Ulcerative colitis (UC) and Crohn's disease (CD) are two types of inflammatory bowel disease (IBD) that lead to chronic inflammation in the digestive tract. The mechanism leading to inflammation in IBD is poorly understood, yet it is thought to involve a complex interaction between the immune system, the gut and gut microbes. New evidence suggests that the composition of gut microbes in a patient with IBD is different and possibly abnormal, and that correction of this abnormality might help control the inflammation seen in patients with UC and CD. Stool administration from healthy donors to patients with UC or CD is an intervention that seeks to restore a more healthy balance of gut microbes, and control IBD.
To assess the effectiveness of stool transplantation for the treatment of UC and CD.
We searched multiple databases for randomized studies. A randomized study is a type of study where participants are allocated to an intervention or a control group in a random manner and is considered to be the most superior research design. We pooled data from different studies to obtain overall estimates of the effect of stool transplantation for the treatment of UC and CD. The literature search is current to 19 March 2018.
We found four studies (277 participants) that assessed the effectiveness of stool transplantation for the treatment of adults with active UC. We did not find any randomized studies that assessed stool transplantation in participants with CD or in children. In addition, we did not find any studies that assessed maintenance of remission in participants with inactive IBD. Two of the identified studies were conducted in Australia, one in Canada, and one in the Netherlands. The dose, route, frequency, volume, type of donor, and severity of disease of recipients varied among the studies.
Combined results from four studies including 277 participants indicated that stool transplantation increased rates of resolution of symptoms (also termed clinical remission) of UC patients by two-fold compared to controls. At 8 weeks after transplantation, 37% (52/140) of participants in the stool transplant group were in remission compared to 18% (24/137) of participants in the control group. Combined data from the same four studies showed similar rates of serious side effects. Seven per cent (10/140) of the stool transplantation group had a serious side effect compared to 5% (7/137) of the control group. Serious side effects included worsening of ulcerative colitis that required intravenous steroids or surgery; infections such as Clostridium difficile and cytomegalovirus, small bowel perforation, and pneumonia. The incidence of side effects were similar in both stool transplant and control groups and included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Data from three included studies showed that stool transplantation helped improve UC when the assessment of disease resolution was made by the appearance of the intestinal lining when visualized with an endoscope.
Quality of evidence
We rated the overall quality of the evidence using the GRADE approach, which takes into account the type of studies, methodological flaws within studies, the consistency in reporting of results across studies, method of measurement of effect of intervention and statistical confidence in the summary estimates. Based on these criteria, we judged the overall quality of the evidence for most of the outcomes to be low based on a small number of events and participants and inconsistency of results.
Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious side effects. Thus, no firm conclusions can be drawn regarding the benefits and harms of stool transplantation in people with active UC. We did not find any studies that addressed treatment of CD with stool transplantation or studies that assessed stool transplantation in children with IBD. In addition, we did not find any studies that assessed long-term maintenance of remission in participants with inactive IBD. More studies are needed to enhance the knowledge about use of stool transplantation for treatment of IBD.
Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.
Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal tract that is thought to be associated with a complex interplay between microbes and the immune system, leading to an abnormal inflammatory response in genetically susceptible individuals. Dysbiosis, characterized by the alteration of the composition of the resident commensal bacteria in a host compared to healthy individuals, is thought to play a major role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD. There is growing interest to correct the underlying dysbiosis through the use of fecal microbiota transplantation (FMT) for the treatment of IBD.
The objective of this systematic review was to assess the efficacy and safety of FMT for the treatment of IBD.
We searched the MEDLINE, Embase, Cochrane Library, and Cochrane IBD Group Specialized Register databases from inception to 19 March 2018. We also searched ClinicalTrials.gov, ISRCTN metaRegister of Controlled Trials, and the Conference Proceedings Citation Index.
Only randomized trials or non-randomized studies with a control arm were considered for inclusion. Adults or pediatric participants with UC or CD were eligible for inclusion. Eligible interventions were FMT defined as the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a someone with UC or CD. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, or no intervention.
Two authors independently screened the titles and extracted data from the included studies. We used the Cochrane risk of bias tool to assess study bias. The primary outcomes were induction of clinical remission, clinical relapse, and serious adverse events. Secondary outcomes included clinical response, endoscopic remission and endoscopic response, quality of life scores, laboratory measures of inflammation, withdrawals, and microbiome outcomes. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference and 95% CI for continuous outcomes. Random-effects meta-analysis models were used to synthesize effect sizes across trials. The overall certainty of the evidence supporting the primary and selected secondary outcomes was rated using the GRADE criteria.
Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I² = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I² = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I² = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I² = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I² = 0%; low certainty evidence).