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Fecal microbiota transplantation as a therapy for treating ulcerative colitis: an overview of systematic reviews

BMC Microbiology volume 23, Article number: 371 (2023) Cite this article

Abstract

Aim

The current overview on published systematic reviews (SRs) and meta-analysis (MAs) aimed to systematically gather, evaluate, and synthesize solid evidence for using fecal microbiota transplantation (FMT) to treat ulcerative colitis (UC).

Methods

Relevant articles published before January 2023 were collected from Web of Science, Embase, PubMed, and Cochrane Library. Two authors used Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) tool, PRISMA checklists, and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system were applied by two authors to independently evaluate the methodological quality, reporting quality, and evidence quality, respectively. Re-meta-analysis on the primary RCTs was conducted after excluding overlapping randomized controlled trials (RCTs).

Results

Six SRs/MAs involving 12 primary RCTs and 544 participants were included. According to the AMSTAR-2 tool and PRISMA checklist, methodological quality and reporting quality of the included studies was overall satisfactory. The evidence quality of a great majority of outcomes was rated as moderate to high according to the GRADE system. Compared to placebo, the re-meta-analysis found a great advantage of use FMT in inducing combined clinical and endoscopic remission (OR 3.83 [2.31, 6.34]), clinical remission (3.31 [2.09, 5.25]), endoscopic remission (OR 3.75 [2.20, 6.39]), clinical response (OR 2.56 [1.64, 4.00]), and endoscopic response (OR 2.18 [1.12, 4.26]). Pooled data showed no significant difference in serious adverse events between patients receiving FMT and those receiving placebo (OR 1.53 [0.74, 3.19]). Evidence quality of the outcomes derived from re-meta-analysis was significantly higher after overcoming the limitations of previous SRs/MAs.

Conclusion

In conclusion, moderate- to high-quality evidence supported a promising use of FMT to safely induce remission in UC. However, further trials with larger sample size are still required to comprehensively analyze the delivery route, total dosage, frequency, and donor selection in FMT.

Peer Review reports

Introduction

Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease that primarily affects distal colonic mucosa and submucosa [1]. UC is characterized by remission and alternating active phases, with abdominal pain, anemia, and bloody diarrhea as the main clinical manifestations. UC is correlated with an increased risk of colectomy [2], and patients with recurrent or persistent UC are more likely to develop colitis-associated cancer (CAC) [3]. The induction and maintenance of long-term stable remission are currently the main objectives in UC treatment in order to lower the possibility of relapse and prevent further development of CAC [4]. Mounting evidence have indicated the relation between the colonic microbiome and the pathogenesis of UC [1], but a majority of current treatments for UC still focus on immune system and pro-inflammatory factors rather than luminal microbial environment [5, 6]. Fecal microbiota transplantation (FMT) has been widely accepted as a highly effective treatment for persistent or resistant Clostridium difficile infection [7,8,9]. This also encourages researchers to consider FMT as a potential treatment for other illnesses that might be influenced by microbiota [10]. Given the critical role of the microbiome in UC and the fact that colonic ecosystem could be altered by FMT, there is growing interest in treating UC with FMT [11, 12].

Evidence derived from systematic reviews (SRs) and meta-analyses (MAs) are typically believed to be able to offer a solid foundation for clinical decision-making, but this is not always reliable because clinical decision-making process could be misled by poor-quality evidence [13]. Hence, it is necessary to systematically compile, assess, and synthesize evidence from numerous SRs/MAs on the same topic [14]. Compared to traditional SRs/MAs, an overview that minimizes duplication of information and presents findings from SRs/MAs in a uniform format could serve as a "friendly front end" for decision makers, healthcare professionals, and patients with UC [15]. In addition, an overview as such often focuses on the methodological aspects of SRs/MAs and can therefore guide future high-quality SRs/MAs by identifying potential risks of bias that could downgrade the quality of evidence [15]. A rising number of SRs/MAs have examined the efficacy and safety of using FMT in treating UC. Therefore, to systematically compile, assess and analyze evidence from multiple SRs/MAs on this particular topic, we carried out a comprehensive evaluation on the methodological quality, reporting quality and evidence quality of related SRs/MAs.

Methods

Registration and protocol

The methodology of this study was performed following the Cochrane Handbook [16]. The protocol was registered in the PROSPERO database. This overview was reported in accordance with the PRIOR statement [15].

Inclusion and exclusion criteria

Studies adhering to the following criteria were included: (1) Randomized clinical trials (RCTs) that examined the potential of FMT in treating UC were enrolled by SRs/MAs; (2) Participants met internationally recognized criteria for the diagnosis of UC regardless of gender, age, ethnicity, or duration of diseases [17]; (3) FMT was an intervention of interest for UC treatment, with a control group consisting of placebo or conventional medication; (4) Combined clinical and endoscopic remission, clinical remission, clinical response, endoscopic remission, endoscopic response, and serious adverse events were considered as outcomes.

The exclusion criteria were as follows: (1) Reviews including non-RCTs; (2) Reviews that included both UC patients and Crohn’s disease (CD) patients; (3) Reviews that were not efficacy evaluations; (3) Publications (e.g. conference abstracts, letters, and comments) without complete data.

Searching methods for identifying eligible reviews

Until January 14, 2023, papers published in Web of Science, PubMed, Embase, and Cochrane Library were comprehensively searched. In order to identify eligible studies, references to systematic reviews on the related subject were also reviewed. Specific searching strategy was adjusted in different databases. Table 1 shows the searching strategy on these databases.

Table 1 Search strategy for PubMed
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Evaluation of eligible papers and data extraction

Endnote X9 was used to import the retrieved papers and delete duplicates. The titles and abstracts of these papers were independently read by two authors to select eligible papers under inclusion criteria. For the final inclusion, the papers were read in full text.

Data extraction was independently performed by two authors using predesigned forms. For the included SRs/MAs, characteristics of reviews (country, publication year, first author) and characteristics of design (interventions, comparisons, quality assessment tool) were extracted. For the enrolled RCTs, methodological characteristics, reporting characteristics, and findings (outcomes, conclusions) were extracted. For the primary RCTs of the included SRs/MAs, the following data were collected: first author, publication year, country, sample size, methodological characteristics, severity of the disease, interventions, comparisons, concomitant treatment, duration to follow-up, and treatment outcomes of each patient.

Quality assessment

The Assessment of Multiple Systematic Reviews 2 (AMSTAR2) tool [18], Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklists [19], and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [20] were applied by two authors to independently evaluate methodological quality, reporting quality, and evidence quality, respectively. There are 16 items in AMSTAR-2, and 7 of them are critical items (2, 4, 7, 9, 11, 13 and 15). The PRISMA consists of 27 items, each of which is rated as “no” (not reported), “yes” (fully reported), or “partially yes” (partially reported). GRADE system was applied to assess the evidence quality for the outcomes from SRs/MAs in terms of limitations, imprecision, indirectness, inconsistencies, and publication bias.

Data synthesis

Summary statistics from the included reviews were analyzed. It was difficult to avoid overlapping trials because the reviews included in this overview all focused on the same topic. Considering that there might be overlapping trials and participants, we analyzed the data of the primary RCTs of the included SRs/Mas and conducted a re-analysis using RevMan 5.4. Pooled effect was presented as an odds ratio (OR) with 95% confidence intervals (CIs) for dichotomous variables. The presence of statistical heterogeneity was assessed by the Cochran’s Q test (χ2) and reported as I2 [21]. Fixed-effects model was applied in meta-analysis when the I2 < 50%, otherwise a random-effects model was used [22, 23]. Subgroup and sensitivity analyses were further performed to investigate source of heterogeneity when the I2 was higher than 50%. When possible and appropriate, number of stool donors, protocol of FMT (pre-FMT treatment, mode, frequency, route of FMT delivery), and concomitant use of topical rectal therapy or biologics were included in planned subgroup analyses. When more than 10 studies were pooled for a given outcome, a funnel plot was used to explore publication bias [24, 25]. Furthermore, GRADE system was employed to assess evidence quality for the outcomes obtained from data synthesized from the primary RCTs.

Results

Results on the publication selection

In total, 399 publications were filtered, 279 of which were excluded after reviewing their abstracts and titles. Full text of the remaining publications was carefully read, and 13 of which were further excluded. Finally, 6 studies were considered to meet the inclusion criteria [26,27,28,29,30,31]. A flow chart of publication selection is shown in Fig. 1.

Fig. 1
figure 1

Flow-chart of study selection

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Characteristics of the included studies

Table 2 provides an overview on the characteristics of the included SRs/MAs. Studies included in this overview were published between 2017 and 2022. In all SRs/MAs, the searching was limited to RCT designs. Quality assessment was based on the Cochrane risk-of-bias tool (random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective reporting; sponsorship; and other potential sources of bias). A total of 35 RCTs involving 2053 participants were included in these SRs/MAs. Notably, the CCA value was calculated to be 38.33%, indicating a noticeably high overlapping of RCTs included in these SRs/MAs (Fig. 2).

Table 2 Characteristics of the included reviews
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Fig. 2
figure 2

Overlap of trails included in reviews

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After removing overlapping RCTs (23 RCTs with 1509 participants), there  remained 12 primary RCTs [32,33,34,35,36,37,38,39,40,41,42,43] with 544 participants. Table 3 provides an overview of characteristics of the primary RCTs of the included SRs/MAs. All the 12 primary RCTs used FMT as experimental intervention, but 10 of them set placebo as control intervention and two RCTs used 5-aminosalicylate enema (1 RCT with 43 participants) and dietary treatment with an UC exclusion diet (1 RCT with 34 participants) as control intervention.

Table 3 Characteristics of the primary RCTs of included reviews
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Results of the methodological quality assessment

The AMSTAR-2 assessment of the methodological quality is shown in Table 4. Two included studies met all the critical items of AMSTAR-2 and were therefore rated at as having a high methodological quality. The remaining 4 studies were rated as having a moderate methodological quality because they did not provide a list of excluded trials. Overall, the methodological quality of the included studies was satisfactory.

Table 4 Methodological quality of the included reviews
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Results of the reporting quality assessment

The reporting quality assessed by PRISMA is presented in Table 5. Although no studies reported all 42 the items, all of them reported over 88% of the PRISMA checklists. Overall, the reporting quality of the included studies was satisfactory. However, poor reporting quality was common in additional analyses such as sensitivity (items 13f and 20d), summary of the main findings including certainty of the evidence (items 15 and 22), and lack of registration (item 24a).

Table 5 Reporting quality of the included reviews
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Results of the evidence quality assessment

Evidence quality of outcomes from the included studies was evaluated by the GRADE system (Table 6). Among the 22 outcomes, 8 showed high-quality confidence (36.4%), 12 showed moderate-quality confidence (54.5%), and 2 two showed low-quality confidence (9.1%). Small sample size in the existing studies were the most common factor for downgrading the evidence quality.

Table 6 Evidence quality of the included reviews
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Efficacy and safety of interventions

Reported efficacy and safety of FMT from the included reviews

Combined clinical and endoscopic remission of UC patients receiving FMT or placebo was assessed in 3 reviews, and their results showed a significantly greater benefit for patients receiving FMT than placebo (RR 2.97 [1.66, 5.33]; RR 3.14 [1.78, 5.55]; OR 4.11 [2.19,7.72]). FMT was reported to have a significant effect on endoscopic remission compared to the controls in 4 reviews (RR 3.26 [1.90, 5.59]; RR 2.26 [1.28, 5.53]; OR 3.78 [1.59, 8.97]; RR 1.94 [1.14, 3.31]). FMT also achieved significant clinical remission compared to the controls in all the reviews (RR 1.87 [1.29, 2.70]; OR 3.47 [1.93, 6.25]; OR 2.29 [1.48, 3.53]; RR 1.85 [1.28, 2.67]; OR 3.06 [1.35, 6.89]; RR 1.84 [1.37, 2.47]). Furthermore, patients treated by FMT showed more endoscopic responses than those receiving control therapy in 1 review (OR 2.17 [1.05, 4.50]). Additionally, clinical response of UC patients treated by FMT or placebo was assessed in 2 reviews, which manifested a significantly greater benefit for patients receiving FMT than placebo (OR 2.48 [1.18, 5.21]; OR 2.17 [1.05, 4.50]).

Rate of serious adverse events showed no significant statistical significance in between the FMT and control groups in 5 reviews (RR 1.40 [0.55, 3.58]; OR 1.29 [0.46, 3.57]; RR 1.37 [0.63, 2.96]; RR 0.98 [0.93, 1.03]; OR 1.38 [0.58, 3.30]). However, 1 study found that 10.3% of the participants in the FMT group experienced serious adverse events in comparison to 5.19% of the participants in the control group (RR 2.05 [1.03, 4.09]).

Reported efficacy and safety of FMT from re-analysis of the primary trials

The 12 primary RCTs with 544 participants were used to perform an additional meta-analysis. Combined clinical and endoscopic remission was reported in 8 trials involving 384 patients, and the pooled results demonstrated a significantly greater benefit for patients receiving FMT than placebo (OR 3.83 [2.31, 6.34]) (Fig. 3). Clinical remission was reported in 8 RCTs with 428 patients, and the pooled results showed that significantly more patients in the FMT group (51.87%) had clinical remission (3.31 [2.09, 5.25]) than the control group (16.14%) (Fig. 4). Similarly, endoscopic remission was reported in 7 trials with 388 patients, and the pooled analysis revealed that 33.69% of patients in the FMT group achieved endoscopic remission in comparison to 12.82% in the placebo group (OR 3.75 [2.20, 6.39]) (Fig. 5). Clinical response was reported in 7 RCTs with 348 patients, and the pooled results demonstrated a significantly greater benefit for patients receiving FMT than placebo (OR 2.56 [1.64, 4.00]) (Fig. 6). Furthermore, 4 trials with 179 patients evaluated endoscopic response, and the pooled analysis revealed that 37.21% of patients in the FMT group and 22.58% of patients in the control group had endoscopic response (OR 2.18 [1.12, 4.26]) (Fig. 7). Additionally, rate of serious adverse events was reported in both primary trials, and no statistical difference between the FMT and control groups was shown in the pooled results (OR 1.53 [0.74, 3.19]) (Fig. 8).

Fig. 3
figure 3

Forest plot comparing the rate of combined clinical and endoscopic remission in patients with UC receiving FMT vs placebo

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Fig. 4
figure 4

Forest plot comparing the rate of clinical remission in patients with UC receiving FMT vs placebo

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Fig. 5
figure 5

Forest plot comparing the rate of endoscopic remission in patients with UC receiving FMT vs placebo

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Fig. 6
figure 6

Forest plot comparing the rate of clinical response in patients with UC receiving FMT vs placebo

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Fig. 7
figure 7

Forest plot comparing the rate of endoscopic response in patients with UC receiving FMT vs placebo. CI, confidence interval; M-H, Mantel–Haenszel

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Fig. 8
figure 8

Forest plot comparing the rate of serious adverse events in patients with UC receiving FMT vs placebo

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Furthermore, evidence quality from re-analysis of the outcomes were further evaluated using GRADE system (Table 7). In summary, all the outcomes reached positive conclusion, and the outcomes of combined clinical and endoscopic remission, clinical remission, clinical response, endoscopic remission, and serious adverse events showed a high-quality confidence. Endoscopic response showed a moderate-quality confidence due to a small sample size in the available trials.

Table 7 Evidence quality of re-analysis on FMT for UC with data from primary trials
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Discussion

The number of SRs/MAs investigating FMT as a treatment for UC has shown an increase in recent years [26,27,28,29,30,31]. These studies had varying degrees of overlaps in terms of inclusion of trials, interventions, comparisons, and outcomes, and their results were not always organized in a consistent manner. Therefore, a more comprehensive overview is required to improve the current understanding of the effectiveness and safety of using FMT for treating UC.

Summary of main results

In this study, data from 35 RCTs with a total of 2053 participants were synthesized to provide evidence for the effectiveness and safety of using FMT to treat UC. Firstly, evidence from the included reviews indicated that FMT better improved the combined clinical and endoscopic remission, clinical response, endoscopic remission, endoscopic response, and clinical remission compared to the control group. However, results of SRs/MAs on serious adverse events related to the safety of FMT in UC were inconsistent. Secondly, the included SRs/MAs had less serious methodological flaws or reporting gaps, with an overall satisfactory quality evaluated by the AMSTAR-2 tool and PRISMA checklists. Thirdly, using GRADE system, we found that the overall evidence quality was unsatisfactory, which was mainly due to a small sample size in the previous studies that may lower the evidence confidence. Therefore, the conclusions reached by the included studies differed from the actual results. Fourthly, given the considerable overlap among these reviews and a small sample size, we performed an additional meta-analysis containing more primary trials than individual SRs/MAs (12 primary trials, 544 participants). The pooled analysis revealed that FMT better improved the combined clinical and endoscopic remission, endoscopic remission, clinical remission, endoscopic response, and clinical response than using placebo. Interestingly, after expanding the number of trials and sample size, the pooled analysis results showed that the conflicting outcomes in the incidence of serious adverse events were confirmed to be similar when using FMT or placebo. Additionally, the evidence quality on the outcomes derived from the additional meta-analysis was significantly higher after expanding the number of trials and sample size.

Overall completeness and applicability of evidence

The current overview included the latest studies published before January 2023, most of which were published within the last three years. UC patients in all the reviews were included regardless of their age, gender, or severity of illness. Outcomes included in the reviews were also relatively comprehensive. All the primary outcomes and most secondary outcomes in each review were included. Importantly, all reviews were consistent in their conclusions regarding the effects of FMT in UC, and incidence of serious adverse events were confirmed by additional meta-analyses with more trials and expanded sample sizes.

Various FMT protocols placed restrictions on the overall completeness and applicability of the evidence. Although no statistically significant heterogeneity was found in the previous SR/MA and current additional meta-analyses, there were differences between the main study experiments in terms of delivery route, total dosage, frequency, and donor selection. Fecal quality of donors, quantity of infusions, and mode of administration all affect how FMT works [44]. To date, the protocol of FMT has not been standardized [44]. Therefore, more trials are needed to determine the optimal timing, total dosage, frequency, delivery route, and the most suitable donor for FMT.

Implications for research

The GRADE system was applied to evaluate the certainty of evidence for using FMT to treat UC, where the majority of comparisons were rated as moderate or low, suggesting that additional studies may have a significant impact on the level of confidence in the estimate of effect or could even change estimate. As for sample size, the vast majority of the primary trials included were considered as having a small sample size, which was the main reason for downgrading the certainty of evidence of primary trials. Small trials could increase the risk of small-trail biases and relevant issues of publication bias, because small negative trials are less likely to reach full publication, which can result in overly positive results in comparisons [45, 46]. Thus, more future trials using a standard FMT protocol (such as best timing, total dosage, frequency, delivery route, and the best donor) with greater participant motivation and larger sample size are needed.

Strengths and limitations

To the best of our knowledge, this was the first overview of SRs/Mas that investigated the efficacy of using FMT for UC treatment. By systematically collecting, evaluating, and synthesizing the evidence for FMT for UC, the findings of this study could facilitate evidence-based decision-making process [47]. However, assessing methodological quality, reporting quality, and evidence quality could be a subjective process, as a result, outcomes may differ depending on the decisions made by various researchers in evaluating each factor. Furthermore, reviews that included both UC patients and Crohn’s disease patients were excluded, which may lead to selection bias.

Conclusion

In conclusion, moderate- to high-quality evidence supported a promising use of FMT to safely induce remission in UC. However, various FMT protocols placed restrictions to the overall completeness and applicability of the evidence because fecal quality of donors, quantity of infusions, and mode of administration could all affect FMT. Therefore, further trials with larger sample sizes are needed to analyze the delivery route, total dose, frequency and donor selection of FMT, so as to develop a mature standardized protocol for FMT in clinical application.

Availability of data and materials

The datasets used and analyzed during the current study were available from the corresponding author on reasonable request.

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Acknowledgements

We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

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Authors and Affiliations

  1. The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

    Haixia Liu & Youqi Xu

  2. Guang’an Hospital of Traditional Chinese Medicine, Guang’an, China

    Jing Li

  3. Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China

    Jiaxin Yuan

  4. Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China

    Jinke Huang

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  1. Haixia Liu
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  4. Jinke Huang
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Contributions

Conceptualization: Haixia Liu; Methodology: Jinke Huang, Jing Li, Jiaxin Yuan; Supervision: Haixia Liu, Jing Li, Jiaxin Yuan; Writing—original draft: Haixia Liu; Writing—review & editing: Youqi Xu. All authors read, critically reviewed and approved the final manuscript as submitted.

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Correspondence to Youqi Xu.

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Liu, H., Li, J., Yuan, J. et al. Fecal microbiota transplantation as a therapy for treating ulcerative colitis: an overview of systematic reviews. BMC Microbiol 23, 371 (2023). https://doi.org/10.1186/s12866-023-03107-1

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Keywords

BMC Microbiology

ISSN: 1471-2180

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