DOI: https://doi.org/https://doi.org/10.57187/smw.2023.40100
Faecal microbiota transplantation (FMT) is a procedure in which faeces from a healthy donor are transferred to the gastrointestinal tract of a recipient patient. Over the past 10 years, studies have demonstrated that FMT is an effective treatment for recurrent Clostridioides difficile infection (rCDI), recently reclassified as Clostridioides difficile infection (CDI) [1–3]. In recent years, the role of the gut microbiota has been recognised in a variety of immune-mediated diseases and other disorders (e.g. metabolic disorders), raising the question of whether FMT has therapeutic potential [4–7]. Studies on the use of FMT in inflammatory bowel disease (IBD) have shown some benefits, mostly in patients with ulcerative colitis; studies on FMT in Crohn’s disease have been less conclusive [8–10].
Currently, there is no international consensus on how FMT should be legislated, and standardised policies are lacking [11, 12]. Some countries handle FMT as a tissue sample, whereas others handle it as a medicinal product, demonstrating that different countries have very different regulation procedures [12, 13]. United European Gastroenterology (UEG) advocates that FMT should be uniformly recognised and regulated as a transplant product and not as a drug [14]. In July 2022, the EU Commission released a legislative proposal to include faecal microbiota in the European legislation on blood, tissues, and cells [15, 16]. The Council of Europe published the fifth version of the Guide to Quality and Safety of Tissues and Cells, which includes a chapter on intestinal microbiota. Screening recommendations are made but the most suitable framework remains a choice of the member states [17].
Recently, stool transplants were not regulated in Switzerland, leading to many procedural disparities. For example, the selection of donors varied depending on the centre; CHUV (Lausanne University Hospital) proceeded with a strict selection of traceable, healthy medical student donors, whereas in some private gastroenterology clinics, the patient had to recruit friends or relatives. As of 2019, stool transplants are considered a non-standardised medicinal product, with a standardised production process requiring authorisation by Swissmedic (the Swiss Agency for Therapeutic Products) [18]. CHUV is accredited for the production of stool transplants. The obligation to obtain a marketing authorisation came into force in July 2020, and obtainment procedures are ongoing [12]. Since then, the administration of FMT outside of accredited centres is out of regulation. Each approval by Swissmedic is centre- and indication-dependent, and the administrative procedure must be repeated as indications evolve. This leads to reduced FMT accessibility. In 2021, CHUV estimated that, according to their local practices at that time, the cost of an FMT procedure was approximately CHF 15,000 (EUR 15,110) per transplant [12]. This estimate included donor selection (repeated clinical and biological assessment) as well as follow-up (until 5 years after donation) and the preparation of the sample. It did not include the administration to the recipient, which is typically endoscopic. With improved preselection of donors and increased consistency in the procedures, costs are expected to be halved. The final pricing and reimbursement will depend on the acceptance of the marketing authorisation.
FMT is a promising therapy, and the panel of gastroenterologist experts agreed that its accessibility should be improved without compromising its safety. United European Gastroenterology and other national interest groups have provided some guidance on the application of FMT in daily clinical practice, but Switzerland currently lacks such guidance. This paper provides an updated review of the current evidence concerning FMT efficacy, with a special focus on IBD, and establishes statements about the most relevant aspects of the FMT process, from donor screening to administration.
The IBDnet is an official partner organisation of the Swiss Society of Gastroenterology. A panel of seven IBDnet delegates, gastroenterologists with expertise in IBD, from various Swiss academic and private gastroenterology centres was constituted to participate in this position statement. The purpose of this group was to establish statements about FMT following the Delphi method. Key issues regarding FMT were identified and distributed in 6 topics: indications for FMT, donor screening, preparation of donor faeces, transplant recipients, faecal delivery, and safety considerations. For each topic, literature searches were performed on PubMed in March 2022 to obtain the best available evidence. After the literature review, one member of the panel formulated draft statements.
The elaborated statements were distributed to each IBD expert for anonymous electronic voting in May 2022. For each statement, experts were asked to rate their level of agreement on a 4-item Likert scale: (1) strongly disagree, (2) disagree, (3) agree with reservation, and (4) strongly agree. All seven experts voted on each statement, and there were no missing or blank votes. The votes were collected by the facilitator, Nadine Zahnd, PhD, managing director of IBDnet, and then they were merged. A statement was accepted if its average rating was greater than or equal to 3. Panel experts gathered on 7 June 2022 to discuss the statements. If a mean score of 3 was not achieved, the statement was discussed to identify any ambiguities or contradictions with the available literature and then rephrased, after which a new voting round was performed. This process was repeated until a mean rating of greater than or equal to 3 was obtained. After redaction, the initial manuscript was sent to the head of CHUV’s FMT Unit, Tatiana Galperine, MD, infectiologist, for interdisciplinary review.
In 2021, the American College of Gastroenterology (ACG) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published guidelines on Clostridioides difficile infection treatment [19, 20]. The ESCMID recommended fidaxomicin as first-line therapy because it is associated with a reduced recurrence rate and has a narrower spectrum of activity compared with vancomycin and metronidazole [20–22]. However, this recommendation was controversial. The ACG considers both vancomycin and fidaxomicin to be valid first-line options [19]. The Swiss Society for Infectious Diseases (SSI) still recommends vancomycin (or even metronidazole) as the first-line treatment in patients without risk factors and with a low risk of relapse [23]. This is because they have satisfactory efficacy fidaxomicin C. difficile colitis in Switzerland and are less expensive and more accessible than fidaxomicin [23]. Fidaxomicin is recommended in patients at risk of Clostridioides difficile infection recurrence (i.e. patients older than 65 years meeting at least one of the following criteria: healthcare-associated Clostridioides difficile infection, recent hospitalisation, concomitant antibiotic use, and new proton pump-inhibitor prescription) [20]. In patients with Clostridioides difficile infection recurrence, antibiotic treatment can be further optimised by switching their medication to fidaxomicin if they have not yet received it, or combining fidaxomicin with bezlotoxumab, a monoclonal antibody against C. difficile toxin B [20, 23]. The AGC, ESCMID and the SSI agree that for further recurrences, FMT should be discussed [19, 20, 23].
The efficacy of FMT for recurrent C. difficile colitis has been demonstrated in multiple randomised studies, and the most recent European and American guidelines recommend FMT after the second recurrence of Clostridioides difficile infection [20, 24–27]. The efficacy of FMT in Clostridioides difficile infection is estimated to lie between 85% and 90%, and it has better cure rates than vancomycin and fidaxomicin regimens [28–30]. Despite the initial impression that FMT is associated with high costs, its efficacy in preventing further Clostridioides difficile infection makes it a cost-effective procedure [31]. This strong evidence led to statement 1.1 (see supplementary table S1 in the PDF version of this article).
A retrospective clinical review indicated that FMT could be an effective first-line treatment for initial Clostridioides difficile infection in a small population (54 patients) [32]. This was confirmed in a recent randomised placebo-controlled study in which FMT was compared with placebo after a 10-day vancomycin treatment for the first and second episodes of Clostridioides difficile infection [33]. Because FMT is more complex and costly than 10-day antibiotic treatment alone, we do not currently recommend FMT as a first-line treatment for Clostridioides difficile infection (statement 1.2).
A recent meta-analysis showed that FMT could be used not only for recurrent Clostridioides difficile infection but also for antibiotic-refractory Clostridioides difficile infection (statement 1.3) [34]. In such cases, the diagnosis must first be challenged, and other causes of diarrhoea apart from C. difficile colonisation must be ruled out. Another meta-analysis has also found that FMT was effective and safe in patients with severe C. difficile infections [35]. After consideration of this article, we rephrased statement 1.4 and revoted on it.
According to a meta-analysis published in 2021, FMT for Clostridioides difficile infection in patients with underlying IBD is highly effective, with a pooled cure rate of 78% [36].
Contrary to initial fears that FMT could induce flares, FMT can be used to treat Clostridioides difficile infection in patients with IBD; in these patients, FMT has a potential secondary benefit of improving their underlying disease, as clinical IBD-scores (partial Mayo score or Harvey-Bradshaw index) were improved in patients with ulcerative colitis and those with Crohn’s disease (supplementary table S1, statement 1.5) [37, 38].
FMT may be a therapeutic option to induce remission in ulcerative colitis (supplementary table S2). Over the past years, several randomised controlled trials (RCTs) have shown increased remission rates in patients with ulcerative colitis who received FMT compared to those who received placebo [39–45]. However, all these studies included a limited number of patients (between 15 and 42 in the FMT arms) and had different methodologies. The route of administration (nasoduodenal tube, enema, colonoscopy, or oral lyophilised tablets) as well as the frequency of administration varied. The remission rates varied between 24% and 57% in the FMT groups compared with between 5% to 36% in the placebo groups. Overall, the mean benefit difference was 22% between FMT and placebo. A nonsignificant difference was only observed in the study in which the FMT was administrated via nasoduodenal tube [42]. FMT seems to be a promising therapy to induce remission in patients with active ulcerative colitis, but this treatment must be studied further before it is encouraged more strongly (statement 1.7). These remission rates must be put into perspective. On the one hand, the response rates of FMT therapy in patients with ulcerative colitis are not quite as impressive as those in patients with Clostridioides difficile infection. This could be explained by the difference in underlying pathogenesis; Clostridioides difficile infection is a typical example of gut microbiota dysbiosis, whereas in ulcerative colitis, the gut microbiota is only part of a complex multifactorial etiological model [46]. On the other hand, the FMT remission rate is similar to the remission rate seen with biological therapies (approximately 30%), making it a relevant therapeutic option to consider [47].
A randomised pilot study conducted on patients with ulcerative colitis in remission in which FMT was administered via repeated colonoscopy also showed increased maintained remission rates compared with placebo [48].
In severe ulcerative colitis, the expert panel agreed that FMT should not be used as rescue therapy before colectomy until further evidence is available (statement 1.8) because of the potential complications among this subgroup of patients.
Although FMT in patients with Crohn’s disease could result in an expansion of the microbial bacterial diversity, the clinical response is not obvious, and robust data are lacking [8, 49]. Most studies have been performed on small clinical cohorts without control groups [50, 51]. A cohort study including 174 patients showed clinical improvement after FMT [52]. One RCT compared upper gastrointestinal and lower gastrointestinal administration routes of FMT and showed similar response rates of over 60%, but it did not include a placebo group [53]. To assess the efficacy of FMT for maintaining remission, another RCT compared colonoscopy FMT with sham transplantation, but only included nine patients with Crohn’s disease, making drawing conclusions difficult [54]. Therefore, until further data are available, FMT is not recommended in patients with Crohn’s disease (statement 1.9).
Gut microbiota has been suggested to play a role in many diseases, but the available evidence does not currently support the use of FMT in these clinical scenarios [55–59] (supplementary table S3, statement 1.10). At the moment, if FMT is considered in these indications, it should only be performed within a clinical study protocol.
A 2022 study showed symptomatic improvement in irritable bowel syndrome (IBS) up to 3 years after FMT in 65% to 72% of patients (depending on the faeces volume delivered) compared with 27% of patients in the placebo group [60]. This response rate was higher than that reported in previous studies. The authors hypothesised that the administration route, which was duodenal and not colonic, may have played a significant role in the response difference [61]. Further studies are needed to support FMT for this indication.
A recent placebo-controlled study on 55 patients with small intestinal bacterial overgrowth (SIBO) showed clinical improvement after FMT (lyophilised capsules once weekly for 4 weeks) and no clinical improvement with placebo [62]. However, larger studies are needed to make clear recommendations.
Donor selection is crucial to reducing adverse events related to the administered faecal material by minimising the risk of transferring infectious diseases as well as adverse gut microbiota traits.
The European Commission established a directive for the selection of allogenic living donors of human tissue transplants in 2006 (updated in 2012), which requires a thorough donor assessment to exclude persons with active/past malignant disease; those with recent (not further specified) vaccination with a live attenuated vaccine; and those with a risk of transmission of diseases caused by prions, systemic infection (bacterial, viral, fungal, or parasitic), or blood-born diseases, such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and syphilis (as well as human T-lymphotropic virus type 1 [HTLV-1] in populations in high-prevalence areas) [63]. The last European consensus conference on FMT in 2017 and the French Group of FMT made detailed recommendations for donor screening [27, 64]. Our expert panel considered these recommendations, as well as the international consensus conference statements on stool banking and the latest foreign national consensus (Korea), to make the following statements: 2.1.5, 2.1.7, 2.1.9, 2.1.10. 2.1.13, 2.2.2 to 2.2.10, 2.3.1, and 2.3.2 (supplementary tables S4–S6) [26, 65].
As highlighted by a recent United States Food and Drug Administration (FDA) alert, Shiga toxigenic Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) should also be tested [66]. As these are included in the PCR multiplex test, they are not explicitly mentioned in the table but should be tested for. In a Dutch study, the transmission of Blastocystis hominis by FMT was documented and did not result in complications, symptoms, or adverse FMT outcomes in the recipient [67]. Nevertheless, the international consensus statements recommend testing for Blastocystis hominis, so we included it in this expert statement. However, if the non-pathogenicity of this strain is confirmed, this statement could be adapted. In addition, the pathogenicity of Entamoeba histolytica and Dientamoeba fragilis and their FMT transmission risk are subject to debate [68, 69]. In the United States, stool donors are no longer screened for Blastocystis hominis or Dientamoeba fragilis [70], and CHUV has adopted the same practice [12].
Our panel added an extra donor prerequisite for immunocompromised recipients − donors should not carry out cytomegalovirus (CMV), Epstein-Barr virus (EBV), or toxoplasmosis (statement 2.2.1) − following consensus reports for additional safety in this at-risk subpopulation [13, 26]. However, in the absence of reported cases of FMT-associated transmission of CMV, EBV, and toxoplasmosis, the benefit of this practice is unclear [70].
There have been reports of FMT complicated by extended-spectrum beta-lactamase E. Coli (ESBL) bacteraemia, with one case leading to death, in which ESBL was subsequently identified in the donor’s stool by genome sequencing [71]. The implicated donor did not have any risk factors of multidrug-resistant organism carriage and was thus not tested for them. Other data show that a substantial proportion of healthy donors (17%) carried multidrug-resistant organisms [72]. This reminds us that healthy, fit individuals can harbour organisms that might be fatal to others; therefore, testing for these is crucial [73]. To prevent the transmission of multidrug-resistant organisms and possible subsequent complications, our panel recommends systematic screening for the most common multidrug-resistant strains (statement 2.2.11).
The SARS-CoV-2 pandemic required FMT services to adapt to optimise safety for donors, recipients, and healthcare professionals [74]. It has been demonstrated that patients infected with SARS-CoV-2 shed virus in their stool well beyond the average clearance time for upper respiratory tract shedding, independent of the presence of symptoms [75]. The pathogenic consequences of this shedding remain unclear. Currently, donors with recent SARS-CoV-2 infection should be excluded (statement 2.2.14).
Because of the role the microbiota could play in the development of autoimmune diseases, including inflammatory bowel disease, allergies, and psychiatric diseases, the expert panel recommends that people suffering from these diseases should not become stool donors (statements 2.1.3, 2.1.4, 2.1.6, 2.1.12, and 2.3.3) [6, 76–78]. Because microbiota composition seems to differ in underweight people with anorexia and obese individuals, the panel recommends that donors should have a normal body mass index (BMI) (statement 2.1.2) [5, 79]. Antibiotic treatment influences the microbiota composition and increases the risk of Clostridioides difficile infection up to 3 months after treatment; therefore, individuals with recent antibiotic use should also be excluded as donors (statement 2.1.11) [80, 81].
A recent study demonstrated that bariatric surgery (sleeve gastrectomy and Roux-en-Y bypass) influences microbiota composition [82]. Thus, our panel recommends excluding donors who have had major surgeries, especially those leading to blind loop syndromes, because of the risk of altered microbiota (statement 2.1.8) [82].
Older adults have an increased risk of comorbidities and may have modified microbiota [83]. Therefore, following international consensus, our panel suggests that donors should be between 18 and 70 years old (statement 2.1.1) [26, 64]. Given the age-dependent risk of colorectal cancer, stricter policies excluding donors over 50 years old should also be discussed [84].
These statements consider proven risks (transmission of pathogenic bacteria) as well as potential risks that are more debatable (colorectal cancer, dysbiotic traits, etc.). In addition, the frequency (single vs repeated) of FMT administration, should be considered in the risk balance. The enforcement of the different statements can thus vary. Restrictive donor screening criteria ultimately lead to a small pool of eligible donors − 10% of possible donors, according to Dutch and Swiss estimates − as well as increased costs [12, 85]. In the Dutch study, a large proportion of screen failures were due to the asymptomatic carriage of bacteria with controversial pathogenicity (Dientamoeba fragilis and Blastocystis spp.) [85]. This raises difficult questions about screening strategies, safety, and the costs we are willing to accept to achieve said safety.
Despite the lack of comparative studies, the response rate of FMT in Clostridioides difficile infection was better in studies in which donor faeces were processed within 6 hours of defecation compared with those in which an interval of up to 48 hours was allowed. Therefore, we recommend that fresh stool should be used within 6 hours of defecation, and the storage and preparation of stool should be as brief as possible (statements 3.1 and 3.2) (supplementary table S7).
Initial recommendations encouraged the transplantation of a minimum weight of 50 g of stool because higher relapse rates of Clostridioides difficile infection (up to 4 times higher) were observed with lower amounts [11, 13, 86, 87]. Newer data indicate that 30 g or even 25 g could suffice [88, 89]. Following the European consensus, statement 3.3 was made [27]. However, stool weight is an imperfect measure of microbiota quantity [90]. This could partially explain the divergent study results. The stool amount also depends on the modality of administration [87]. The above-mentioned stool weights are applicable for colonoscopy only. These studies were performed on patients with Clostridioides difficile infection; therefore, our statement is only applicable in this clinical context. The optimal FMT stool weight for recipients with UC has still not been defined.
Following previously published consensus reports and considering the absence of new relevant data, the expert panel made statements 3.4 to 3.6 [11, 13, 26].
Frozen and fresh faecal suspensions are equally effective for the treatment of Clostridioides difficile infection [89, 91, 92]. However, frozen samples have some advantages over fresh samples: safety (allows for donor retesting and sample quarantine for possible incubating viral infections) and availability (the sample does not need to be used within 6 hours) [93].
Frozen samples can be stored at −20 °C for up to 30 days, but long-term storage should be performed at −80 °C [11, 13, 26]. Two RCTs have shown similar efficacy for the treatment of Clostridioides difficile infection between lyophilised products and fresh or frozen faecal products [94, 95].
According to these data, statement 3.7 was made.
Both anaerobically and aerobically prepared stool samples are effective for the treatment of Clostridioides difficile infection. However, it is possible that in other disorders, such as IBS and IBD, in which the anaerobic bacteria content of the microbiota is reduced, the preparation method is relevant for therapeutic success [27].
Bowel preparation is essential before any colonoscopy, including colonoscopy for FMT. It is unknown whether bowel lavage increases the clinical efficacy of Clostridioides difficile infection treatment. However, bowel lavage could help eliminate C. difficile toxins, spores, vegetative cells, and residual antibiotics, and it could facilitate the engraftment of the transplanted microorganisms [96]. This benefit would be expected to be seen independently from the means of administration. A recent trial showed improved response outcomes for Clostridioides difficile infection following oral capsule FMT administration with prior bowel preparation compared with the outcomes of prior studies with capsule administration without bowel preparation [97]. In a recent meta-analysis, poor bowel preparation was associated with a significantly increased risk of failure after FMT [98]. Therefore following current consensus guidelines, we recommend performing bowel preparation regardless of the FMT application method (statement 4.1, table 8) [13, 27, 65]. Prior intestinal cleansing could also have benefits for patients with ulcerative colitis, but robust data are lacking [99].
Because antibiotics may adversely affect the FMT material, most studies have implemented a washout period between antibiotic regimen completion and FMT administration. The duration of the washout varied greatly between study protocols and was never specifically compared. On the other hand, the first-line treatment for a Clostridioides difficile infection includes antibiotic treatment, and it is unclear whether pretreatment with antibiotics increases the effectiveness of FMT.
Antibiotic treatment for Clostridioides difficile infection should be administered before FMT because outcomes are worse with FMT alone, particularly for severe Clostridioides difficile infection [100].
Interestingly, one study showed that antibiotic pretreatment could also be beneficial when FMT was administered in patients with ulcerative colitis without Clostridioides difficile infection [101].
Consensus guidelines recommend stopping antibiotic treatment between 24 and 48 hours before FMT [13, 27]. Our panel of experts recommends stopping antibiotic use 48 hours prior to FMT. A longer washout period of 4 days may be reasonable for vancomycin because inhibitory concentrations can remain in stool for 4 to 5 days after suspending therapy [102]. Therefore, statement 4.2 was rephrased for more flexibility depending on the antibiotic treatment.
FMT can be administered via upper gastrointestinal routes (through gastroscope, nasojejunal tube, or oral capsule) or lower gastrointestinal routes (through colonoscopy, sigmoidoscopy, or retention enema). Supplementary table S9 summarises the expert statements on this topic.
Lower gastrointestinal route
FMT administration via colonoscopy is a clearly established method in Clostridioides difficile infection [1, 103]. According to the Europe-wide survey that took place in FMT centres in 2020, most centres preferred colonoscopy as the FMT delivery method [104]. Following all recent consensuses, our expert panel stated that when delivered through colonoscopy, the stool should preferably be administered in the right colon to increase the retention time (statement 5.1) [27, 65, 105]. However, in cases of severe colitis, the faecal suspension could be administered in the left colon for safety reasons.
Last year, a published meta-analysis concluded that Clostridioides difficile infection cure rates with colonoscopy-administered FMT were superior to those of FMT administered via nasogastric tube or enema, whereas the cure rates with capsule FMT were comparable to those of colonoscopy-administered FMT [106].
Independent of the route of administration, the cure rate of Clostridioides difficile infection after FMT is higher with repeated FMT than with a single administration. This is particularly true for enema-administered FMT, for which the response rises from 56% to 92% [87]. Enemas can be a good alternative to colonoscopy because of their ease of administration and reduced invasiveness, but they need to be repeated to achieve similar high cure rates of Clostridioides difficile infection to those for colonoscopy [107, 108]. To increase the retention time, previous consensus and our expert panel recommend that the patient should retain the stool for at least 30 minutes after the infusion while maintaining a supine position (statement 5.3) [27, 65]. Failed retention contributes to response failure, and we encourage a careful selection of eligible patients with a good understanding of the instructions and preserved continence.
Upper gastrointestinal route
Multiple RCTs and meta-analyses support the use of oral capsule FMT as an effective treatment for Clostridioides difficile infection, reporting similar cure rates compared to FMT via colonoscopy [97, 106, 109].
This justifies statement 5.4.
FMT administration via nasogastric tube (NGT) is more controversial.
Its efficiency in Clostridioides difficile infection has been demonstrated, and it could be more appealing because it is less invasive than colonoscopy, especially in patients with an inflamed bowel [2, 110, 111].
However, a review article and a recent meta-analysis showed that NGT FMT had inferior efficacy compared with colonoscopy [106, 112]. Furthermore, it was associated with more complications (regurgitations, vomiting, and broncho-aspiration) [113]. Additionally, from the patient’s perspective, it seems to be the most unappealing application route [114]. Considering this information, our expert panel favours other ways of administration when possible.
If FMT is administered with NGT, preventive measures should be implemented to minimise risks, such as maintaining a 45° upright position during the 4 hours following the delivery (statement 5.2) [27, 113].
A question that remains unanswered regarding upper gastrointestinal administration FMT is what impact gastric acidity has and how it influences the engraftment of transplanted microorganisms [105, 115]
The above data refer to FMT in Clostridioides difficile infection. In patients with ulcerative colitis, the same modalities of administration − repeated enemas with and without initial colonoscopy and oral capsules − have been studied and have shown efficacy [39–41, 43, 44]. With nasoduodenal tube administration, more disease improvement was observed in the FMT group compared with the placebo group, but this difference was not statistically significant, possibly because the study population was too small [42]. In the absence of head-to-head trials, we cannot easily compare the efficacy of each modality of administration.
In conclusion, the route of FMT application, regardless of its indication, should be guided by the complication risk of each patient and local expertise.
In severe Clostridioides difficile infection, repetition of faecal infusion has shown better results for inducing clinical remission compared with a single administration [27, 116, 117].
In ulcerative colitis, repeated FMTs have been reported to increase the success rate, but the optimal frequency remains to be determined [27].
In ulcerative colitis, it is not known whether individual-donor protocols and pooled multi-donor protocols have different impacts on the effectiveness of the FMT, as these strategies have not been compared head-to-head. However, a super donor phenomenon has been suggested in two studies, in which an increased response was observed in patients who received stool from a particular donor [40,43]. This supports the hypothesis that FMT efficacy could be improved by carefully selecting donors, but the exact selection criteria are unknown [118].
In chronic pouchitis, multiple studies have been performed to assess the response to FMT. Interestingly, only one multi-donor FMT study showed a statistically significant remission rate [119]. By contrast, studies that used a single donor’s stool have not shown results in favour of FMT [120]. Other parameters also differed between the studies (delivery method and administration frequency), making it difficult to draw firm conclusions.
Multi-donor FMTs have the disadvantage of complexifying pharmacovigilance in cases of adverse events, raising safety concerns.
Overall, FMT is a safe procedure, and our expert panel made the statements summarised in supplementary table S12 [121].
It is important to distinguish the risks attributable to the delivery method, such as perforation or aspiration risk, from those attributable to FMT itself.
Most FMT adverse events are mild and self-limiting, and they disappear within a few days. They consist of fever, abdominal discomfort (cramps, bloating, and flatulence), and changes in stool consistency (diarrhoea and constipation) [122–124].
According to a systematic review of the FMT studies published over the past 20 years, the most frequently reported gastrointestinal FMT-related adverse events include diarrhoea (in 10% of cases), abdominal discomfort, pain, or cramping (in 7% of cases), nausea or vomiting (in 3% of cases), and flatulence (in 3% of cases) [124]. Severe adverse events were reported in 1.4% of patients who underwent FMT. Interestingly, all the FMT-related severe adverse events occurred in the subgroup of patients with mucosal barrier injuries. Over the past 20 years, five FMT-related deaths (out of a total of 5688 FMT administrations) were declared. Four were a consequence of aspiration (one during colonoscopy sedation and three after inhalation of the gastroscopy-administered faecal suspension). The remaining FMT-related death was due to resistant E. coli bacteraemia. Recent systematic reviews have shown that FMT treatment via the upper gastrointestinal route was associated with a higher incidence of adverse events and severe adverse events [122, 124]. This can be partially explained by the known increased aspiration risk, but unspecific adverse events, such as abdominal discomfort, were described more frequently [122, 125].
The risk of infectious complications after FMT due to pathogen transfer was addressed earlier in this article, and it can be minimised by vigorous screening [65]. As was the case when the SARS-CoV-2 pandemic began, it is important to continue adapting procedures with the arrival of new pathogens [74]. Recently, the FDA issued a safety alert regarding the use of FMT during the current monkeypox outbreak, emphasising the need to stay updated and flexible [126].
Long-term adverse events are more difficult to determine. Long-term donor/recipient traceability and centralised databases are valuable in addressing the long-term safety concerns of FMT [104]. Many concerns still exist regarding the risk of transmission of non-infectious diseases, such as metabolic diseases (e.g. obesity), immune-mediated diseases, and procarcinogenic bacteria [127, 128]. A long-term safety study with a mean follow-up of over 1 year reported the development of new disorders after FMT (neuropathy, Sjögren’s disease, idiopathic thrombopenic purpura, and rheumatoid arthritis) but was not able to determine whether this was associated with FMT [129]. A recent cohort study included 1000 patients with more than 1 year follow-up after FMT; the results did not show an increased risk of immune-mediated disease (rheumatoid arthritis, psoriasis, or IBD), irritable bowel syndrome, diabetes, hypertension, or stroke in patients treated with FMT compared with patients treated with antibiotics [130]. However, a slightly elevated risk of myocardial infarctions was observed in the FMT group. Furthermore, confounding bias was likely because the patients with Clostridioides difficile infection treated with FMT tended to have a higher Charlson comorbidity score and thus might have had a different baseline cardiovascular profile than their counterparts in the control group.
Several studies have suggested worsening IBD activity following FMT, motivating meta-analyses [38, 131]; according to high-quality studies and RCTs, the risk of IBD activity worsening is 4.6%. This is considered a marginal risk and may also reflect the natural course of IBD.
Most long-term safety data concern FMT for Clostridioides difficile infection because it is a longer established indication.
The safety profile of FMT for ulcerative colitis seems to be similar to that for Clostridioides difficile infection, as the same adverse events have been reported [43, 48]. Additionally, rectal abscesses were observed after infusion of both faeces and placebo enemas [40]. This could be associated with the administration method or IBD itself.
The current article summarises the position of experts in gastroenterology, which is based on current guidelines, literature review, and clinical expertise. This article is not a systematic review, and grey literature may have been omitted.
Currently, robust evidence supports the use of FMT for Clostridioides difficile infection. FMT can also be effective in ulcerative colitis and should be considered in selected patients who are refractory to standard therapies. FMT can only be offered off-label to these patients at the moment. This paper highlights the need for updated regulations to make FMT more accessible to patients who could benefit from it, preventing the use of do-it-yourself FMTs and exposure to significant risks. We hope that the expert statements detailed in this article will serve as a framework for the standardised use of FMT in Switzerland.
FMT is generally well-tolerated and safe. Extensive donor screening is necessary to limit infectious and non-infectious disease transmission. The traceability of donors, an important factor to improve safety, can be offered by specialised FMT centres.
FMT administration via the lower gastrointestinal tract seems to be the optimal administration method, with fewer adverse events, but the selected route should ultimately be based on local expertise, patient characteristics, and indication. With the expected increase in FMT indications, transitioning to treatment modalities other than colonoscopy, such as oral capsules, could be necessary to improve logistics. It is important to keep in mind that most FMT studies have focused on Clostridioides difficile infection, and their findings and recommendations should not be generalised to emerging indications. This refers, for example, to the stool amount and the route and frequency of administration as well as pre-FMT preparation (bowel preparation and antibiotic treatment).
Many questions remain unanswered, particularly regarding the determination and selection of donors with the most adequate microbiota profile as well as the prediction of responses in the recipients.
This research received no specific grant from any funding agency.
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflict of interest related to the content of this manuscript was disclosed.
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The appendix is available in the pdf version of the article.