Nowadays, FMT is accepted as a feasible and effective treatment for recurrent Clostridium difficile ( C. difficile ) infections, whose proliferation in the gut is primarily dependent on an alteration of the intestinal milieu, usually promoted by antibiotic exposure. 16 - 18 Other proposed indications, based on preclinical or preliminary data and deserving further investigation, are obesity, metabolic syndrome, irritable bowel syndrome and, as previously mentioned, IBD, including CD and ulcerative colitis (UC). 19 In this review, we described the current evidence on the use of FMT in patients with UC and CD.

Human stools were firstly historically reported as clinical medication for food poisoning or severe diarrhea in a fourth‐century Chinese medical handbook ( Zhouhoubeijifang or Handbook of Prescriptions for Emergencies, by Hong GE). 12 , 13 The oral consumption of fresh camel stool was traditionally performed by Bedouins in cases of dysentery, and also adopted by German soldiers in Africa during the World War II. 14 In the modern clinical literature, Eiseman et al . described in 1958 a dramatic clinical response in patients with antibiotic‐associated diarrhea treated with enema containing healthy donor stools. 15

Due to the proinflammatory role of dysbiosis, fecal microbiota transplantation (FMT) has recently been advocated as a possible additional measurement to improve the outcome of IBD. FMT, or fecal bacteriotherapy, consists of the inoculation of filtrated stools (by gastroscopy, nasogastric, nasojejunal or nasoduodenal tube, retention enema or colonoscopy) from a healthy donor into the enteric tract of a recipient patient in order to re‐equilibrate the microbiota composition. 11

However, whether variations in the gut microbiota composition cause IBD or are just a consequence of an abnormal immunity in genetically predisposed individuals remains an open issue and the current medical treatment of IBD predominantly focuses on ameliorating the dysregulated mucosal immune response rather than on correcting dysbiosis per se . As such, treatment aims to suppress the abnormal inflammatory response using a range of drugs including aminosalicylates, corticosteroids, immunomodulators and biological therapies. These treatments, however, are not exempt from side effects, and not all patients respond optimally. 10

The role of gut flora in the pathogenesis of IBD has been investigated with increasing frequency, and it is now clear that dysbiosis, defined as qualitative or quantitative alteration in the intestinal flora, along with changes in its metabolic activity and distribution, 2 exists in IBD, which may lead to an abnormal immune response. 3 Patients with IBD have a reduced variety in the composition of the gut microbiota, 4 with proportionally decreased Firmicutes and increased Proteobacteria. 5 The reduced presence of Faecalibacterium prausnitzii ( F. prausnitzii ) , a butyrate‐producing species belonging to the phylum Firmicutes and showing immunomodulatory activity, has been well documented, particularly in individuals with Crohn's disease (CD). 6 On the other hand, the increase in Proteobacteria supports a possible pathogenic role of dysbiosis in starting or contributing to chronic inflammation in patients with IBD. 7 - 9

Inflammatory bowel disease (IBD) is a collection of disorders characterized by chronic inflammation of the gastrointestinal tract. The precise cause of IBD has not been identified yet. However, a dysregulated mucosal immune response to commensal gut flora (also known as intestinal microbiota) is thought to trigger chronic bowel inflammation in genetically susceptible individuals. 1

LITERATURE ANALYSIS

Literature search We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines.20 We completed an extensive literature search on PubMed and the Cochrane Library electronic databases up to 24 January 2017. The complete string is: (‘fecal microbiota transplantation’ OR ‘faecal microbiota transplantation’ OR ‘fecal microbiota transplant’ OR ‘faecal microbiota transplant’ OR ‘intestinal microbiota transplantation’ OR ‘intestinal microbiota transplant’ OR ‘fecal transplantation’ OR ‘faecal transplantation’ OR ‘fecal microbial transplant’ OR ‘faecal microbial transplant’ OR ‘bacteriotherapy’ OR ‘fecal enema’ OR ‘faecal enema’ OR ‘donor stool’ OR ‘colonic flora’) AND (‘inflammatory bowel disease’ OR ‘Crohn disease’ OR ‘Crohn's disease’ OR ‘Crohn's colitis’ OR ‘ulcerative colitis’ OR ‘IBD’ OR ‘CD’ OR ‘UC’). In addition, the bibliography of relevant articles was hand‐searched to provide further references.

Inclusion and exclusion criteria The following inclusion criteria were used: (i) patients of any age with IBD who underwent FMT for disease management; (ii) studies comparing placebo with FMT, standard‐of‐care or without control group; (iii) studies with explicitly described clinical end‐points; and (iv) abstracts, letters to the editor and journal articles. Exclusion criteria were: (i) in vitro or animal studies; (ii) written in a language other than English; (iii) patients with concomitant C. difficile infection; (iv) meta‐analyses, reviews, editorials and commentaries; and (v) studies with unreported clinical outcomes. The flowchart of study selection is shown in Fig. 1 and the characteristics of the selected studies21-39 are shown in Table 1. We discussed our own findings, as well as those of other systematic studies available in the literatures. Eventually, seven subheadings were selected for a narrative presentation of the topic: (i) characteristics of patients and preparation to FMT; (ii) characteristics of fecal donors; (iii) FMT procedure; (iv) outcome after FMT; (v) safety of FMT in patients with IBD; (vi) changes in microbiota composition; and (vii) future perspectives. Figure 1 Open in figure viewer PowerPoint Flowchart of identified studies. Table 1. Clinical studies assessing the role of fecal microbiota transplantation (FMT) in Crohn's disease (CD) and ulcerative colitis (UC) patients Authors (publication year) Trial design Patients (N) Mean age (years) IBD type and severity Outcome definition FMT Outcome measure Follow‐up Vermeire et al.36 (2012) Uncontrolled trial 4 37.5 (median) CD (therapy‐refractory) Clin rem: endoscopic healing† NJT (200 g stool mixture) three times within 36 h Clin rem: 0/4 (0%) at 8 weeks 2 months Angelberger et al.30 (2013) Retrospective case series 5 34.2 UC (moderate to severe) Clin resp: decrease in Mayo score by ≥3 and ≥30% with decrease in RBS ≥1 or absolute RBS ≤1 Clin rem: decrease in Mayo score to ≤2 with no subscore >1 NJT (17–25 g stool/250 mL saline) and enema (6–22 g stool/100 mL saline) daily for 3 days Clin resp: 1/5 (20%) at 12 weeks Clin rem: 0/5 (0%) at 12 weeks 7 months Kump et al.31 (2013) Uncontrolled trial 6 36.5 UC (moderate to severe) Clin resp: decrease in Mayo score by ≥3 Clin rem: decrease in Mayo score to ≤2 Colonoscopy (100–150 g stool/200–350 mL saline) once Clin resp: 2/6 (33%) at 90 days Clin rem: 0/6 (0%) at 90 days 1 year Kunde et al.21 (2013) Uncontrolled trial (NCT01560819) 9 15 UC (mild to moderate) Clin resp: decrease in PUCAI by >15 Clin rem: decrease in PUCAI to <10 Retention enema (90 g stool/250 mL saline) daily for 5 days Clin resp: 6/9 (67%) at 1 month Clin rem: 3/9 (33%) at 1 month 6 weeks Damman et al.22 (2014) Uncontrolled trial 5 NR UC (mild to moderate) Clin resp: improvement in histological score Clin rem: decrease in UCDAI to ≤2 and remission in histological score Colonoscopy once Clin resp: 3/5 (60%) at 1 month Clin rem: 1/5 (20%) at 1 month 1 month Suskind et al.25 (2014) Uncontrolled trial 10 16.2 CD (mild to moderate) Clin rem: decrease in PCDAI to <10 NGT once Clin rem: 5/10 (50%) at 6 weeks 6 weeks Vaughn et al.39 (2014) Uncontrolled trial (NCT01847179) 8 NR CD (active) Clin rem: decrease in HBI to <5 Colonoscopy (50 g stool/250 mL solution) once Clin rem: 5/8 (62.5%) at 4 weeks 12 weeks Cui et al.32 (2015) Uncontrolled trial (NCT01793831) 30 38 CD (moderate to severe) Clin resp: decrease in HBI by >3 Clin rem: decrease in HBI to <5 Gastroscopy (mid‐gut) once Clin resp: 26/30 (87%) at 1 month 20/30 (67%) at 6 months Clin rem: 23/30 (77%) at 1 month 18/30 (60%) at 6 months 6–15 months Cui et al.33 (2015) Uncontrolled trial (NCT01790061) 14 32 UC (moderate to severe) Clin resp: decrease in Montreal classification by ≥1 grade Clin rem: decrease in Montreal classification to S0 Gastroscopy (duodenum)applied once or twice‡ Clin resp: 8/14 (57%) at 1 weeks Clin rem: 4/14 (29%) at 3–18 months 3–18 months Moayyedi et al.38 (2015) RCT (FMT vs placebo) (NCT01545908) 38 (FMT) 37 (placebo) 42.2 UC (active) Clin resp: decrease in Mayo score by ≥3 Clin rem: decrease in Mayo score to ≤2 and endoscopic Mayo score: 0 Retention enema (50 g stool/300 mL water) 50 mL, once/week for 6 weeks Clin resp: 15/38 (39%) at 7 weeks Clin rem: 9/38 (24%) at 7 weeks 9–12 months Rossen et al.26 (2015) RCT (FMT from healthy donors vs autologous FMT) (NCT01650038) 23 (FMT from healthy donors) 25 (control autologous stool) 40 UC (mild to moderate) Clin resp: decrease in SCCAI by >1.5 Clin rem: decrease in SCCAI to ≤2 NDT (min 60 g stool/500 mL saline) twice, on day 1 and 3 weeks later Clin resp: 10/23 (43%) at 6 weeks; 11/23 (48%) at 12 weeks Clin rem: 6/23 (26%) at 6 weeks 7/23 (30%) at 12 weeks 12 weeks Suskind et al.23 (2015) Uncontrolled trial (NCT01757964) 4 14.5 UC (mild to moderate) Clin rem: decrease in PUCAI to <10 NGT (30 g stool/100 mL saline) once Clin rem: 0/4 (0%) at 2 weeks 12 weeks Suskind et al.24 (2015) Uncontrolled trial (NCT01757964) 9 16.2 CD (mild to moderate) Clin rem: decrease in PCDAI to <10 NGT (30 g stool/100–200 mL saline) once Clin rem: 7/9 (78%) at 2 weeks 5/9 (56%) at 6 and 12 weeks 12 weeks Paramsothy et al.28 (2016) RCT (FMT vs placebo) 41 (FMT) 40 (placebo) NR UC (mild to moderate) Clin resp: Mayo score ≤2 with subscores ≤1 for each RBS, stool frequency and endoscopic appearance, and ≥1 reduction from baseline in endoscopic subscore Clin rem: combined Mayo subscores of ≤1 for RBS and stool frequency Colonoscopy at day 1, followed by enemas 5 days/week for 8 weeks Clin resp: 22/41 (54%) at 8 weeks Clin rem: 18/41 (44%) at 8 weeks 8 weeks Vaughn et al.37 (2016) Uncontrolled trial (NCT01847170) 19 36 CD (active) Clin resp: decrease in HBI by >3 Clin rem: decrease in HBI to <5 Colonoscopy (50 g stool/250 mL saline) once Clin resp: 11/19 (58%) at 4 weeks Clin rem: 10/19 (53%) at 4 weeks 12 weeks Vermeire et al.35 (2016) Uncontrolled trial 14 38.6 UC (n: 8) CD (n: 6) Therapy‐refractory Clin resp: approx. changes in CDAI, Mayo score and CRP Clin rem: endoscopic healing§ NJT or rectal tube (200 g stool/400 mL saline) daily for 2 days Clin resp: 0/6 (0%) (CD) at 8 weeks NR (UC) Clin rem: 0/6 (0%) at 8 weeks (CD) 2/8 (25%) at 8 weeks (UC) 6 months Wei et al.29 (2016) RCT (FMT vs FMTP) (NCT02016469) 10 (FMT) 10 (FMTP) 43.5 (FMT) 37.4 (FMTP) UC (mild to moderate) Clin resp: decrease in Mayo score of >30% from baseline or 1‐point improvement in tarry stools or increase of >16 points in IBDQ criteria Clin rem: decrease in Mayo score to ≤2 Colonoscopy (60 g stool/500 mL saline) once¶ Clin resp: 7/10 (70%) in FMT group at 12 weeks 6/10 (60%) in FMTP group at 12 weeks Clin rem: 3/10 (30%) in FMT group at 12 weeks 4/10 (40%) in FMTP group at 12 weeks 12 weeks Zhang et al.34 (2016) Uncontrolled trial (NCT01790061) 19 39.2 UC (moderate to severe) Clin resp: decrease in Mayo score by ≥3 or ≥30% and a decrease in RBS ≥1 or absolute RBS ≤1 Clin rem: decrease in Mayo score to ≤2 with no subscore ≥1 Gastroscopy (mid‐gut) once Clin resp: 9/19 (47%) at 3 months Clin rem: 2/19 (11%) at 3 months 3 months Nishida et al.27 (2017) Uncontrolled trial 41 40 UC (mild to moderate) Clin resp: decrease in Mayo score by ≥3 or by ≥2 with a reduction in RBS of ≥1 Clin rem: decrease in Mayo score to ≤2 with no subscore >1 Colonoscopy (cecum; 150–200 g stool/500 mL saline) once Clin resp: 11/41 (27%) at 8 weeks 9/41 (22%) at 12 weeks Clin rem: 0/41 (0%) at 8 weeks 0/41 (0%) at 12 weeks 12 weeks

Characteristics of patients and preparation of FMT The studies demonstrated high heterogeneity in the age (from 7 to 71 years) of patients with IBD receiving FMT and in the severity of their baseline diseases. Overall, 51% of patients had mild‐to‐moderate disease,21-29 and 23% had moderate‐to‐severe disease30-34. It is important to bear in mind the limited proportion of patients with severe disease when interpreting the currently available efficacy and safety data. All but one study reported data on the preparation of the patients before FMT.21-30, 32-39 In nine studies the patients received antibiotics before FMT (vancomycin, metronidazole or rifaximin).22-24, 26, 27, 29, 30, 35, 36 Polyethylene glycol was used for bowel cleansing in more than half the studies.22-24, 26, 27, 29-31, 35, 36 with magnesium citrate being administered in a single study37. In order to inhibit gastric acid secretion before the FMT procedure administered via gastroscopy or a nasojejunal tube, proton pump inhibitors were used in seven studies.23-25, 30, 32-34 Metoclopramide was used in three studies to prevent adverse events, such as vomiting, during the endoscopic administration of FMT.32-34 Most patients received more than one type of preparation. Overall, the preparation procedures were very heterogeneous and differences in protocols were observed across studies. However, whether these differences may act as confounders of either the efficacy or safety of FMT in patients with IBD remains unclear. Dedicated studies comparing the impact of different preparation strategies may provide clarification.

Characteristics of fecal donors In most of the studies retrieved, the donors were related to the recipient (such as relatives, friends or partners), whereas stool from unrelated donors was less frequently used (Table 2). This may be because it was initially thought that using related donors might lead to a better tolerance of FMT. However, it has recently been found that the relatives of patients with IBD may themselves have gut dysbiosis.40, 41 Therefore, unrelated donors are usually used in current practice for this indication. To add, FMT from certain donors was more likely to achieve remission than from others, suggesting the donor's microbiota has a major impact on the clinical outcome of FMT.38 Table 2. Characteristics of fecal donors Study Donor characteristics (n) Fecal suspension characteristics Vermeire et al.36 (2012) NR NR Angelberger et al.30 (2013) Partner (1), friend (1), sister‐in‐law (1), son of a work colleague (1) Fresh Kump et al.31 (2013) Non‐relative (4) Frozen Kunde et al.21 (2013) Relative (9), friend (1) Fresh Damman et al.22 (2014) Relative (NR), friend (NR) NR Suskind et al.25 (2014) NR NR Vaughn et al.39 (2014) Unknown to recipients (NR) NR Cui et al.32 (2015) Relative (6), friend (NR), stool bank (NR) Frozen or fresh Cui et al.33 (2015) Relative (NR), friend (NR) NR Moayyedi et al.38 † (2015) Anonymous (5), spouse (1) Frozen or fresh Rossen et al.26 † (2015) Anonymous (13), partner (1), friend (1) Fresh Suskind et al.23 (2015) NR NR Suskind et al.24 (2015) Parent (9) NR Paramsothy et al.28 † (2016) Not related to recipient (NR) NR Vaughn et al.37 (2016) Not related to recipient (4) Frozen Vermeire et al.35 (2016) Relative (4), friend (10) Frozen Wei et al.29 † (2016) Not related to recipient (1) Frozen Zhang et al.34 (2016) NR Fresh Nishida et al.27 (2017) Relative (NR) Fresh Pre‐transplant screening procedures in donors were described in all but two studies28, 39. Although it was not standardized, screening commonly included serological testing for viruses (e.g., hepatitis A, B and C viruses, Epstein–Barr virus, cytomegalovirus and human immunodeficiency virus) and stool testing for C. difficile toxins, parasites, ova and commonly detected bacterial enteropathogens.21-27, 29-33, 35-38

FMT procedure The methods employed for performing FMT in patients with IBD were highly heterogeneous. For instance, the quantity of fecal donation varied from 30 to 200 g. In order to remove crude fecal components that could clot the endoscopes, in most studies the stool donation was diluted in a saline solution, blended and manually filtrated many times through gauze, paper filters38 or metal strainers27. In two other studies the stool donation was filtrated with an automatic purification system,33, 34 and in two other studies35, 39 the transplanted feces were administrated without purification. There is scant data on the microbiota composition of the transplanted stools, although in most studies aliquots of the fecal suspension were frozen for further metagenomic analysis of the transferred microbiota.21, 22, 24, 28, 29, 31-34, 38 As summarized in Table 2, even though in a relevant proportion of the studies the characteristics of the fecal suspension were not reported, the transplanted fecal suspensions were administrated after having been freshly collected or frozen and subsequently thawed, in order to be administrated at a later time. Several different routes of administration were reported: via an enema in four studies (n = 93);21, 28, 30, 38 colonoscopy in seven studies (n = 140);22, 27-29, 31, 37, 39 gastroscopy in three (n = 63);32-34 nasojejunal tube in three (n = 18);30, 35, 36 nasogastric tube in three (n = 23);23-25 nasoduodenal tube in one (n = 23);26 rectal tube in one (n = 5)35 and a combination of two routes in two studies (n = 46)28, 30. Overall, 127 patients received FMT by the upper gastrointestinal route (including gastroscopy, nasojejunal, nasogastric or nasoduodenal tube) and 197 patients by the lower gastrointestinal route (including enema, colonoscopy and rectal tube). The number of FMT procedures performed per patient also varied. In 58% of studies only one procedure was performed,22-25, 27, 29, 31, 32, 34, 37, 39 whereas in the remaining studies21, 26, 30, 33, 35, 36, 38 the number of procedures per patient ranged from two to six infusions (excluding the 41 infusions given in the study by Paramsothy et al.28). Such heterogeneity may confound our ability to compare the impact of FMT on the outcome of IBD across different studies, as discussed further below.

Outcomes of IBD after FMT The main outcomes reported in studies assessing the effect of FMT in patients with IBD were clinical response and clinical remission, although their definitions varied across the studies (Table 1). This makes direct comparisons between non‐randomized studies quite challenging, as highlighted by a recent meta‐analysis.42 Indeed, reviewing cohort studies, Paramsothy et al.42 found that the pooled proportion of patients reaching clinical remission after FMT was 33% (95% confidence interval [CI] 23–43%) for UC patients and 52% (95% CI 31–72%) for those with CD. There was a moderate risk of heterogeneity being detected in both analyses (I2 = 54% and I2 = 52%, respectively), partly reflecting the different definitions employed for the outcome measures.42 However, despite their heterogeneity, these data support the view that FMT has a positive effect on the outcome of IBD, at least in some patients. For CD, current evidence is limited to non‐randomized studies and randomized controlled trials (RCTs) are required to test the null hypothesis further. On the other hand, for the treatment of UC four RCTs26, 28, 38, 43 have been performed comparing FMT to placebo, including the recent study by Costello et al.43 which is still to be published as a full manuscript. As summarized by the recent meta‐analysis by Costello et al.,44 the effect size of the intervention, measured as pooled odds ratio, was 3.67 for clinical remission (95% CI 1.82–7.39, P < 0.01, I2 = 0%), 2.48 for clinical response (95% CI 1.18–5.21, P = 0.02, I2 = 52%), and 2.69 for endoscopic remission (95% CI 1.07–6.74, P = 0.04, I2 = 0%). Summary effects from the same RCTs were also computed by Paramsothy et al. in their meta‐analysis.42 Interestingly, they noted that, when the smallest RCT26 (in which patients received only two infusions) was excluded from the analysis, the magnitude of the effect increased to 4.05 for clinical remission (95% CI 2.08–7.89, P < 0.001, I2 = 0%) and 3.39 for clinical response (95% CI 1.90–6.04, P < 0.001, I2 = 0%). Considered altogether, these data support the use of FMT as part of the management strategy to treat UC. However, several key aspects remain to be clarified and future efforts should aim to identify baseline disease characteristics as predictors of clinical response to FMT, its most appropriate route of administration and the most appropriate quantity or quality of microbiota to be transplanted, in order to maximize efficacy. As to the administration route, potential confounding factors should be further considered. For example, in agreement with Paramsothy et al.,42 who reported there was a possible increased benefit in using the lower gastrointestinal route of administration in subgroup analyses, it has been speculated that the upper gastrointestinal route could interfere with the activity of some FMT components before they reach the colon (since gastric acid can damage Bacteroidetes).45, 46 However, many bacteria belonging to the Firmicutes phylum require an upper gastrointestinal tract transit in order to be activated, supporting a possible advantage of the upper gastrointestinal route.45, 46 However, it should be noted that in most studies in which the upper gastrointestinal route was employed,23-25, 30, 32-34 patients received peri‐procedural proton pump inhibitors, which might have interfered with the assessment of the impact of the route of administration on the outcome. Finally, in most of the studies reviewed, patients with IBD showed decreasing rates of remission or response over time (Table 1). This further highlights the need for dedicated studies assessing the long‐term outcomes of FMT.

Safety of FMT in patients with IBD According to our systematic search, FMT was well tolerated, with just two studies21, 29 reporting intolerance to FMT in two patients (due to the immediate leaking of the enema during administration). Adverse events were monitored and reported in all but one study.21, 23-39 Table 3 provides an overview of adverse events reported. The most commonly reported adverse events were classified as mild to moderate, and included abdominal pain, cramping, bloating, flatulence, increased stool frequency and fever within a few days after the transplant. Most were self‐resolving. Some of the reported adverse events appeared to be related to the route of administration (e.g., a mild stuffy nose, sore throat, rhinorrhea and vomiting were more common when the upper gastrointestinal route was used, especially with a nasogastric or nasojejunal tube). A few severe adverse events were reported, which were often deemed to be unrelated to FMT, although worsening abdominal discomfort with positive C. difficile toxin detected in the stool (1/38) and worsening colitis (2/41) were reported by Moayyedi et al.38 and Paramsothy et al.28. Vermeire et al.35 described four patients who developed five severe adverse events, possibly related to FMT or to administration via a nasojejunal tube, consisting of four episodes of high fever and one of vomiting after FMT administration, which led to aspiration pneumonia. Table 3. Reported adverse events (AEs) in patients treated with fecal microbiota transplantation (FMT) for inflammatory bowel disease (IBD) Studies Route of infusion AEs, n (patients with AEs/total patients) Vermeire et al.36 (2012) NJT High fever and abdominal tenderness (3/4); disappearing in 2 days Angelberger et al.30 (2013) NJT Fever (5/5), increased CRP (5/5), worsened diarrhea (5/5), sore throat (5/5), flatulence (2/5), vomiting (1/5). During follow‐up: common cold (3/5), pancreatitis of unknown origin (1/5), itchiness (1/5), erythema (1/5), paresthesia of the hip (1/5), collapse due to orthostatic disorder (1/5), blisters on the tongue (1/5) Kump et al.31 (2013) Colonoscopy Increase in stool frequency and fever (1/6) 1 day after FMT, which ceased after 3 days Kunde et al.21 (2013) Retention enema Bloating/flatulence (9/9), abdominal pain/cramping (6/9), diarrhea (6/9), blood in stool (3/9), fatigue (3/9), fever (2/9); all self‐limiting Damman et al.22 (2014) Colonoscopy NR Suskind et al.25 (2014) NGT Mild abdominal pain (5/10), mild bloating (5/10), mild diarrhea (4/10); all disappearing in 2 days. Vomiting (2/10), mild stuffy nose/sore throat/drippy nose (4/10) Vaughn et al.39 (2014) Colonoscopy No SAEs Cui et al.32 (2015) Gastroscopy Fever (2/30), increased diarrhea (7/30) Cui et al.33 (2015) Gastroscopy Fever (2/14), increased diarrhea (2/14), mild testicular pain; all self‐resolving in 1 day Moayyedi et al.38 † (2015) Retention enema SAEs in 3 patients: developing patchy inflammation of the colon and rectal abscess (2/38), worsening abdominal discomfort that tested positive for C. difficile toxin (1/38) Rossen et al.26 † (2015) NDT Discomfort at tube placement (1/23), fever (2/23), nausea (2/23), increased stool frequency (5/23), headache (1/23), vomiting (4/23), abdominal pain (1/23), abdominal murmurs (4/23), mild constipation (1/23) SAEs in 2 patients, unrelated to FMT: severe small bowel CD (1/23), cervical carcinoma (1/23) Suskind et al.23 (2015) NGT Nasal stuffiness (1/4), bloating (1/4), mild increased flatulence (1/4), vomiting (2/4), C. difficile diarrhea (2/4) Suskind et al.24 (2015) NGT Mild‐to‐moderate abdominal pain (5/9), mild bloating (5/9), diarrhea (4/9), mild flatulence (1/9), mild stuffy nose (1/9), rhinorrhea (1/9), sore throat (2/9); all self‐resolving in 3 days Paramsothy et al.28 † (2016) Colonoscopy and enema 2 SAEs: worsening colitis (2/41) Vaughn et al.37 (2016) Colonoscopy Mild abdominal cramping (NR), constipation (NR), fever (NR), hives (1/19), worsening of symptoms (1/19) Vermeire et al.35 (2016) NJT or rectal tube 5 SAEs in 4 patients: high fever (4/14) that disappeared spontaneously after 2 days, vomiting with aspiration and bilateral pneumonia (1/14) Wei et al.29 † (2016) Colonoscopy Fever (2/20) Zhang et al.34 (2016) Gastroscopy Increased diarrhea frequency (7/19), mild skin pruritus (1/19), borborygmus (2/19); all self‐resolving Nishida et al.27 (2017) Colonoscopy No AEs The short follow‐up period in the published studies prevents us from formulating a correct assessment of the possible non‐immediate unintended consequences of FMT in patients with IBD and therefore, long‐term safety data are still lacking.