al., 201646 4 [paediatric] Mild- moderate, PCDAI < 40 Recipient- identified [related & unrelated] Both duodenoscopy and jejunoscopy [20–30 ml] and colonoscopy [200-250 ml] 150 g stool in 250 ml saline Single Fresh Metronidazole/vancomycin for 5 days, ceasing 48 h before FMT yes 2/4 [50%] PCDAI < 10 or | normalisation of lactoferrin/ calprotectin 3/4 [75%] PCDAI drop ≥ 12.5 NR NR 6 months 4 View Large

Table 5. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic outcomes Histologic outcomes Follow-up NOS total Case report Fang et al., 201662 1 [primary diagnosis: UC] Chronic antibiotic- refractory pouchitis [mPDAI 10; clinical mPDAI 6] NR Pouchoscopy Stool diluted in 250 ml saline Single Fresh Antibiotics ceased 48 h before FMT NR 1 [clinical PDAI 0] - NR NR 6 months - Cohort Landy et al., 201563 8 [primary diagnosis: UC] Chronic pouchitis [PDAI > 7] Unrelated & related Nasogastric 30 g stool in 50 ml saline Single Fresh No, antibiotic- free for 2 weeks before FMT NR 0 2/8 [25%] [PDAI drop ≥ 3] NR NR 4 weeks 6 Cohort El-Nachef et al., 201664 9 [4 weeks’ data on 7] [primary diagnosis: NR] NR Unrelated Pouchoscopy NR Single Frozen NR NR NR 5/7 [71%] [global symptom improvement] NR NR 4 weeks 5 Cohort Stallmach et al., 201665 5 [primary diagnosis: NR] Chronic antibiotic-refractory pouchitis

[PDAI 9–14] Unrelated UGI [jejunum] via endoscopy 75 g stool in 200 ml saline 1–7 [at 3–4-week intervals] Fresh for initial; either frozen or fresh for subsequent infusions Not part of FMT protocol. All patients failed ≥ 3 cycles of metronidazole and ciprofloxacin +/- rifaximin NR 4/5 [80%] 5/5 [100%] Endoscopic remission: 1/5 [20%] endoscopic response:

5/5 [100%] [based on endoscopy subscore on PDAI] 0

[histology subscore of 0 on PDAI] 3 months 6 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic outcomes Histologic outcomes Follow-up NOS total Case report Fang et al., 201662 1 [primary diagnosis: UC] Chronic antibiotic- refractory pouchitis [mPDAI 10; clinical mPDAI 6] NR Pouchoscopy Stool diluted in 250 ml saline Single Fresh Antibiotics ceased 48 h before FMT NR 1 [clinical PDAI 0] - NR NR 6 months - Cohort Landy et al., 201563 8 [primary diagnosis: UC] Chronic pouchitis [PDAI > 7] Unrelated & related Nasogastric 30 g stool in 50 ml saline Single Fresh No, antibiotic- free for 2 weeks before FMT NR 0 2/8 [25%] [PDAI drop ≥ 3] NR NR 4 weeks 6 Cohort El-Nachef et al., 201664 9 [4 weeks’ data on 7] [primary diagnosis: NR] NR Unrelated Pouchoscopy NR Single Frozen NR NR NR 5/7 [71%] [global symptom improvement] NR NR 4 weeks 5 Cohort Stallmach et al., 201665 5 [primary diagnosis: NR] Chronic antibiotic-refractory pouchitis

[PDAI 9–14] Unrelated UGI [jejunum] via endoscopy 75 g stool in 200 ml saline 1–7 [at 3–4-week intervals] Fresh for initial; either frozen or fresh for subsequent infusions Not part of FMT protocol. All patients failed ≥ 3 cycles of metronidazole and ciprofloxacin +/- rifaximin NR 4/5 [80%] 5/5 [100%] Endoscopic remission: 1/5 [20%] endoscopic response:

5/5 [100%] [based on endoscopy subscore on PDAI] 0

[histology subscore of 0 on PDAI] 3 months 6 View Large

Table 5. Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic outcomes Histologic outcomes Follow-up NOS total Case report Fang et al., 201662 1 [primary diagnosis: UC] Chronic antibiotic- refractory pouchitis [mPDAI 10; clinical mPDAI 6] NR Pouchoscopy Stool diluted in 250 ml saline Single Fresh Antibiotics ceased 48 h before FMT NR 1 [clinical PDAI 0] - NR NR 6 months - Cohort Landy et al., 201563 8 [primary diagnosis: UC] Chronic pouchitis [PDAI > 7] Unrelated & related Nasogastric 30 g stool in 50 ml saline Single Fresh No, antibiotic- free for 2 weeks before FMT NR 0 2/8 [25%] [PDAI drop ≥ 3] NR NR 4 weeks 6 Cohort El-Nachef et al., 201664 9 [4 weeks’ data on 7] [primary diagnosis: NR] NR Unrelated Pouchoscopy NR Single Frozen NR NR NR 5/7 [71%] [global symptom improvement] NR NR 4 weeks 5 Cohort Stallmach et al., 201665 5 [primary diagnosis: NR] Chronic antibiotic-refractory pouchitis

[PDAI 9–14] Unrelated UGI [jejunum] via endoscopy 75 g stool in 200 ml saline 1–7 [at 3–4-week intervals] Fresh for initial; either frozen or fresh for subsequent infusions Not part of FMT protocol. All patients failed ≥ 3 cycles of metronidazole and ciprofloxacin +/- rifaximin NR 4/5 [80%] 5/5 [100%] Endoscopic remission: 1/5 [20%] endoscopic response:

5/5 [100%] [based on endoscopy subscore on PDAI] 0

[histology subscore of 0 on PDAI] 3 months 6 Study type Author Patients Severity Donor Route Dosage [volume] Frequency [number of infusions] Fresh vs frozen Pre-antibiotic Bowel lavage Clinical remission Clinical response Endoscopic outcomes Histologic outcomes Follow-up NOS total Case report Fang et al., 201662 1 [primary diagnosis: UC] Chronic antibiotic- refractory pouchitis [mPDAI 10; clinical mPDAI 6] NR Pouchoscopy Stool diluted in 250 ml saline Single Fresh Antibiotics ceased 48 h before FMT NR 1 [clinical PDAI 0] - NR NR 6 months - Cohort Landy et al., 201563 8 [primary diagnosis: UC] Chronic pouchitis [PDAI > 7] Unrelated & related Nasogastric 30 g stool in 50 ml saline Single Fresh No, antibiotic- free for 2 weeks before FMT NR 0 2/8 [25%] [PDAI drop ≥ 3] NR NR 4 weeks 6 Cohort El-Nachef et al., 201664 9 [4 weeks’ data on 7] [primary diagnosis: NR] NR Unrelated Pouchoscopy NR Single Frozen NR NR NR 5/7 [71%] [global symptom improvement] NR NR 4 weeks 5 Cohort Stallmach et al., 201665 5 [primary diagnosis: NR] Chronic antibiotic-refractory pouchitis

[PDAI 9–14] Unrelated UGI [jejunum] via endoscopy 75 g stool in 200 ml saline 1–7 [at 3–4-week intervals] Fresh for initial; either frozen or fresh for subsequent infusions Not part of FMT protocol. All patients failed ≥ 3 cycles of metronidazole and ciprofloxacin +/- rifaximin NR 4/5 [80%] 5/5 [100%] Endoscopic remission: 1/5 [20%] endoscopic response:

5/5 [100%] [based on endoscopy subscore on PDAI] 0

[histology subscore of 0 on PDAI] 3 months 6 View Large

2.3. Data extraction

References were imported into a bibliographic database [Microsoft Excel 2015]. Two authors [SP, RP] independently reviewed all articles, initially by title and abstract, then by full text review where relevant, to determine eligibility. Duplicate studies/data were removed manually; when multiple publications related to the same patient group, the most complete data set was included. Eligible studies were categorised based on FMT indication. Data related to the study design and characteristics, treatment groups, and outcome measures were recorded. Where there was disagreement on study eligibility or data extraction, consensus was achieved through discussion [SP, RP, NCR].

2.4. Study quality assessment

For eligible cohort studies, the methodological quality was assessed using the Newcastle-Ottawa Scale [NOS]16 on the standard 9-point scale. Included RCTs were assessed using the Cochrane risk of bias score17 incorporating random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting.

2.5. Statistical analysis

Descriptive statistics were performed on data extracted from all included studies. The efficacy of treatment [clinical remission and/or response] was compared across studies per IBD subtype. For disease subtypes where three or more cohort or RCT studies were included, a meta-analysis was performed. The pooled effect sizes, as well as 95% confidence intervals [CIs], were calculated using both fixed and random effects models. However, the random effects model was the preferred option as it assumes that there is a distribution of true effect sizes rather than one true effect, and it assigns a more balanced weight to each study. For meta-analyses including cohort studies, the effect size refers to the pooled estimate proportion of patients that achieved efficacy. For meta-analyses including RCTs, pooled odd ratios [P-ORs] were calculated by weighting individual ORs by the inverse of their variance. p-values < 0.05 were considered significant. Heterogeneity was assessed using Cochran′s Q test [p-value < 0.10 is indicative of heterogeneity] and Higgins′ test [I2] [low heterogeneity: < 25%, moderate heterogeneity: 25–75%, and high heterogeneity: > 75%].18 Moderator variables including disease severity [mild vs moderate vs severe], route of administration [upper vs lower gastrointestinal FMT infusion], number of infusions (low [1 infusion] vs medium [2–4 infusions] vs high [5–10] vs very high [> 10]), population [paediatric vs adult], preparation of inoculum [fresh vs frozen], FMT donor source [related vs unrelated donor], antibiotic pre-treatment, and bowel lavage, were used to perform subgroup analyses. Sensitivity [leave-one-out] analyses were also conducted to assess statistical robustness. Publication bias was assessed using the Egger’s regression asymmetry test as well as funnel plots. Statistical analyses were performed using the Comprehensive Meta-Analysis software V. 3.0 [Biostat, Englewood, NJ, 2004].

3. Results

3.1. Study characteristics

A total of 6806 articles were identified in the search, which included 261 internal and external duplicates [Figure 1]. Titles and abstracts of 6545 articles were screened and only 109 were deemed potentially eligible, of which 107 were available for review. A total of 53 articles or abstracts of FMT in IBD were deemed to satisfy the study selection criteria and were included in the final analysis, of which three included more than one IBD subtype. This included 41 articles or abstracts assessing FMT in UC and reporting on 555 UC patients, 11 in CD reporting on 83 CD patients, and four in pouchitis reporting on 23 patients.

Figure 1. View largeDownload slide Flow diagram of search strategy.

Figure 1. View largeDownload slide Flow diagram of search strategy.

3.2. Study quality

The methodological quality of the included cohort studies and RCTs are outlined in the Appendix [Tables A2, A3, available as Supplementary data at ECCO-JCC online]. Only four cohort studies included a control group, with a mean NOS score of 5 [range 3 to 9] out of 9. The risk of bias in the included randomized trials was low [Costello et al., 2017,12 presented in abstract form but yet to undergo full publication peer review]. All significant results obtained through the meta-analyses remained significant in sensitivity analyses, inferring statistical robustness.

3.3. Ulcerative colitis

A total of 41 studies were identified assessing FMT in UC (nine case reports, five case series, 24 prospective cohort studies [20 uncontrolled, four controlled] and four RCTs), reporting on 555 UC patients [Tables 1-3].

Overall, 36% [201/555] of UC patients achieved clinical remission during follow-up. Among the 24 cohort studies included in the meta-analysis [Figure 2], which comprised 307 individuals, the pooled proportion of patients that achieved clinical remission was 33% [95% CI = 23–43%] for UC, with a moderate risk of heterogeneity [Cochran’s Q, p = 0.001; I2 = 54%] [Table A4, available as Supplementary data at ECCO-JCC online] and no publication bias [Table A5, available as Supplementary data at ECCO-JCC online]. The pooled proportion of patients that achieved clinical response was 52% [95% CI = 40–64%] in a meta-analysis that included 234 individuals from 20 cohort studies [Figure A1, available as Supplementary data at ECCO-JCC online]; a moderate level of heterogeneity [Cochran’s Q, p = 0.001; I2 = 58%] and no publication bias was observed in this meta-analysis [Table A5].

Figure 2. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in ulcerative colitis including available cohort studies to date. The pooled proportions with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights. In this meta-analysis, four case-control studies [Kump et al. 2015, Scaldaferri et al. 2015, Pai et al. 2016, and Ishikawa et al. 2017] were included as cohorts [data from controls was removed] as the software did not allow the combination of one and two groups comparison analyses.

Figure 2. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in ulcerative colitis including available cohort studies to date. The pooled proportions with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights. In this meta-analysis, four case-control studies [Kump et al. 2015, Scaldaferri et al. 2015, Pai et al. 2016, and Ishikawa et al. 2017] were included as cohorts [data from controls was removed] as the software did not allow the combination of one and two groups comparison analyses.

Meta-analysis including four RCTs of FMT in UC [Figure 3], which comprised a total of 140 FMT-treated individuals, showed that FMT was significantly associated with clinical remission in these patients [P-OR = 2.89, 95% CI = 1.36–6.13, p = 0.006]. Heterogeneity was moderate in this meta-analysis [Cochran’s Q, p = 0.188; I2 = 37%] with no publication bias [Table A5]. A significant association was also found between FMT and clinical response in UC patients [P-OR = 2.48, 95% CI = 1.18-5.21, p = 0.016] [Figure A2, available as Supplementary data at ECCO-JCC online], with a moderate level of heterogeneity [Cochran’s Q, p = 0.102; I2 = 52%] and no publication bias [Table A5].

Figure 3. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in ulcerative colitis including four randomised controlled trials [RCTs] available to date. The pooled odds ratios [ORs] with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights.

Figure 3. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in ulcerative colitis including four randomised controlled trials [RCTs] available to date. The pooled odds ratios [ORs] with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights.

Interestingly, sensitivity analyses showed that on removal of the RCT by Rossen et al.10 [which in contrast to the other studies used only two infusions and administered them via an upper gastrointestinal infusion] the association between FMT and clinical remission in UC patients was highly significant [P-OR of 4.05, 95% CI = 2.08–7.89, p = < 0.001; Cochran’s Q, p = 0.783; I2 = 0%] [Figure A3, available as Supplementary data at ECCO-JCC online]. Similarly, the association between FMT and clinical response in these patients when the RCT by Rossen et al.10 was removed showed a higher P-OR of 3.39 [95% CI = 1.90–6.04, p = < 0.001; Cochran’s Q, p = 0.442; I2 = 0%] [Figure A4, available as Supplementary data at ECCO-JCC online].

3.4. Crohn’s disease

Eleven studies in CD [four case reports, seven prospective uncontrolled cohort studies] reporting on 83 CD patients were included [Table 4]. Overall 50.5% [42/83] of CD patients achieved clinical remission during follow-up. Among the six cohort studies included in the meta-analysis [Figure 4], comprising 71 individuals, the pooled proportion of CD patients that achieved clinical remission was 52% [95% CI = 31–72%] with a moderate risk of heterogeneity [Cochran’s Q, p = 0.063; I2 = 52%]; however, publications bias was observed in this meta-analysis [Table A5]. A meta-analysis including four cohort studies [Figure A5, available as Supplementary data at ECCO-JCC online], which comprised 59 individuals, showed that the pooled estimate proportion of patients that achieved clinical response was 63% [95% CI = 30–88%]. Moderate heterogeneity was observed in this meta-analysis [Cochran’s Q, p = 0.016, I2 = 71%]; no publication bias was detected [Table A5].

Figure 4. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in Crohn’s disease including available cohort studies to date. The pooled proportions with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights.

Figure 4. View largeDownload slide Forest plot of the meta-analysis of clinical remission and faecal microbiota transplantation [FMT] in Crohn’s disease including available cohort studies to date. The pooled proportions with 95% confidence intervals [CIs] were calculated using the random effects model [diamond]. The filled squares represent the studies in relation to their weights.

3.5. Pouchitis

Three prospective uncontrolled cohort studies and one case report assessing FMT in pouchitis were identified [Table 5], reporting on 23 patients. Two of the cohort studies used a single FMT infusion; no patients achieved clinical remission, with 2/8 [25%] achieving clinical response in one study63 and, in the other study, 5/7 [71%] had global symptom improvement [not defined] at 1 month.64 In the only study that allowed for multiple FMT infusions, 4/5 patients achieved clinical remission [with the other patient achieving clinical response].65 We did not perform a pouchitis meta-analysis as only three small cohort studies were identified which had differing endpoints and conflicting outcomes.

3.6. Endoscopic data

Specific endoscopic outcomes were reported in the four RCTs and six of the 24 cohort studies of FMT in UC [Table 2]. Accounting for differing definitions of endoscopic outcomes, endoscopic remission or endoscopic response rates of 24–55% with allogeneic FMT vs 5–17% with control [placebo or autologous FMT] [mean difference 26.3% ± 9.9, p-value: 0.057] were noted in the RCTs involving multiple lower gastrointestinal FMT infusions,9,11,12 whereas no difference was noted in endoscopic response between allogenic or autologous FMT administered by two nasoduodenal infusions [35% vs 36%]10 [Table 3]. Only one study in CD reported endoscopic outcomes,42 with none of six patients achieving endoscopic remission. In the one pouchitis study that reported endoscopic outcomes, all five patients had an endoscopic response and one patient [20%] achieved endoscopic remission after 1–7 FMT infusions.65

3.7. Histologic data

Only a small number of studies in UC reported histologic outcomes. Post hoc analysis of one RCT identified that 7/38 patients in the FMT arm and 1/37 in the placebo arm achieved histologic remission.9 Only two of the 24 identified cohort studies of FMT in UC reported histologic data.36,38 Only one case report of FMT in CD provided histologic outcomes.57 In the one pouchitis study that reported histologic outcomes, none of five patients achieved a PDAI histologic subscore of 0.65

3.8. Paediatric vs adult populations

Subgroup analyses were performed for a number of variables thought to be of importance [Table A6, available as Supplementary data at ECCO-JCC online], including population age [paediatric vs adult]. There were six cohort studies assessing 34 patients in paediatric UC and only two cohort studies assessing 13 patients in paediatric CD. The pooled estimate proportion of patients that achieved clinical remission was 23% [95% CI = 7–51%; Cochran’s Q, p = 0.171; I2 = 35%] for paediatric UC and 34% [95% CI = 24–46%; Cochran’s Q, p = 0.001; I2 = 58%] for adult UC. For CD, the pooled estimate of clinical remission was 54% [95% CI = 28–78%; Cochran’s Q, p = 0.853; I2 = 0%] in paediatric CD patients and 46% [95% CI = 18–77%; Cochran’s Q, p = 0.017; I2 = 71%] in adult CD patients. No completed randomised controlled trials have been published assessing FMT in paediatric IBD.

3.9. FMT methodology

The included studies varied substantially in FMT infusion methodology/protocol, including route of administration, number and frequency of infusions, dosage of stool per infusion, preparation of inoculum [fresh or frozen], antibiotic pre-treatment, bowel lavage, and FMT donor source [related or unrelated].

Subgroup analyses of the cohort studies [Table A6] showed that route of administration might play a significant role in clinical remission among UC patients, as the pooled proportion of UC patients receiving upper gastrointestinal infusions was 17% [95% CI = 8–32%; Cochran’s Q, p = 0.604; I2 = 0%] whereas the pooled proportion of UC patients receiving lower gastrointestinal infusions was 36% [95% CI = 24–50%; Cochran’s Q, p = 0.004; I2 = 57%]. Further subgroup analyses by number of infusions showed that the pooled proportion of UC patients receiving a high number of infusions [> 10 infusions] that achieved clinical remission was 49% [95% CI = 21–77%; Cochran’s Q, p = 0.246; I2 = 29%], which was considerably higher than in those UC patients who received ≤ 10 infusions [pooled proportion = 27%, 95% CI = 17–40%; Cochran’s Q, p = 0.001; I2 = 58%]. Although the pooled proportion of UC patients receiving fresh infusions that achieved clinical remission [28%, 95% CI = 15–46%; Cochran’s Q, p = 0.001; I2 = 63%] was less than with frozen infusions [36%, 95% CI = 13–67%; Cochran’s Q, p = 0.045; I2 = 63%], this was likely confounded by association with an increased number of infusions. Further, the pooled proportion of UC patients who received an antibiotic course before FMT and achieved clinical remission was 33% [95% CI = 17–54%; Cochran’s Q, p = 0.026; I2 = 58%], whereas the proportion in UC patients who did not receive an antibiotic course pre-FMT was 28% [95% CI = 16–44%; Cochran’s Q, p = 0.002; I2 = 61%]. The relevance of the other subgroup analyses findings is uncertain, given the small number of studies and patients. Only a few studies used a multi-donor infusion,11,12,50 but all reported some degree of clinical and endoscopic benefit [clinical remission rates 15–50%, endoscopic remission or response rates 10–55%] despite varying number of infusions [Tables 2, 3].

3.10. Safety

The majority of studies did not report major adverse events or serious adverse events that were deemed clinically related to FMT therapy. Most reported adverse events were transient minor gastrointestinal complaints [bloating, diarrhoea, flatulence, abdominal pain/cramping, borborygmus] and/or fever.31-35,44,46–48,52,54,58–61,63 The lack of a control arm in most of the studies makes it difficult to determine to what degree symptoms are specifically attributable to FMT. Nasogastric FMT infusion was associated with aspiration pneumonia in one study,42 prompting a switch to lower gastrointestinal [GI] administration. A few reports of disease worsening40,49,55 were identified, including one of cytomegalovirus [CMV] colitis in a patient who self-administered unscreened FMT.21 One death due to toxic megacolon and sepsis was reported.53

The RCTs found no difference between FMT and control arms in terms of minor or serious adverse events or disease worsening [Table 6], though it must be noted that these studies were not powered to specifically assess for safety.

Table 6. Author Minor adverse events Serious adverse event Moayeddi et al., 20159 Not specified 3/38 [8%] vs 2 /37 [5%] [p = 1.0]: instead of, 2 FMT patients had change in diagnosis to Crohn’s colitis, 1 FMT patient had Clostridium difficile infection Rossen et al., 201510 78.3% of donor arm vs 64% placebo [p = 0.28], most commonly transient borborygmus or increase in stool frequency; 2 patients in FMT arm vomited, 2 patients in FMT arm had transient fever 2 FMT, 2 control: instead of, 1 admitted for suspicion of small bowel perforation [noted to have small bowel CD], 1 with severe cytomegalovirus [autologous arm], 1 with cervical cancer requiring surgery, 1 severe abdominal pain requiring admission with spontaneous recovery Paramsothy et al., 201711 78% in FMT arm vs 83% in placebo [p = NS], mostly self-limiting GI complaints [abdominal pain, bloating, flatulence] 3 worsening colitis requiring hospitalisation [2 FMT including 1 colectomy, 1 placebo] Costello et al., 201712 Not specified 3 FMT group, 2 control: instead of, 3 worsening colitis [2 autologous arm], 1 Clostridium difficile colitis requiring colectomy, 1 pneumonia Author Minor adverse events Serious adverse event Moayeddi et al., 20159 Not specified 3/38 [8%] vs 2 /37 [5%] [p = 1.0]: instead of, 2 FMT patients had change in diagnosis to Crohn’s colitis, 1 FMT patient had Clostridium difficile infection Rossen et al., 201510 78.3% of donor arm vs 64% placebo [p = 0.28], most commonly transient borborygmus or increase in stool frequency; 2 patients in FMT arm vomited, 2 patients in FMT arm had transient fever 2 FMT, 2 control: instead of, 1 admitted for suspicion of small bowel perforation [noted to have small bowel CD], 1 with severe cytomegalovirus [autologous arm], 1 with cervical cancer requiring surgery, 1 severe abdominal pain requiring admission with spontaneous recovery Paramsothy et al., 201711 78% in FMT arm vs 83% in placebo [p = NS], mostly self-limiting GI complaints [abdominal pain, bloating, flatulence] 3 worsening colitis requiring hospitalisation [2 FMT including 1 colectomy, 1 placebo] Costello et al., 201712 Not specified 3 FMT group, 2 control: instead of, 3 worsening colitis [2 autologous arm], 1 Clostridium difficile colitis requiring colectomy, 1 pneumonia View Large

Table 6. Author Minor adverse events Serious adverse event Moayeddi et al., 20159 Not specified 3/38 [8%] vs 2 /37 [5%] [p = 1.0]: instead of, 2 FMT patients had change in diagnosis to Crohn’s colitis, 1 FMT patient had Clostridium difficile infection Rossen et al., 201510 78.3% of donor arm vs 64% placebo [p = 0.28], most commonly transient borborygmus or increase in stool frequency; 2 patients in FMT arm vomited, 2 patients in FMT arm had transient fever 2 FMT, 2 control: instead of, 1 admitted for suspicion of small bowel perforation [noted to have small bowel CD], 1 with severe cytomegalovirus [autologous arm], 1 with cervical cancer requiring surgery, 1 severe abdominal pain requiring admission with spontaneous recovery Paramsothy et al., 201711 78% in FMT arm vs 83% in placebo [p = NS], mostly self-limiting GI complaints [abdominal pain, bloating, flatulence] 3 worsening colitis requiring hospitalisation [2 FMT including 1 colectomy, 1 placebo] Costello et al., 201712 Not specified 3 FMT group, 2 control: instead of, 3 worsening colitis [2 autologous arm], 1 Clostridium difficile colitis requiring colectomy, 1 pneumonia Author Minor adverse events Serious adverse event Moayeddi et al., 20159 Not specified 3/38 [8%] vs 2 /37 [5%] [p = 1.0]: instead of, 2 FMT patients had change in diagnosis to Crohn’s colitis, 1 FMT patient had Clostridium difficile infection Rossen et al., 201510 78.3% of donor arm vs 64% placebo [p = 0.28], most commonly transient borborygmus or increase in stool frequency; 2 patients in FMT arm vomited, 2 patients in FMT arm had transient fever 2 FMT, 2 control: instead of, 1 admitted for suspicion of small bowel perforation [noted to have small bowel CD], 1 with severe cytomegalovirus [autologous arm], 1 with cervical cancer requiring surgery, 1 severe abdominal pain requiring admission with spontaneous recovery Paramsothy et al., 201711 78% in FMT arm vs 83% in placebo [p = NS], mostly self-limiting GI complaints [abdominal pain, bloating, flatulence] 3 worsening colitis requiring hospitalisation [2 FMT including 1 colectomy, 1 placebo] Costello et al., 201712 Not specified 3 FMT group, 2 control: instead of, 3 worsening colitis [2 autologous arm], 1 Clostridium difficile colitis requiring colectomy, 1 pneumonia View Large

3.11. Microbiological analyses

Microbiota analysis was performed in 17/41 UC, 4/11 CD, and 3/4 pouchitis studies [Table A7, available as Supplementary data at ECCO-JCC online]. Most studies assessed luminal [faecal] samples with only a limited number analysing mucosal [biopsy] samples.33,63,66,67 A range of studies commented on recipient microbiota changes after FMT, with increased α-diversity or richness9,11,38,42,48,50,61,66 and a shift towards the donor profile, which in some cases was associated with colonisation by donor-derived taxa, though this was reported in patients both with clinical benefit10,26,32,35,57,60,65 and without improvement.33,36 Some studies did report that the increase in recipient microbial diversity after FMT was greater in responders relative to non-responders.11,42,61,66 In particular, the study by Paramsothy et al.11, 66 found that recipient microbial diversity at baseline predicted response to FMT, that microbial diversity increased with FMT, and that this persisted for 8 weeks following FMT. In this study, the multi-donor FMT batches used for the FMT infusions had substantially greater microbial diversity relative to the individual donors. A correlation between increased donor microbial diversity and therapeutic success of FMT in UC has been identified in some studies42,68 but not others.51 In the RCT by Moayeddi et al.,9 there was a trend towards a difference in recipient outcomes based on particular donor, with improved outcomes noted in patients receiving infusions derived from donor B [p = 0.06]. A variety of taxa were reported to be associated with both FMT in IBD in general, and more sp