As a major subtype of inflammatory bowel disease (IBD), ulcerative colitis (UC) is a chronic, relapsing, and remittable immunologically mediated disease affecting the colonic mucosa. With the increasing incidence rate around the world [
We aim to induce and maintain remission and reduce the risk of complications. Conventional treatments, including aminosalicylate, corticosteroid, thiopurine, and immunosuppressant, for UC are based on the severity of disease and patient preference [
Fecal microbiota transplantation (FMT) is the transfer of stool from a healthy donor into the colon of a patient in order to change the microbial communities. Since multiple studies have demonstrated differences in the composition of the gut microbiota between patients with UC and healthy individuals, plus in recent decades, genome-wide associated studies and other genetic analyses showed that intestinal microbiota plays roles in aberrant immune response in IBD [
After the first case of fecal microbiota transplantation for the treatment of ulcerative colitis was described in the year 1989 [
As a result, in order to investigate both general and steroid-free FMT treatment effects, we decided to carry out this systematic review with meta-analysis by evidence from controlled studies.
This systematic review with meta-analyses was conducted in line with the recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [
Search strategy.
Ovid Medline and Ovid EMBASE search strategy
1 | Colitis.mp. |
---|---|
2 | Exp colitis/ |
3 | Proctosigmoiditis.mp. |
4 | Rectocolitis.mp. |
5 | Rectosigmoiditis.mp. |
6 | Haemorrhagic proctocolitis.mp. |
7 | Proctitis.mp. |
8 | Inflammatory bowel disease.mp. |
9 | Exp inflammatory bowel disease/ |
10 | IBD.mp. |
11 | 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 |
12 | Fecal microbiota transplant |
13 | Faecal microbiota transplant |
14 | Fecal microbiome transplant |
15 | Fecal microflora transplant |
16 | Stool transplant |
17 | FMT.mp. |
18 | Fecal transfusion |
19 | Fecal bacteriotherap |
20 | 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 |
23 | 11 and 20 |
Cochrane Library search strategy
#1 | Colitis |
---|---|
#2 | MeSH: [Colitis] explode all trees |
#3 | Proctosigmoiditis |
#4 | Rectocolitis |
#5 | Rectosigmoiditis |
#6 | Haemorrhagic proctocolitis |
#7 | Proctitis |
#8 | Inflammatory bowel disease |
#9 | MeSH: [inflammatory bowel disease] explode all trees |
#10 | IBD |
#11 | #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 |
#12 | MeSH: [Fecal microbiota transplantation] explode all trees |
#13 | Fecal microbiota transplant |
#14 | Faecal microbiota transplant |
#15 | Fecal microbiome transplant |
#16 | Fecal microflora transplant |
#17 | Stool transplant |
#18 | FMT |
#19 | Fecal transfusion |
#20 | Fecal bacteriotherap |
#21 | #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 |
#22 | #11 and #21 |
The following inclusion criteria were applied: (1) prospective study including RCTs, and cohort studies, (2) patients who are diagnosed with UC; (3) patients who received any FMT type or combination therapies compared with placebo.
EndNote X8 software was used to manage the literatures searched from the database for omitting duplicates (Figure
Workflow.
Two review authors (CZ and WJM) independently extract data from the included studies. The following information will be extracted using an Excel 2017 software data form: general information (title, authors, country of study, funding, year of publication, and registry number (if any)); details of study (aim, design type, and inclusion and exclusion criteria); study population (age, sex, sample size, number for analysis, and severity of UC); FMT characteristics (type of FMT, dose, pretreatment, and combination therapies); outcome (primary and secondary outcomes, time points, response rate, and method of response assessment).
Two independent authors (WJM and LY) assessed article quality according to the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale (NOS) for cohort studies [
RevMan 5.3 software was used for statistical analyses. Meta-analysis was conducted in subgroups about clinical remission, clinical response, steroid-free remission, and serious adverse events (SAE). Dichotomous outcomes used a pooled odds ratio (OR) with 95% confidence interval (CI) to estimate the report effect. Heterogeneity was assessed using the
Egger’s test would be performed to explore publication bias when applicable (the number of included studies no less than 10).
Four RCTs [
Characteristics of the included studies.
Study | Type | Country | Sample | Severity of the disease | Route | Fresh/frozen | Placebo type |
---|---|---|---|---|---|---|---|
Costello et al. [ |
RCT | Australia | 73 | Mild-moderate active UC | Transplantation | Frozen | Autologous FMT |
Moayyedi et al. [ |
RCT | Canada | 75 | Active UC | Retention enema | Fresh and frozen | Consisting of 50 mL water |
Rossen et al. [ |
RCT | Netherlands | 48 | Mild to moderate active UC | Nasoduodenal tube | Fresh | Autologous fecal microbiota |
Paramsothy et al. [ |
RCT | Australia | 81 | Active UC | Infusion | Frozen | Isotonic saline adding brown food colourant, odourant, and glycerol cryoprotectant |
Ishikawa et al. [ |
COHORT | Japan | 36 | Mild-to-severe active UC | Colonoscopy | Fresh | AFM monotherapy |
Kump et al. 2017 [ |
COHORT | Austria | 27 | Refractory ulcerative colitis, chronic active ulcerative colitis | Endoscopy | Frozen | Antibiotic treatment |
Note: RCT: random controlled trials; COHORT: cohort studies; UC: ulcerative colitis; FMT: fecal microbiota transplantation; AFM: amoxicillin, fosfomycin, and metronidazole.
Risk assessment of included random controlled trials is shown in Table
Risk of bias assessment of included random controlled trials.
Study | Random sequence generation | Allocation concealment | Blinding of participants and personal | Blinding of outcome assessment | Incomplete outcome data | Selection reporting |
---|---|---|---|---|---|---|
Costello et al. [ |
Low risk | Unclear | Low risk | Unclear | Low risk | Low risk |
Moayyedi et al. [ |
Low risk | Unclear | Unclear | Unclear | High risk | Low risk |
Rossen et al. [ |
Low risk | Low risk | Low risk | High risk | Low risk | Low risk |
Paramsothy et al. [ |
Low risk | Low risk | Low risk | Unclear | Low risk | Low risk |
Risk of bias assessment of included cohort studies.
Study | Item 1 | Item 2 | Item 3 | Item 4 | Item 5 | Item 6 | Item 7 | Item 8 |
---|---|---|---|---|---|---|---|---|
Kump et al. [ |
1 | 1 | 0 | 0 | 1 | 1 | 1 | 1 |
Ishikawa et al. [ |
1 | 1 | 0 | 0 | 1 | 1 | 1 | 1 |
Item 1: representativeness of the exposed cohort; Item 2: selection of the nonexposed cohort; Item 3: ascertainment of exposure; Item 4: demonstration that the outcome of interest was not present at the start of study; Item 5: comparability of cohorts on the basis of the design or analysis; Item 6: assessment of outcome; Item 7: was follow-up long enough for outcomes to occur; Item 8: adequacy of the follow-up of the cohort.
Four RCTs and 2 cohort studies (340 cases in total) reported the clinical remission compared to FMT with placebo. The average clinical remission of FMT was 33.6% (23.7-50%) in the RCT group and 47% (35.3-58.8%) in the cohort. Meta-analysis results showed that there was a significant difference between FMT and placebo (Figure
Meta-analysis of clinical remission in patients undergoing FMT versus placebo;
The total overall OR of RCTs and cohort studies was 3.85 (2.21, 6.7); there was a statistical difference between FMT and placebo and no or low heterogeneity among all studies (
Four RCTs and two cohort studies (340 cases in total) reported the clinical response compared to FMT with placebo. The average clinical response of FMT was 45% (39.5-55.3%) in RCT and 70.6% (58.8-82.4%) in cohort. The pooled results showed that there was a significant difference between FMT and placebo of RCTs, but no significant difference in cohort studies (Figure
Meta-analysis of clinical response in patients undergoing FMT versus placebo;
The total overall OR of RCTs and cohort studies was 2.75 (1.33, 5.67), there was a statistical difference between FMT and placebo, and there was low heterogeneity among all studies (
Two RCTs (121 cases in total) reported the steroid-free remission. The average steroid-free remission of FMT was 32.7% (31.6-34.8%) in RCT. The pooled results showed that there was no significant difference between FMT and placebo in steroid-free remission (Figure
Meta-analysis of steroid-free remission in patients undergoing FMT versus placebo;
Three RCTs (229 cases in total) reported the patients with SAE. The average rate of serious adverse events was 6.8% (4.9-7.9%) in RCT. Meta-analysis showed that there was no significant difference between FMT and placebo (Figure
Meta-analysis of patients with serious adverse events undergoing FMT versus placebo;
Since the number of studies included was less than 10, no Egger test was performed.
This systematic review and meta-analysis showed that in FMT studies, there are differences in the significance between clinical remission and clinical response on the patients receiving FMT. The pooled analysis demonstrated, especially in RCTs, that FMT were significantly associated with improved clinical remission and clinical response compared to placebo. These results are consistent with those of a recent systematic review and meta-analysis of RCTs by Costello et al. and Narula et al. [
Furthermore, unlike the pervious systematic reviews mentioned [
Although the insignificant serious adverse effects reported in patients with UC supported its safety for application, the elephant in the room is not only for our included studies, but there is no common consensus on the route, volume, timing, preferred donor characteristics, and frequency of fecal administration necessary to achieve remission [
For the route of FMT, in our included studies, all the transplantations are through fresh or frozen feces. In general, frozen feces have advantages over fresh in aspects of preparation, storage, monitoring, and delivering FMT at centers that do not have on-site laboratory facilities [
It is important to mention that all studies included have undergone pretreatment with antibiotics. As highlighted by other reviewers [
Clinically, UC is a chronic disease without a pharmacological cure that usually requires regular, indefinite therapy to maintain remission [
Characteristics and results of large case series (
Study | Sample | Country | Age (year) | Severity | Route | Donor | Fresh/frozen | Clinical response | Clinical remission | Steroid-free remission | Serious adverse events | Follow-up (months) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Kunde et al. [ |
10 | America | 7-21 | Mild-moderate | Colonoscopy | Family members or close friends | Fresh | 6 (60%) | 3 (30%) | NR | 0 | 1 |
Cui et al. [ |
15 | China | 11-48 | Moderate-severe | Gastroscope | Patients’ healthy relatives or friends | Frozen | 12 (80%) | 4 (26.7%) | NR | 0 | 4-72 |
Nishida et al. [ |
41 | Japan | NR | Mild-moderate | Colonoscopy | Family members | Fresh | 11 (26.8%) | 0 (0) | NR | 0 | 2 |
Wei et al. [ |
20 | China | 18-70 | Mild-moderate | Colonoscopy | Healthy people | Fresh | 13 (65%) | 7 (35%) | NR | 0 | 3 |
Zhang et al. [ |
19 | China | 19-60 | Moderate-severe | Gastroscope | NR | Fresh | 11 (57.9%) | 2 (10.5%) | NR | 0 | ≥3 |
NR: not reported.
Several limitations are encountered during this study. First, the number of clinical trials and cohort studies is limited. There is lack of large amount of patients with the same subtype and stage of UC; thus, the generalizability is limited. Second, the FMT and placebo in studies are prepared differently and with various dosages. Therefore, we could not effectively examine the dosage effect across the outcomes. Third, although the AE/SAE profile is an important factor for choosing treatment options, it was not possible to perform an analysis to deal with such a concern because AE/SAE are not fully reported in all included trials. Fourth, in the included trials, FMT can be independently applied or combined with other drugs as interventions; therefore, some of the therapeutic effects can be due to the interacted result between FMT and other components.
Fecal microbiota transplantations were associated with significant clinical remission and response in ulcerative colitis patients while there was no significant difference found between FMT and placebo in steroid-free remission. Moreover, a common consensus on the route, volume, timing, preferred donor characteristics, and frequency of fecal administration is necessary to achieve remission.
There are no competing interests declared.
Wai Ching Lam, Chen Zhao, and Wen Juan Ma contributed equally to this work.