Background: Considerable research supports an important role for the microbiome and/or microbiome-host immune system interactions in the pathogenesis of inflammatory bowel disease (IBD). Consequently, microbiota-modulating interventions, such as fecal microbiota transplantation (FMT), have attracted interest in the management of IBD, including ulcerative colitis (UC). Summary: While the clinical response to FMT in UC has varied between different studies, results to date may offer guidance toward optimal use of FMT. Thus, increased microbiome biodiversity, the presence of short-chain fatty acid-producing bacteria, Clostridium clusters IV and XIVa, Odoribacter splanchnicus, and reduced levels of Caudovirales bacteriophages have been identified as characteristics of the donor microbiome that predict a positive response. However, inconsistency in FMT protocol between studies confounds their interpretation, so it is currently difficult to predict response and premature to recommend FMT, in general, as a treatment for UC. Additional randomized controlled trials designed based on previous findings and employing a standardized protocol are needed to define the role of FMT in the management of UC. Key Messages: There is a well-developed rationale for the use of microbiome-modulating interventions in UC. Despite variations in study protocol and limitations in study design that confound their interpretation, FMT seems to benefit patients with UC, overall. Available data identify factors predicting FMT response and should lead to the development of optimal FMT study protocols.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder of the colon with incidence and prevalence rates of 1.2–20.3 and 7.6–245 per 100,000 persons per year, respectively [1]. While several studies have described altered microbiota in UC, the precise compositional changes and downstream pathways involved in the pathogenesis of UC remain undefined [1, 3]. However, it seems to be based on interactions between genetic and environmental factors, gut microbiota, and the interface between microbiota and the host [4].

Patients with UC have reduced bacterial diversity characterized by decreases in Firmicutes populations such as Faecalibacterium prausnitzii and other short-chain fatty acid (SCFA)-producing bacteria [5]. Butyrate is associated with maintaining epithelial barrier integrity and also has immunomodulatory effects through G-protein-coupled receptor-mediated signaling cascades like GPR41, GPR43, and GPR109A [6, 7]. Additional microbiota changes in UC include a low prevalence of Clostridium clusters IV, XIVa, and XVIII, and a high prevalence of Bacteroides, Bacilli, Proteobacteria, and Clostridium clusters IC and XI [8]. Clostridium clusters IV and XIVa suppress colitis by inducing interleukin (IL)-10-producing regulatory T cells in mouse models [9, 10]. Specifically, Clostridium butyricum prevents acute experimental colitis by inducing IL-10 by intestinal macrophages in inflamed mucosa via the Toll-like receptor 2/myeloid differentiation primary response 88 pathway [11]. This colitis-preventing effect was negated in mice deficient in IL-10-producing macrophages, suggesting that the induction of IL-10 by intestinal macrophages is necessary for C. butyricum’s anti-inflammatory action [11].

The reduction in microbial diversity in UC correlates with disease severity, as those with acute severe colitis have less diversity than UC patients in remission and healthy cohort. Additionally, the gut microbiome in patients hospitalized with UC shows significant reductions in richness, evenness, and biodiversity [5].

It is unknown whether dysbiosis precedes the development of UC, or whether UC pathogenesis induces dysbiosis, but microbiome-altering exposures have been associated with UC. The largest study thus far linking antibiotic therapy with inflammatory bowel disease (IBD) found that frequent antibiotic use was associated with a higher risk for the development of both Crohn’s disease and UC with an adjusted odds ratio of 1.74 for UC, specifically [12]. Even children exposed to antibiotics during pregnancy had a greater risk of developing IBD [13]. Enteric infections, such as those caused Clostridioides difficile, Campylobacter, Plesiomonas, and Escherichia coli, have also been linked with acute flares among those with pre-existing UC and Crohn’s disease [14]. Lastly, a systematic review found that a high dietary intake of total fats, poly-unsaturated fatty acids, omega-6 fatty acids, and protein was associated with a greater risk of developing UC. In contrast, high vegetable intake, a dietary pattern associated with greater microbiota diversity, was associated with lower risk of developing UC [15].

In the context of these microbiome changes, fecal microbiota transplantation (FMT), a microbiota-modulating intervention, has emerged as a potentially viable treatment option [16, 21]. This review examines the role of FMT for treating UC considering current concepts on the pathogenesis of UC and the role of gut microbiota compositional changes in predicting response to FMT.

English abstracts were first identified in PubMed using primary search phrases “randomized controlled clinical trials” and “fecal microbiota transplant in ulcerative colitis.” All randomized controlled clinical trials (RCTs) conducted up to July 2022 were included in this review. A secondary bibliography was developed from the references cited in the selected full-length articles, and additional PubMed searches were conducted to elaborate on concepts presented in the identified RCTs. This process was repeated to develop a tertiary bibliography after reviewing articles from the secondary bibliography. In total, six RCTs were identified evaluating the efficacy of FMT in UC. One RCT (Crothers et al.) was excluded from the section directly comparing and contrasting RCTs since the number of patients included was not enough to evaluate statistical significance. As such, a total of 5 RCTs were evaluated.

The goal of FMT is to replace a disturbed microbiome with a healthy one and, thereby, to “reset” the microbiome (Fig. 1). FMT has enjoyed its greatest and most consistent success in treating recurrent C. difficile infection, with cure rates of up to 90% [22, 23]. In reviewing results of FMT in UC, we differentiate between observational studies and RCTs.

Fig. 1.

A graphical representation of the potential etiology of ulcerative colitis (UC) and the alterations induced by fecal microbiota transplantation to induce remission in patients with UC.

Fig. 1.

A graphical representation of the potential etiology of ulcerative colitis (UC) and the alterations induced by fecal microbiota transplantation to induce remission in patients with UC.

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Observational FMT Studies

The first report of treating UC with FMT, from 1989, suggested complete reversal of disease in a single patient. The patient remained endoscopically and histologically disease-free for over 20 years, spurring additional investigations into the use of FMT as a therapy [24]. A case series of 6 patients with UC (left-sided colitis only) was treated with what the authors described as colonic human probiotic infusions (HPIs) [25]. All patients had established UC for at least 5 years and had all failed maximum tolerated standard UC therapies. HPIs were screened for common infectious pathogens but were not analyzed for composition. Prior to infusion, patients received an antibiotic to suppress Clostridia (vancomycin 500 mg b.i.d. for 7–10 days) followed by a single lavage of 3 L of a polyethylene glycol-based oral solution. The HPIs were administered via enema and retained for at least 6 h. Concurrently with HPI, patients received their usual medical therapies which included various combinations of mesalamine, olsalazine, salazopyrin, 6-mercaptopurine, and corticosteroids. HPIs were repeated daily for 5 days. All anti-inflammatory therapy was withdrawn immediately post-HPI therapy in patient 2 and at 4–6 weeks for the others. In all patients, symptoms improved by week 1, and all symptoms had completely resolved by month 4 post-HPI. At 1–13 years post-HPI and without any UC medications, none of the patients showed clinical, endoscopic, or histological evidence of UC [25]. More recently, observational studies have yielded mixed results, with benefits appearing to be short-lived at best [26, 29]. A systematic review and meta-analysis of 168 articles showed remission rates of UC at 39.6% (95% CI: 25.4%–54.6%) [30]. Although this analysis noted comparable rates of remission for all routes of FMT administration, it is limited by the varying definitions of remission in the articles reviewed. However, this remission rate is similar to commonly used biologic therapies in UC, such as vedolizumab (31% clinical remission at 52 weeks) or adalimumab (22.5% clinical remission at 52 weeks) [31]. Additionally, remission rates with infliximab have been reported in 25.6–36.9% at 30 weeks of therapy [32].

Randomized Controlled Trials

RCTs have studied FMT’s effects on inducing remission in UC patients, most recently in the LOTUS study conducted by Haifer et al. [21] (Table 1) [16, 20]. Prior meta-analyses were based on the previous RCTs (292 patients) and concluded that FMT was associated with higher combined clinical and endoscopic remission rates than placebo (28.6% vs. 9%, p < 0.0001), without an increase in adverse events [33]. The positive results from Haifer et al. [21] will undoubtedly underscore FMT’s benefit in inducing remission. Differences between the various RCTs are further discussed in the FMT protocol subsection and summarized in Table 2.

Table 1.

Double-blinded, multi-center randomized controlled trial (RCT) clinical and endoscopic outcomes

RCTNumber of FMTNumber of placeboClinical response in FMT subgroupClinical response in placebo subgroupp valueClinical remission in FMT subgroupClinical remission in placebo subgroupp valueEndoscopic remission in FMT subgroupEndoscopic remission in placebo subgroupp value
Moayyedi et al., 2015 [16] 38 37 15 0.16 0.03 n/a 
Rossen et al., 2015 [17] 23 25 11 13 n/a 0.2 
Costello et al., 2017 [18] 38 35 21 0.007 21 0.01 0.12 
Paramsothy et al., 2017 [19] 41 40 22 0.004 18 0.021 0.48 
Crothers et al., 2018 [20] n/a n/a n/a 
Haifer et al., 2020 [21] 15 20 11 0.94 11 0.005 0.062 
RCTNumber of FMTNumber of placeboClinical response in FMT subgroupClinical response in placebo subgroupp valueClinical remission in FMT subgroupClinical remission in placebo subgroupp valueEndoscopic remission in FMT subgroupEndoscopic remission in placebo subgroupp value
Moayyedi et al., 2015 [16] 38 37 15 0.16 0.03 n/a 
Rossen et al., 2015 [17] 23 25 11 13 n/a 0.2 
Costello et al., 2017 [18] 38 35 21 0.007 21 0.01 0.12 
Paramsothy et al., 2017 [19] 41 40 22 0.004 18 0.021 0.48 
Crothers et al., 2018 [20] n/a n/a n/a 
Haifer et al., 2020 [21] 15 20 11 0.94 11 0.005 0.062 

FMT, fecal microbiota transplantation.

Table 2.

Double-blinded, multi-center randomized controlled trial (RCT) descriptions with sample sizes, recruitment protocols, and clinical endpoints

RCTLocationNumber of FMTNumber of PlaceboUC inclusion criteriaPre-FMT antibioticsFMT descriptionPlacebo descriptionRoute of administrationFMT response evaluationClinical response definitionClinical remission definitionEndoscopic remission/response definition
Moayyedi et al., 2015 [16] CAN 38 37 Mayo score =4 with endoscopic subscore =1 No Single-donor FMT Water retention enema Rectally administered enema weekly Week 7 =3-point reduction in Mayo score SCCAI =2 Mayo endoscopic score = 0 
Rossen et al., 2015 [17] NED 23 25 SCCAI 4–11 with endoscopic subscore =1 No Fresh single-donor FMT Autologous stool Nasoduodenal tube at time 0 and week 3 Week 6 and week 12 =1.5 reduction in SCCAI SCCAI =2 Mayo endoscopic score = 0 
Costello et al., 2017 [18] AUS 38 35 Mayo score 3–10 with endoscopic subscore =2 No Anaerobically prepared, pooled donor stool (3–4 donors) Aerobically prepared, autologous stool Colonoscopy at time 0, then two enemas on day 7 Week 8 =3-point reduction in Mayo score SCCAI =2 Mayo endoscopic score =1 
Paramsothy et al., 2017 [19] AUS 41 40 Mayo score 4–10 with endoscopic subscore =1 No Pooled donor stool (3–7 donors) Saline + odorant + food coloring in enema Colonoscopy at time 0, then 5 enemas per week for 8 weeks Week 8 =3-point reduction in Mayo score, or 50% or greater reduction in rectal bleeding plus stool frequency subscores, or both Mayo score <3 Mayo endoscopic score = 0 
Crothers et al., 2018 [20] USA Mayo score 4–10 Ciprofloxacin 250 mg PO q12 and metronidazole 500 mg PO q8 × 7 days Colonoscopic infusion followed by frozen FMT capsules Sham colonoscopic infusion followed by sham capsules Oral capsule taken daily Week 12 Decrease in Mayo score =3 Mayo score <3 Decrease in Mayo endoscopic score =1 
Haifer et al., 2020 [21] AUS 20 15 Mayo score 4–10 and endoscopic subscore of =1 14 days of amoxicillin hyclate 500 mg thrice daily, doxycycline hyclate 100 mg twice daily, metronidazole hyclate 400 mg twice daily Lyophilized capsule Capsule Oral capsules taken daily Week 8 =3-point reduction in Mayo score, or 50% or greater reduction in rectal bleeding plus stool frequency subscores, or both Mayo score =2 UCEIS =1/UCEIS score reduction =3 or 50% reduction from baseline UCEIS 
RCTLocationNumber of FMTNumber of PlaceboUC inclusion criteriaPre-FMT antibioticsFMT descriptionPlacebo descriptionRoute of administrationFMT response evaluationClinical response definitionClinical remission definitionEndoscopic remission/response definition
Moayyedi et al., 2015 [16] CAN 38 37 Mayo score =4 with endoscopic subscore =1 No Single-donor FMT Water retention enema Rectally administered enema weekly Week 7 =3-point reduction in Mayo score SCCAI =2 Mayo endoscopic score = 0 
Rossen et al., 2015 [17] NED 23 25 SCCAI 4–11 with endoscopic subscore =1 No Fresh single-donor FMT Autologous stool Nasoduodenal tube at time 0 and week 3 Week 6 and week 12 =1.5 reduction in SCCAI SCCAI =2 Mayo endoscopic score = 0 
Costello et al., 2017 [18] AUS 38 35 Mayo score 3–10 with endoscopic subscore =2 No Anaerobically prepared, pooled donor stool (3–4 donors) Aerobically prepared, autologous stool Colonoscopy at time 0, then two enemas on day 7 Week 8 =3-point reduction in Mayo score SCCAI =2 Mayo endoscopic score =1 
Paramsothy et al., 2017 [19] AUS 41 40 Mayo score 4–10 with endoscopic subscore =1 No Pooled donor stool (3–7 donors) Saline + odorant + food coloring in enema Colonoscopy at time 0, then 5 enemas per week for 8 weeks Week 8 =3-point reduction in Mayo score, or 50% or greater reduction in rectal bleeding plus stool frequency subscores, or both Mayo score <3 Mayo endoscopic score = 0 
Crothers et al., 2018 [20] USA Mayo score 4–10 Ciprofloxacin 250 mg PO q12 and metronidazole 500 mg PO q8 × 7 days Colonoscopic infusion followed by frozen FMT capsules Sham colonoscopic infusion followed by sham capsules Oral capsule taken daily Week 12 Decrease in Mayo score =3 Mayo score <3 Decrease in Mayo endoscopic score =1 
Haifer et al., 2020 [21] AUS 20 15 Mayo score 4–10 and endoscopic subscore of =1 14 days of amoxicillin hyclate 500 mg thrice daily, doxycycline hyclate 100 mg twice daily, metronidazole hyclate 400 mg twice daily Lyophilized capsule Capsule Oral capsules taken daily Week 8 =3-point reduction in Mayo score, or 50% or greater reduction in rectal bleeding plus stool frequency subscores, or both Mayo score =2 UCEIS =1/UCEIS score reduction =3 or 50% reduction from baseline UCEIS 

FMT-Related Changes in Host Microbiome Linked to Clinical Response

Species Richness, Secondary Bile Acids, and SCFA Production

To date, there does not appear to be sufficient data to indicate that the recipient’s baseline microbiome pre-FMT is predictive of success. However, response to FMT treatment is associated with the recipient’s microbiome shifting toward a population close to the donor’s [17, 26]. In a study among nine children with UC (aged 7–20), the patients’ alpha diversity was significantly less than donor levels at baseline. FMT success was associated with an increase in overall mean species richness; non-responders showed minimal improvements in mean species richness. Additionally, virome and metabolome profiles of responders to FMT shifted toward those of their donors [26]. Similarly, another RCT identified an increase in microbiota richness and evenness in all FMT responders [17].

Sustained remission (defined as remission at 1-year follow-up) following FMT therapy has been associated with the presence of known butyrate producers, such as Roseburia hominis and Faecalibacterium prausnitzii, and an overall increase in butyrate production capacity, while relapse was associated with Proteobacteria and reduced numbers of Bacteroidetes and Firmicutes (butyrate-producing bacteria) [8]. The benefit of Firmicutes, specifically, in UC was further evidenced by the phase IB trial of SER-287 (an oral formulation containing exclusively firmicute spores derived from donor stools) which they received either daily or weekly. Both the daily and weekly treatment groups were pre-treated with vancomycin (125 mg 4 times daily). This was followed by administration of 1 × 107 colony-forming units of SER-287 either once daily or weekly for 8 weeks. Patients in the daily treatment arm achieved a clinical remission rate (defined as total modified Mayo score =2 and an endoscopic subscore =1) of 40% compared to 0% in placebo antibiotic/placebo treatment and 17.7% in the weekly SER-287 treatment arm [34]. Treatment success in the RCT by Paramsothy et al. [35] was similarly associated with SCFA production and the presence of Eubacterium and Roseburia species in addition to secondary bile acids. Although the role of secondary bile acids in the pathogenesis of UC remains unclear, this finding is consistent with findings in patients receiving FMT therapy for C. difficile[36, 37]. Failure of FMT was associated with the presence of Fusobacterium and Sutterella species [35].

Clostridium Clusters IV and XIVa

At baseline, patients with UC have fewer bacterial taxa from Clostridium clusters IV and XIVa than their healthy FMT donors [8]. Multiple studies have associated an increase in Clostridium clusters IV and XIVa with a positive response to FMT, with mean relative abundance shifting toward donor levels after FMT therapy [8, 17, 26]. Additionally, a microbial ecosystem low in Clostridium clusters IV and XIVa in UC patients after FMT indicates a poor sustained response, unless modified by donor microbiota rich in specific members from Clostridium clusters IV and XIVa.

Odoribacter splanchnicus

Metagenomic and strain tracking was performed on 60 samples from donors and recipients of FMT for UC from an open-label trial by Jacob et al. [29, 38]. These samples were stained with anti-human immunoglobulin A to identify immunoreactive bacteria. Genetically engineered mice were then colonized with patient-derived strains to determine the impact on intestinal immunity. This identified Odoribacter splanchnicus (O. splanchnicus) as a transferable strain correlating with a reduction in intestinal inflammation. O. splanchnicus colonization resulted in an increase of Foxp3+/ROR?t+ regulatory T cells, induction of IL-10, and the production of SCFAs [38].

Caudovirales Bacteriophages

The viral populations of patients with UC have not been as thoroughly investigated as their bacterial counterparts. Unlike bacterial populations, the enteric virome of patients with UC shows an increased species richness, as defined by the number of taxa present [39]. Most notably, there is an increase in the number of bacteriophages, most prominently in the population of Caudovirales [39, 41].

Caudovirales bacteriophages are present in greater numbers in patients who do not respond to FMT. Gogokhia et al. [41] proposed that the response to FMT is actively inhibited by the presence of Caudovirales bacteriophages that exacerbate intestinal colitis. Although Caudovirales does not directly infect the host, the virus produces molecules that interact with the host’s immune system [42, 43]. Mice exposed to bacteriophages mount upregulated innate and adaptive immune responses, supported by increases in CD4+ and CD8+ T cells in their mesenteric lymph nodes. Exposure to a Caudovirales cocktail augmented these responses, as a larger proportion of cells exhibited an activated phenotype and more IFN-gamma and IL-17a-producing T cells [41].

FMT Protocol

The precise protocol employed is an important consideration in determining the response of patients with UC to FMT. This includes donor selection, preparation of the fecal bacterial material to be transferred, FMT storage, frequency of FMT administration, and the delivery route. Of note, although the study by Crothers et al. is included in Tables 1 and 2 as an RCT, it is excluded from the following discussion since the number of patients included was insufficient to determine statistical significance [20].

Preparation of Donor Stool

The preparation of stool samples varied significantly across the RCTs. Some studies used frozen-thawed stool samples, while others used fresh fecal matter. This is relevant in the context of the microbiota, because low storage temperatures can interfere with bacterial DNA [44]. Additionally, Rossen et al.’s RCT showed that even autologous FMT can alter the patient’s microbiota. This suggests that sample processing alone can significantly alter a patient’s microbiota and thus must be regarded as a potential outcome confounder in FMT studies. RCT by Haifer et al. [21] was the first to exclude donor stools based on donor microbiota composition, excluding donor samples with Sutterella and Fusobacterium species. The remaining donor samples were lyophilized in oral capsules, which patients were instructed to keep refrigerated at 4°C. It was stated that the encapsulated lyophilized FMT contained a significant (but undefined) quantity of viable bacteria for up to 3 months post-production.

Patient Preparation

The RCTs also varied in their approach to patient preparation prior to FMT administration. Some studies used bowel lavage or antibiotics to “cleanse” the patient. Bowel cleansing significantly alters intestinal microbiota composition, resulting in a 31-fold decrease in total microbial load. This was also associated with notably increased levels of Proteobacteria, a phylum associated with lack of response to FMT [45]. This suggests that bowel lavage and cleansing with antibiotics might compromise outcomes following FMT therapy. Despite this, Haifer et al. [21] treated patients for 14 days with an antibiotic regimen comprising amoxicillin hyclate 500 mg 3 times daily, doxycycline hyclate 100 mg twice daily, and metronidazole hyclate 400 mg twice daily, to specifically deplete Fusobacterium species. Because the antibiotics were given to both the treatment and the placebo groups, it is difficult to define the impact of pre-FMT antibiotic use on FMT outcome. Patients that received pre-FMT antibiotics and then FMT saw exponential increases in their microbiota alpha diversity, while pre-FMT antibiotics followed by placebo saw a linear increase. Notably, however, patients treated with antibiotics alone followed by placebo showed an endoscopic response rate of 15% at week 8, indicating that pre-FMT antibiotics might confer benefits. This rate is significantly higher than the results from the similar FOCUS study, which did not use priming antibiotics, indicating a potential benefit to antibiotic use prior to FMT administration designed to target bacteria associated with lack of FMT response [46].

Inclusion Criteria

These RCTs employed similar inclusion criteria in selecting UC patients for FMT (Table 2). They required active disease based on the Mayo scoring system and confirmed by endoscopy. In all RCTs, patients were excluded if they had used antibiotics recently, or if they had not been on a stable dose of an anti-tumor necrosis factor agent, thiopurine, mesalamine, or other IBD drug for a defined period: 4 weeks in the studies by Paramsothy et al. [35] and Haifer et al. [21], 8 weeks in Rossen et al. [17], and 12 weeks in Moayyedi et al. [16]. This time period varied according to prior therapy in the study by Costello et al. [18]: 4 weeks for 5-ASAs, 6 weeks for thiopurines and methotrexate, and 8 weeks for biological agents. Additionally, Moayyedi et al. [16] utilized immunosuppressant therapy alongside FMT and found that these patients were more likely to reach remission than those who received FMT alone. In contrast, Paramsothy et al. [35] required participants to wean off steroid treatment to isolate the efficacy of FMT.

Route and Frequency of Administration

The route and frequency of administration also contribute to FMT response, especially in the context of the microbiome. The RCTs differed in their approach here, with two opting for delivery via colonoscopy and enema (Costello et al. [18] and Paramsothy et al. [35]), one via enema alone (Moayyedi et al. [16]), one by infusing the fecal material via nasoduodenal tube (Rossen et al. [17]), and one via lyophilized oral ingested capsules (Haifer et al. [21]). Additionally, the frequency and duration of treatments varied significantly, with Moayyedi opting for enemas once weekly for 7 weeks and Paramsothy opting for five enemas a week for 8 weeks prior to evaluating FMT response. Some of the bacterial species discussed here and linked to FMT response are pH tolerant (Firmicutes) and can survive in the upper gastrointestinal tract, while others are not (Bacteroidetes) [44]. The route of administration was tailored to disease extent, with enemas used to target distal inflammation and the nasoduodenal route used to target more proximal inflammation. The duration of follow-up after treatment also varied. Of the 35 responders Paramsothy et al. [35] followed for 8 weeks after completion of FMT, 23 remained in remission (defined as combined Mayo subscores of =1 for rectal bleeding plus stool frequency). Similarly, only five of the 12 participants who reached the primary endpoint of steroid-free remission in the RCT by Costello et al. [18] were still in remission 12 months later (defined as Mayo total score =2 and endoscopic Mayo score =1). Lastly, of the 10 patients that reached clinical or endoscopic response in the study by Haifer et al. [21], four remained on FMT therapy and maintained remission through week 56. All 6 patients who withdrew from FMT therapy had disease exacerbations [21]. These results suggest that recurrent FMT treatments might be necessary to maintain long-term remission.

Timing of FMT in Relation to Natural History of UC

The timing of FMT administration likely also contributes to the patient’s overall response. Moayyedi et al. found that patients with newly diagnosed UC were more likely to respond to FMT therapy than patients with disease of longer duration [16]. This suggests that there is a treatment window for FMT administration that permits reversal of intestinal dysbiosis.

Adverse Events

Four of the five RCTs found no statistically significant differences in the number or types of adverse events between treatment groups. Costello et al. [18] noted three serious adverse events at week 8 in their FMT treatment group: 1 patient had worsening colitis, one had C. difficile colitis requiring colectomy, and one had pneumonia.

FMT appears to be a promising treatment in the management of UC with 4 out of the 5 current RCTs reporting significant differences in achieving clinical remission between the FMT and control group. Without the inclusion of the most recent RCT by Haifer et al. [21], combined clinical and endoscopic remission rates were still greater than placebo (28.6% vs. 9%, p < 0.0001) [33]. Several studies have proposed the idea of a “super donor.” This concept originated from Moayyedi et al. [16] ’s study, where seven of the nine patients who achieved remission received FMT from the same donor. The microbiome populations outlined in this review could be utilized to select effective donors; however, much remains unknown about what constitutes a super donor. After the Moayyedi et al. [16] study, it was suggested that remission rates could be improved by pooling donor stool to limit the chances that a patient will receive ineffective stool. As such, the Paramsothy et al. [35] RCT utilized a stool mixture with contributions from up to seven different donors. The results also seemed to indicate the presence of a super donor, with patients receiving stool from one donor exhibiting a higher remission rate than those whose FMT was from batches without stool from the super donor (37% vs. 18%, respectively) [47]. Additionally, despite Haifer et al. [21] ’s attempt to select donors based on bacterial sequencing, FMT success differed significantly between the two donors used in their RCT. All the recipients from donor one (four of four) achieved clinical remission and either endoscopic remission or response, while only four of 11 recipients from donor two reached this endpoint [21].

Comparisons of gut microbiota of different donors indicate that donor microbiota diversity reliably indicates FMT success [26, 27]. Similar to changes in patient microbiomes following successful FMT therapy, successful donors are more likely to have a higher relative abundance of Clostridium clusters IV and XIVa. Specifically, the gut microbiome from the super donor in the Moayyedi et al. [16] RCT had higher concentrations of the Ruminococcaceae and Lachnospiraceae families, while the super donor from Haifer et al. [21] had a relative abundance of Bacteroidetes taxa.

Further investigation has shown that donor strains after FMT can cohabit the intestinal microbiome alongside pre-existing isotypes [48]. Cohabitation suggests a donor-recipient symbiosis that determines FMT response, and the importance of donor microbiota composition might be over-emphasized compared to the importance of the donor-recipient interaction. This is consistent with the findings of this review that both donor and recipient microbiota play pivotal roles in patient response to FMT.

For example, Li et al. [48] demonstrated that colonization success following FMT therapy in patients with recurrent C. difficile infections was greater for conspecific strains (strains from the same species) than for new species. The emergence of important recipient-donor interactions seems to reject the “one stool fits all” model, with Li et al. [48] suggesting that differences in FMT outcomes stem from strain incompatibilities between the existing recipient microbiome and the donor FMT.

As such, pre-FMT gut bacterial and viral profiles may not completely predict FMT response. FMT engraftment and positive clinical responses are likely due to a combination of possessing microbiota populations associated with remission and a compatible match between bacterial taxa in donor and recipient. This highlights the importance of pre-screening patients and donors prior to FMT therapy. Pre-screening can identify relevant pre-FMT microbiota populations in the donor and recipient, and allow targeted matching based on the Li et al. [48] findings, with an emphasis on matching donors and recipients with conspecific strains to allow better engraftment.

Although FMT cannot currently be recommended as standard of care in the management of UC, some suggestions have emerged on how to optimize protocols for future studies and tailor the delivery of FMT for a given UC phenotype. For example, FMT success appears to be linked to the promotion of SCFA-producing bacteria (Firmicutes in particular) and Clostridium clusters XIVa and IV. Additionally, specific pathogenic populations such as Caudovirales could be targeted in conjunction with FMT therapy. Future RCTs can improve upon existing ones by selecting donors specifically rich in these populations (in addition to overall bacterial biodiversity) and matching them with compatible donors rich in conspecific strains.

The role of FMT in managing UC remains to be defined. Data are limited and interpretation confounded by inconsistent FMT protocols, rendering it difficult to predict response. Additional RCTs designed based on previous findings can help identify an optimal FMT protocol.

The authors wish to thank Rachael Whitehead for the creation of Figure 1 and Dr. Jonathan Feinberg for his work in editing this manuscript.

The authors have no conflicts of interest to declare.

No funding was received for this research.

A.A.S. and S.P. wrote the initial draft of the article. M.G., E.Q., and B.A. critically revised the manuscript. The manuscript was approved by all authors.

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