Microbiota-Based Therapeutics as New Standard-of-Care Treatment for Recurrent Clostridioides difficile Infection Open Access

Clostridioides difficile (C. difficile) is a gram-positive, spore-forming bacterium known for its role in causing infectious diarrhea, particularly among patients recently treated with antibiotics [1, 2]. C. difficile infection (CDI) stands as the most prevalent healthcare-associated infectious disease [3], leading to extended inpatient care and increased mortality rates [4]. While the European Center for Disease Prevention and Control (ECDC) estimates the overall CDI mortality rate at 4.1% (Annual Epidemiological Report for 2016–2017), hospitalized patients with CDI face mortality rates of up to 28% [5]. In Germany, although CDI incidence has been decreasing since 2015, the severity of individual cases has remained unaltered [6].

Standard treatment commonly involves antibiotic therapy, such as fidaxomicin or oral vancomycin, for an initial CDI episode [7, 8] (Fig. 1). However, a substantial challenge in CDI management is recurrence. It is estimated that over 35% of patients treated for their first CDI episode will experience a recurrent CDI (rCDI), and roughly 65% of those with an initial rCDI will undergo subsequent recurrences [3, 9]. Vulnerable populations, including older patients (>65 years old), individuals with immunodeficiencies, renal insufficiency, ongoing antibiotic treatment, or oncological diseases, are at higher risk. rCDI often results in hospitalization and, in severe cases, can lead to sepsis, colectomy, or even death [10, 11]. Moreover, the economic impact of rCDI is substantial, with per-patient per-year rCDI-attributable direct medical costs ranging from USD 67,837 to USD 82,268 in the USA [12]. Against this background, international experts emphasize the urgent need for enhanced strategies to prevent and manage rCDI [13].

Various strategies have emerged to mitigate the challenge of rCDI (Fig. 1). One successful approach is the administration of bezlotoxumab (ZINPLAVA™), a monoclonal antibody targeting toxin B. Administered as a single treatment after appropriate antibiotic therapy for CDI, bezlotoxumab has been shown to reduce the recurrence rate by around 10–15%. A recent meta-analysis revealed that patients receiving bezlotoxumab exhibited a pooled rCDI rate of 15.8% (95% CI: 14–17.8%), while the standard-of-care (SOC) group had a rate of 28.9% (95% CI: 24–34.4%). Consequently, bezlotoxumab significantly diminished the risk of rCDI compared to SOC, with a relative risk of 0.57 (95% CI: 0.45–0.72, I² = 16%). However, it is important to note that the administration of bezlotoxumab is costly and might not be feasible in all healthcare settings due to its requirement for intravenous administration.

Promising strategies address the core issue of CDI – antibiotic-induced dysbiosis. While probiotics lack sufficient supporting data, fecal microbiota transplantation (FMT) has demonstrated its potent ability to reset a healthy microbiome composition. FMT, endorsed as a highly effective therapeutic option for patients with rCDI, entails transferring fecal material from a healthy donor into the recipient’s gastrointestinal tract. This process aims to reinstate a diverse and healthy gut microbiota, thereby combating C. difficile overgrowth and reducing the likelihood of recurrence. In this review, considering the medico-legal challenges associated with classical FMT, we discuss the current knowledge about the potential of probiotics, classical FMT, and the two new commercial microbiota-based therapeutics, RBX2660 (REBYOTA™) and SER-109 (VOWST™), in preventing rCDI.

rCDI is defined as the recurrence of symptoms accompanied by a positive test for C. difficile toxin within 8 weeks of the preceding CDI episode [14]. The reported incidence of rCDI ranges between 15% and 20% [15, 16]. This variability is attributed to the necessity of considering the specific patient population from which the data were gathered. Patients with significant comorbidities, especially those with immunodeficiencies, individuals over the age of 65, and those requiring repeated inpatient care, bear a notably higher risk of rCDI, with some studies showing rates of up to 50% [17]. Once a second episode of CDI occurs, approximately 50% of patients go on to experience three or more recurrences. Patients with rCDI suffer from more severe disease, are predisposed to recurrent admissions to healthcare facilities, and face an elevated risk of developing sepsis (with up to 43% of patients experiencing three or more recurrences) [9, 15, 16]. Consequently, the identification of effective and safe secondary prophylaxis strategies is of paramount importance to reduce both morbidity and mortality.

Current guidelines recommend the use of fidaxomicin as the SOC in patients at high risk of rCDI [18]. However, there is currently no recommended additional treatment to further diminish the risk of rCDI.

However, the use of probiotics as a practical approach to mitigate rCDI is widespread, despite being associated with a low level of evidence. Only a few randomized controlled trials have been conducted, all featuring small sample sizes [19‒22]. In one of these studies, 124 patients diagnosed with either initial or rCDI were randomly assigned to receive either Saccharomyces boulardii (S. boulardii) CNCM I-745 or a placebo for a span of 28 days [19]. The group receiving S. boulardii exhibited fewer recurrences in comparison to the placebo-treated group. It is noteworthy, however, that the therapeutic impact of S. boulardii was statistically significant solely within the subgroup of patients with at least one prior CDI episode (26.3 vs. 44.8%, p = 0.04). Nevertheless, this outcome could serve as a compelling indicator of S. boulardii’s potential to reinstate the microbiome disrupted by antibiotics, thereby leading to an augmentation in microbial diversity. This phenomenon has been observed in both animal models and human studies [23, 24].

In another study, a cohort of 168 patients with rCDI was treated with one of three distinct antibiotic regimens – high-dose vancomycin (2 g/d), low-dose vancomycin (500 mg/d), or metronidazole (1 g/d) – in combination with either S. boulardii (1 g/d) or a placebo, encompassing a continuous 28-day treatment regimen [20]. Notably, a remarkable reduction in recurrent infections emerged among patients who underwent high-dose vancomycin as the initial regimen, succeeded by S. boulardii (16.7%). This result stood in stark contrast to those treated with high-dose vancomycin followed by placebo (50%, p = 0.05) for the same duration.

Another investigation encompassed a cohort of 20 patients experiencing rCDI, defined by a positive C. diff toxin assay, a minimum of three loose stools per day for at least 2 days, and a prior episode of CDI within the past 2 months [21]. All patients were administered metronidazole for a duration of 10 days, with 11 individuals receiving an additional dose of Lactobacillus plantarum 299v once per day (5 × 10¹⁰ cfu/d) for 38 days. The remaining 9 patients were administered a placebo. The initial response displayed no discernible differences. While a trend toward fewer recurrences emerged in the Lactobacillus group (4 out of 11), as opposed to the placebo group (6 out of 9), the findings did not attain statistical significance.

In 2017, a probiotic mixture comprising Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, Bifidobacterium lactis Bi-07, and Bifidobacterium lactis Bl-04 was administered to 31 patients with an initial mild to moderate CDI [22]. This probiotic capsule, as well as a placebo, was taken once daily over a period of 4 weeks. While patients receiving the probiotic capsules displayed significantly improved infection duration and diarrhea severity, there was no significant difference observed in terms of recurrence (13/15 in the probiotic group and 15/16 in the placebo group).

Given the mixed results from the existing small-scale studies, further clinical trials are necessary to draw definitive conclusions regarding the efficacy and safety of probiotics in preventing rCDI. Since the conduction of the two aforementioned trials several years ago, no more phase 3 trial has been performed concerning this topic.

However, also with regard to probiotics, the consideration of potential adverse events remains crucial. In this context, a randomized, double-blind, placebo-controlled trial that examined the use of probiotics to prevent predicted severe pancreatitis identified a link between probiotic usage and increased mortality [25]. It is not currently possible to generalize that the use of various probiotics is universally safe for every individual [26]. Furthermore, recent findings indicate that the use of probiotics subsequent to antibiotic treatment can lead to a delay in microbiome reconstitution. In contrast, the application of autologous FMT demonstrated a positive influence on the mucosal microbiome [27].

As far back as 1958, Eiseman and colleagues documented the successful treatment of 4 cases of pseudomembranous enterocolitis that were otherwise resistant to therapy through the application of a fecal enema with feces obtained from healthy donors. This innovative approach led to rapid symptom recovery among the four patients [28]. Subsequent to this pioneering work, FMT has evolved into a widely accepted therapeutic rescue option for patients with rCDI. A pivotal contribution to this evolution was a seminal paper published by van Nood and collaborators in the New England Journal of Medicine in 2013 [29]. This study, designed to assess the absence of C. difficile-associated diarrhea by week 10, involved randomly assigning patients to one of three therapeutic arms: initiation with oral vancomycin treatment (500 mg four times daily for 4 days), succeeded by bowel lavage and the infusion of a donor feces solution through a nasoduodenal tube; a standard vancomycin regimen (500 mg orally 4 times daily for 14 days); or a standard vancomycin regimen combined with bowel lavage. The study was prematurely terminated following an interim analysis due to the impressive findings. Among the 16 patients who received donor feces, 13 (81%) experienced complete resolution of C. difficile-associated diarrhea after the initial application. Of the remaining 3 patients, 2 achieved cessation of diarrhea following a second duodenal feces infusion from a different donor. This approach markedly outperformed the other two treatment arms, with only 4 out of 13 patients (31%) in the vancomycin-alone group and 3 out of 13 patients (23%) in the vancomycin with bowel lavage group achieving the primary outcome (p < 0.001 for both comparisons with the feces group). It is noteworthy that apart from mild diarrhea and abdominal cramping in the feces infusion group on the day of the procedure, no substantial differences in adverse events were observed among the three study arms. Notably, in this study, FMT succeeded in reinstating a bacterial diversity closely resembling that of healthy donors. The procedure led to a reduction in the abundance of Proteobacteria while fostering an increase in Bacteroidetes species and distinct Clostridium clusters [29]. A subsequent randomized controlled trial demonstrated that employing FMT via colonoscopy, as opposed to using a nasoduodenal tube for feces infusion, also yielded superior results in treating rCDI, achieving a success rate of 90% in comparison to a vancomycin regimen [30].

While FMT through colonoscopy is now established and often the preferred route of administration, compelling evidence can be deduced from a recent systematic review and meta-analysis comprising 12 case series and three randomized controlled trials, which encompassed a total of 763 patients. This evidence indicates that oral FMT capsules demonstrate comparable efficacy to colonoscopy and are not inferior in treating multiple recurrences of CDI [31]. The overall efficacy of oral FMT stood at 82%, regardless of whether frozen or lyophilized stool was employed for capsule preparation [31]. Another recent network meta-analysis further supports the use of frozen or lyophilized stool for FMT. While there appears to be a marginal decrease in relative efficacy (fresh FMT: 93% efficacy [95% CI: 0.913 to 0.999]; frozen FMT: 88% efficacy [95% CI: 0.857 to 0.947]; lyophilized FMT: 83% efficacy [95% CI: 0.745 to 0.910]), this slight reduction seems to be outweighed by the accessibility and practicality of frozen or lyophilized preparations [32].

To date, multiple studies and meta-analyses have consistently demonstrated the superiority of FMT over vancomycin or fidaxomicin as a secure and effective therapeutic approach for rCDI [33, 34]. Generally, FMT has proven to be safe, with reported adverse events primarily comprising gastrointestinal side effects like loose stool, abdominal discomfort, or diarrhea. Such effects can manifest in up to 50% of patients and are typically transient or self-limiting. Regarding the administration route for FMT, a comprehensive meta-analysis encompassing 26 studies and involving 1,309 patients revealed that colonoscopy (cure rate 94.8% [CI: 92.4–96.8%]) outperforms enema (87.2% [CI: 83.4–90.5%]) or nasogastric tube (78.1% [CI: 71.6–84.1%]). Interestingly, colonoscopy and oral capsules demonstrated comparable efficacy (92.1% [CI: 88.6–95.0%]) [35].

Recently, an enhanced methodology for classical FMT, known as washed microbiota transplantation (WMT), has been developed [36]. This method involves an automatic filtration and washing process of the donated stool specimen. In a small study investigating patients with ulcerative colitis, where fever following FMT is expected to be more prevalent due to bacterial translocation across the ulcerated mucosal surface, the incidence rate of fever significantly decreased from 19.4% in manually prepared FMT to 2.7% in WMT, suggesting a more favorable safety profile [36]. A multicenter real-world cohort study in China, including CDI patients undergoing WMT, revealed a clinical cure rate of 90.7%. In this study, for most patients, FMT was delivered through an innovative route using a colonic transendoscopic enteral tube. This tube is introduced via a colonoscopy and can be secured in the colon using an endoclip, allowing for repeated FMT procedures [37].

However, the considerable effort and challenges associated with implementing FMT in a manner that ensures patient safety remain substantial [38]. As a result, despite its demonstrated superiority in treating rCDI, FMT has not yet become a routine treatment in most hospitals and practices. Regarding the number of FMT procedures in Germany, a recent study analyzing reports from the Institute for Hospital Remuneration (InEK), the Federal Statistical Office (DESTATIS), and hospital quality reports revealed that only 293 FMTs were coded annually by 175 different hospitals between 2016 and 2018. This was followed by a steady decline in subsequent years, with only 119 FMTs recorded in 2021 [39]. This decline is likely partly explained by COVID restrictions, which hindered stool donor recruitment.

National and international guidelines recommend FMT after experiencing two or more recurrences of CDI, provided suitable donors are available, along with facilities for processing and quarantine procedures in compliance with relevant laws [38, 40, 41]. In terms of medico-legal considerations, both FMT and microbiota-modulating interventions reside in a “gray area” within the European Union, giving rise to regulatory challenges for therapeutic implementation. Presently, the absence of European legislation has led to the regulation and classification of FMT on a national level. Across most European countries and within an international context, FMT is typically regarded as a medicinal product or its equivalent. Notably, Belgium and Italy encompass FMT under their national tissues and cell legislation. The Finnish legal framework designates FMT as a therapeutic intervention. In Austria, Denmark, and the Netherlands, the classification remains undecided or is treated on a case-by-case basis (refer to https://www.ema.europa.eu/en/documents/report/faecal-microbiota-transplantation-eu-horizon-scanning-report_en.pdf). This landscape should change by 2024, thanks to the draft for a binding regulation presented by the European Commission in 2022 (accessible via the following link: https://data.consilium.europa.eu/doc/document/ST-11396-2022-ADD-3/en/pdf).

Similar to other European countries, Germany classifies FMT as the administration of a drug or pharmaceutical product. Consequently, the use of FMT falls under the purview of the German Law on Pharmaceuticals (Arzneimittelgesetz [AMG] §2 Abs 1 Nr. 1 and Nr. 2a), and its production necessitates approval. Exceptions arise for medicinal products intended for individual therapeutic applications, wherein a medicinal product is manufactured under the direct professional responsibility of a treating physician for use in a specific patient (AMG, §13, 2b). Consequently, the preparing physician is required to personally administer the preparations; broader distribution or dispatch of such preparations is prohibited.

In accordance with the good manufacturing practice criteria delineated in §13 AMG, clinical trials involving investigational medicinal products with microbiota-modulating properties require manufacturing authorization. This authorization process operates under the stringent oversight of competent state authorities.

Regarding the selection of healthy stool donors for FMT preparations, the German Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte [BfArM]) mandates adherence to specific blood and stool examinations. Furthermore, the institute has established a set of exclusion criteria encompassing preexisting medical conditions, ongoing medical treatments, travel history, social factors, and family medical history. These prerequisites were initially issued in 2019 and lastly updated in 2023 (refer to https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RI/2019/RI-FMT.html and Table 1).

The BfArM’s stipulated requirements align with a global consensus on donor preselection procedures involving questionnaires, medical histories, and thorough stool and blood examinations [38]. Additionally, the implementation of appropriate quarantine procedures serves to close the “diagnostic gap”. This involves conducting a second donor screening a few weeks after an initially unremarkable screening. During the incubation period, pathogen concentrations might initially fall below the technical detection threshold, potentially becoming clinically apparent later. Consequently, donor stool acquired post-initial screening necessitates proper processing, preservation in a “quarantine” state, and can only be employed for an intervention if the second screening is conducted without any exclusion criteria [42].

Given these prerequisites, the task of identifying and maintaining a stable donor cohort for FMT becomes extremely complex and time-intensive. For instance, the validation of specific laboratory tests in accordance with good manufacturing practice might require evaluation within external reference laboratories. Our own experiences with the recruitment of a stool donor pool for a randomized controlled trial examining FMT for the treatment of ulcerative colitis revealed that only 7 out of 81 potential candidates met the criteria for suitability as donors after review of their questionnaires and completion of the two-step blood and stool examinations [43].

This, in turn, underscores the need to establish suitable laboratory conditions for a “stool bank”. These conditions encompass essential safety precautions for the storage, release, and utilization of FMT preparations. This meticulous approach significantly enhances patient safety and has been widely disseminated at both national and international consensus conferences [38]. However, this comprehensive approach does have a drawback in that it restricts the availability of FMT, particularly for individual therapeutic applications. This is due to the necessity of subjecting potential individual donors to a second round of testing, thereby introducing a time delay before FMT can be conducted.

In the processing and preparation of a stool suspension for endoscopic FMT or for the formulation of FMT capsules, we and most colleagues adhere to international consensus guidelines [38, 44, 45]. Specifically, stool donations are sourced from rigorously tested donors, as outlined in the BfArM prerequisites. In detail, 100 g of stool are mixed with 200 mL of 0.9% NaCl, homogenized, and filtered to eliminate coarse particles. The resulting stool suspension can then be administered through various endoscopic procedures. In the production of FMT capsules, this suspension can be encapsulated within enteric-coated hard capsules and subsequently stored at deep-freeze temperatures.

Several countries have already implemented their own national stool banks. Within the European Union, for instance, the Netherlands Donor Feces Bank offers standardized, ready-to-use donor fecal suspensions for FMT to address rCDI. The Dutch experiences show that the establishment of centralized stool banks, complemented by a multidisciplinary expert team, leads to the effective, appropriate, and safe application of FMT for rCDI. Nonetheless, also the Dutch colleagues encountered challenges when it came to selecting suitable healthy stool donors. Out of 871 potential volunteers who initially registered, only 16 ultimately transitioned into active donors. Moreover, within this group, nine donors either ceased participation or were excluded after an average donation period of approximately 6 months [42].

In the USA, the nonprofit organization OpenBiome (https://openbiome.org) operates a public stool bank which provides frozen preparations of screened human stool for use in FMT treatments for rCDI. The frozen stool preparation is shipped within 1–2 business days on dry ice in a temperature-monitored container and is suitable for lower (colonoscopy, sigmoidoscopy, or enema) or upper delivery (nasoenteric/nasogastric tube or esophago-gastro-duodenoscopy).

Another limitation is the lack of systematic reimbursement for FMT interventions. Within Germany, health insurance providers do not offer compensation for FMT, regardless of whether it is administered in an outpatient or inpatient setting. This has to be criticized in light of the considerable individual disease burden attributed to rCDI and the substantial body of evidence supporting FMT, especially when compared to alternative treatment options [46, 47].

Considering the administrative complexities involved in managing a local or national stool bank to meet regulatory demands, the availability of ready-to-prescribe formulations of live biotherapeutic products (LBPs) offering a comparable efficacy to FMT will simplify the integration of microbiota-based treatments for rCDI within daily clinical practice.

In 2022, the US Food and Drug Administration (FDA) granted approval to RBX2660, marketed as REBYOTA™, as the first LBP for preventing the recurrence of CDI in adults who have undergone standard antibiotic treatment for rCDI. RBX2660 consists of a broad consortium of live microbes prepared from human stool and is administered as enema. This approval was underpinned by findings from the phase III PUNCH CD3 trial, a randomized, double-blind, placebo-controlled study involving 267 adult patients with one or more CDI recurrences [48].

The trial demonstrated the efficacy of RBX2660, with a success rate (defined as the absence of C. difficile-associated diarrhea within 8 weeks of study treatment) of 70.6%, as compared to 57.5% for the placebo group, yielding a treatment effect of 13.1%. Interestingly, over 90% of participants who achieved treatment success at 8 weeks maintained this response for 6 months, irrespective of whether they were administered RBX2660 or placebo after a single application.

RBX2660 exhibited a favorable safety profile, with manageable treatment-emergent adverse events, predominantly mild gastrointestinal complaints, more frequently reported in the RBX2660 group. However, it is noteworthy that REBYOTA™ necessitates specialized handling through specialty pharmacies and distributors, requiring refrigeration and use within 5 days by healthcare facilities. Additionally, the mode of administration as an enema may pose logistical challenges for some facilities, and it may not be the preferred route of administration for most patients.

Oral administration is a distinct advantage of the second LBP, SER-109 (VOWST™), which received FDA approval on April 26th, 2023. SER-109 consists of purified encapsulated donor Firmicutes spores. Anticipated to be available from June 2023, the treatment course is estimated to cost 17,500 US dollars. In the respective phase III ECOSPOR III trial, a randomized, double-blind, placebo-controlled study, 182 patients with three or more episodes of CDI received SER-109 or placebo (four capsules daily for 3 days) following standard-of-care antibiotic treatment [49]. Notably, CDI recurrence within 8 weeks after treatment was 12% in the SER-109 group compared to 40% in the placebo group.

Once again, mild to moderate gastrointestinal adverse events were observed, occurring with similar frequency in both study groups. An interesting finding is that the introduced SER-109 species were detectable in treated patients a week after application and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination.

The availability of these two LBPs beyond the USA remains uncertain at present. Ongoing clinical trials are investigating additional candidates for microbiota-based therapies. These explore innovative approaches, such as bacteria cultured in vitro (NTCD-M3) or a defined combination of 8 bacterial strains (VE303), all tailored for oral administration [50, 51].

Depending on the administration route and the utilization of fresh or frozen stool, FMT establishes a remarkable benchmark with its outstanding efficacy of 80–90% in preventing rCDI. As shown in Table 2, both bezlotoxumab and SER-109 (VOWST™) achieve this high standard, with recurrence rates as low as 16.5% and 12.4%, respectively. In contrast, RBX2660 (REBYOTA™) appears to perform slightly less favorably in an indirect comparison, potentially attributed to its enema-based delivery – a modality that also exhibits reduced efficacy in classical FMT.

Indirect comparisons among these studies are challenging due to variations in control or placebo arms. In the pioneering FMT trial by van Nood et al., the control arm (involving only bowel lavage) received a standard vancomycin regimen before (500 mg orally 4 times daily for 14 days). In the PUNCH CD3 trial for RBX2660, both placebo and intervention groups received a standard antibiotic pretreatment, mainly vancomycin (mostly) or occasionally fidaxomicin (less than 10%) [29, 48]. In the ECOSPOR III trial for SER-109, around 70% of participants underwent vancomycin pretreatment, while approximately 30% received fidaxomicin pretreatment [49]. Considering the generally lower recurrence rates following fidaxomicin treatment, the recurrence rates in the control groups, and therefore the numbers needed to treat (NNT), are hardly comparable. Despite this limitation, the NNTs for all approved rCDI therapies – ranging from 4 to 10 – remain favorable; however, FMT with a NNT of 2 seems be superior. Treatment selection hinges on local expertise and availability. While FMT is confined to specialized centers in most global regions, bezlotoxumab is generally accessible through prescription. However, the availability of intravenous infusion facilities for bezlotoxumab may be constrained in outpatient settings, and the treatment carries substantial costs. An advantage of bezlotoxumab lies in its defined and reproducible structure. Similarly, SER-109 stands out as a well-defined and reproducible oral treatment, characterized by high effectiveness, and available on prescription, at least in the USA. Despite shared high costs, SER-109 possesses the potential to become a treatment of choice.

Over the past decade, classical FMT has emerged as the preferred therapeutic approach for rCDI, with a success rate of up to 90% in preventing CDI recurrence. Nonetheless, the intricate process of recruiting potential stool donors, coupled with the costly screening procedures – often not covered by health insurance companies in most countries – alongside the complexities of medico-legal uncertainties, collectively hinder its widespread integration into clinical routine.

In the USA, the recent FDA approval of two LBPs holds the potential to bridge the gap in the availability of microbiota-based therapies for rCDI. The evolution of these new treatments hinges on their acceptance among patients and healthcare providers, taking into account the challenges associated with handling live bacteria and the enema-based application of RBX2660, as well as the notable costs related to SER-109.

Simultaneously, the establishment of national stool banks that offer on-demand stool preparations for clinical practitioners to address rCDI, complemented by expert guidance, emerges as a highly desirable solution. Positive experiences with national stool banks exist in the Netherlands and in the USA, the nonprofit organization OpenBiome operates a public stool bank, providing FMT preparations for rCDI treatment. Unfortunately, in numerous European countries, the absence of easily accessible stool banks is due to national regulations and the classification of FMT as a pharmaceutical product.

The authors have no conflicts of interest to declare.

All authors are employed at Jena University Hospital, Jena, Germany. No external funding concerning this review article has to be reported. FMT research at Jena University Hospital is supported by the Federal Ministry of Education and Research (German: Bundesministerium für Bildung und Forschung, BMBF; Förderkennzeichen: 01KG1814; Andreas Stallmach).

Conception and design: Johannes Stallhofer. Acquisition and interpretation of data, drafting the work or reviewing it critically for important intellectual content, and final approval of the version to be published: Johannes Stallhofer, Arndt Steube, Katrin Katzer, and Andreas Stallmach.