ABSTRACT
As we advance our understanding of the gut microbiota, the implications of dysbiosis are becoming increasingly apparent. Fecal microbiota transplantation (FMT), a well-established procedure, is recognized for effectively treating recurrent Clostridioides difficile infection, prompting further investigation into its other possible clinical applications. Donor selection and screening are essential to ensure safety and efficacy. Product development and standardization, such as the US Food and Drug Administration–approved live biotherapeutic products Rebyota and Vowst, are helping efforts to evaluate FMT for other gastrointestinal and extraintestinal diseases. However, additional clinical trials are needed to support its use beyond recurrent C difficile infection.
The human gut microbiome is a complex and dynamic system that is susceptible to alterations from various factors; dysbiosis of this environment has clinical implications.
FMT is a safe and effective option for the treatment and prevention of recurrent or refractory C difficile infection.
Live biotherapeutic products facilitate standardized clinical application of microbiota restorative therapy.
Microbiota restorative therapy is investigational but promising for future applications beyond C difficile infections.
The human gut microbiome is a diverse ecosystem composed of trillions of microorganisms that support the function of the gastrointestinal, immune, and nervous systems.1 This microbiome is dynamic and subject to variability based on numerous individual and environmental factors.2 Dysbiosis, or disturbances in this complex microbiome, is associated with various gastrointestinal and extraintestinal disorders.2,3
Fecal microbiota transplantation (FMT), the transfer of fecal matter from a healthy donor into a recipient’s gastrointestinal tract, can correct dysbiosis by restoring a balanced microbiome. Treating recurrent Clostridioides (formerly Clostridium) difficile infection is the most successful therapeutic application of FMT, leading to questions about other potential applications.4
Donor criteria and methods used to obtain safe and effective fecal material for FMT have evolved considerably. Initially relying on individual donors, the process has advanced to include stool banks like OpenBiome and, more recently, US Food and Drug Administration (FDA)–approved live biotherapeutic products Rebyota and Vowst.5–7 This has facilitated a more standardized approach to the clinical and investigational use of FMT, furthering our understanding of the role a restored healthy microbiome plays in treating various diseases.
As we evaluate and compare current products and their future uses, it is crucial to understand the function of a healthy gut microbiome and the reason why FMT is effective.
IMPORTANCE OF THE GUT MICROBIOME
The gut microbiome is composed of a wide variety of bacteria, and an estimated 90% come from the phyla Firmicutes and Bacteroidetes.2 Studies evaluating healthy gut microbiomes have found them to be complex and diverse, with microbes encoding for enzymes and metabolites that aid in digestion and nutrition as well as impact maturation and function of the immune and nervous systems.1 The gut microbiome is also dynamic and varies between individuals due to factors such as age, genetics, diet, being breastfed as an infant, environment, socioeconomic status, antibiotic use, and previous infections.1,2,8
Whereas the microbiome encompasses both the microorganisms and their genetic material, the microbiota are the microorganisms present in a particular environment.9 When there is an imbalance in the gut microbiota, this dysbiosis can disrupt digestive and inflammatory functions by altering microbial composition and metabolite production.9 Several gastrointestinal diseases have been linked to dysbiosis, including C difficile infection, inflammatory bowel disease, irritable bowel syndrome, and celiac disease, along with other autoimmune, cardiovascular, metabolic, and neurologic conditions.10
Dysbiosis and the resulting microbial and metabolic dysfunctions can differ across different disease states.1 For example, in C difficile infections, alterations in bile acids and short-chain fatty acids have emerged as key contributors to its pathogenesis.11,12 Despite these associations, our understanding of the full impact of the gut microbiome remains incomplete, and it is unknown whether disease states are caused by dysbiosis or are the result of the disease state itself.
FMT IS NOT A NEW CONCEPT
The increased awareness of the gut microbiome’s importance has made FMT more widely known. However, its first documented use dates back to fourth century China, where a mixture of human fecal matter, known as yellow soup, was administered orally to patients as an effective treatment for those with severe diarrhea or food poisoning.13 The practice continued to be documented into the Ming dynasty during the 16th century to treat abdominal disease.
In 1958, Eiseman et al14 reported the successful use of FMT to treat pseudomembranous colitis in a 4-person case series. As the benefits of FMT gained recognition, its clinical implementation exposed a new array of challenges. At first, fecal samples were obtained from individual donors, with variable screening, preparation, and administration protocols. The FDA classified FMT as an investigational drug in 2012 due to a lack of product standardization. With this classification, an Investigational New Drug application must be completed before the drug can be used in humans, a process that can take months to years.15 After clinicians expressed concern about treatment delays, the FDA approved the use of FMT to treat C difficile infection without filing an application.
To expand clinical access to FMT, OpenBiome was established in early 2013 as a nonprofit stool bank.5 They consolidated the process of donor screening and FMT material preparation to improve safety, quality, and accessibility, and successfully provided their first FMT treatment by the end of the same year. As access to resources grew, so did potential clinical indications.
A RESTORED MICROBIOTA TREATS C DIFFICILE INFECTION
FMT is primarily known as a clinical breakthrough for effectively treating recurrent or refractory C difficile infection. One of the first randomized controlled trials in 2013 showed that providing FMT after an initial course of antibiotics resulted in an 81% cure rate in recurrent C difficile infection, compared with 31% for antibiotics alone.16 Subsequent studies have demonstrated comparable efficacy, and FMT is supported by the American Gastroenterological Association (AGA),17 American College of Gastroenterology,18 and meta-analysis data.19
The standard antibiotics used to treat C difficile infection, like vancomycin or fidaxomicin, target C difficile overgrowth but do not address the underlying dysbiosis.3,20 Studies have shown that C difficile infection is associated with alterations in microbiota composition, including a decrease in Bacteroides, Actinobacteria, Prevotella, and Bifidobacterium, and an increase in Proteobacteria, Lactobacillus, and Clostridium.21 The resulting dysbiosis can result in bile acid or short-chain fatty acid alterations.11,12
Gastrointestinal bile acids play a crucial role in C difficile spore germination. Primary bile acids (eg, cholic acid and chenodeoxycholic acid) promote spore germination, while secondary bile acids (eg, deoxycholate and lithocholate) inhibit C difficile germination and growth.11 Specific microbiota present in a healthy gut are needed to convert primary bile acids to secondary bile acids, a process mediated by 7 alpha-dehydroxylation.11 Healthy gut microbiota are also needed to produce short-chain fatty acids such as butyrate, which inhibits C difficile growth, promotes bile acid conversion, and supports immune modulation.12
Restoring the gut microbiota after completing standard antibiotic therapy addresses dysbiosis, which is why FMT is now the standard treatment for recurrent or refractory C difficile infection.19 Both the AGA17 and the American College of Gastroenterology18 recently updated their guidelines to recommend the use of FMT as an adjunctive treatment for select hospitalized adult patients with severe or fulminant C difficile infection that does not respond to standard antibiotic therapy. (It should be noted that the AGA17 supports the use of conventional FMT only, as opposed to live biotherapeutic products, in these patients.)
HOW FMT WORKS
Donor screening
Identifying suitable donors for FMT remains an area of uncertainty, and screening requirements may vary between institutions. However, the screening process has evolved into a rigorous, multistep evaluation to ensure safety and efficacy while minimizing adverse events. Many protocols start with questionnaires to determine who meets general inclusion or exclusion criteria (Table 1).4,22 This is followed by a wide array of serologic and stool testing (Table 2), which excludes a relatively large number of potential donors who are asymptomatic pathogen carriers.4,22 Once donors are deemed suitable, samples can be prepared for delivery.
Donor screening criteria
Serologic and stool screening for donor selection
Preparation and delivery
Prepared fecal samples can be either fresh or frozen. Randomized controlled trials and subsequent meta-analyses have shown no clinically significant difference between fresh or frozen FMT products in treating C difficile infection.4 This is a significant finding for the operation of stool banks because frozen FMT products reduce costs and the frequency of donor screening, while enhancing availability and distribution.23 Before undergoing FMT, the recipient ideally should abstain from antibiotics for 12 to 48 hours.
Delivery methods include upper-gastrointestinal approaches such as endoscopy, nasogastric tubes, or oral capsules, and lower-gastrointestinal approaches such as colonoscopy, enemas, or percutaneous endoscopic cecostomy.24 When comparing administration routes, efficacy and safety are the primary considerations, alongside cost and patient preference or convenience. The various administration routes have been debated, and previous meta-analysis studies suggest that the lower-gastrointestinal route is more effective for C difficile infection.19 Although all routes are generally deemed safe, options that are minimally invasive and can be self-administered, such as oral capsules and enemas, are particularly appealing. There is no established standard delivery method, so choice may vary depending on clinical presentation, availability, and patient or clinician preferences. Additional randomized controlled studies are needed to determine whether there is an optimal delivery method. Cleveland Clinic is currently conducting a prospective randomized controlled trial to compare the efficacy of Rebyota administered via colonoscopy vs enema to help clarify this topic.
Some studies also suggest administering loperamide 1 hour before FMT to help ensure retention of the transplanted fecal matter.4
Adverse events, safety, and limitations
FMT is generally considered a safe procedure but can be associated with adverse events, most commonly abdominal discomfort, bloating, nausea, and diarrhea.4 A systematic review of FMT from 2000 to 2020 noted adverse events in 19% of patients, with diarrhea in 10% and abdominal discomfort in 7%.25 The reported risk of microbiota-related severe adverse events was 0.99%, but all occurred in patients with a mucosal barrier injury.25 Further information and additional trials are necessary to evaluate the potential long-term adverse effects of FMT.
In 2019, concerns about FMT safety were raised when 2 patients who were immunocompromised developed extended-spectrum beta-lactamase–producing Escherichia coli infection after receiving FMT.26 Genomic sequencing later showed that both patients received stool from the same donor; in response, enhanced donor screening methods were put in place.
Subsequent studies showed FMT is effective and generally safe in patients who are immunocompromised.27,28 The AGA17 recommends the select use of FMT in adults who are mildly to moderately immunocompromised, and recommends against use in adults who are severely immunocompromised. Overall, this shows that the decision to use FMT in patients who are immunocompromised should be based on individual factors, weighing the potential benefits and risks, especially in those considered severely immunocompromised.
In addition to adverse events and safety concerns, potential limitations of FMT include the lack of clarity surrounding the optimal dosage for specific diseases or individuals, regulatory challenges related to clinical application and coverage, and uncertainties regarding long-term effects and outcomes.18,29
LIVE BIOTHERAPEUTIC PRODUCTS
In 2010, the FDA defined a new therapeutic class called live biotherapeutic products that refers to products that contain live organisms intended for preventing, treating, or curing disease in humans but are not vaccines.30 Although FDA approval of FMT and live biotherapeutic products to restore fecal microbiota is currently limited to therapeutic use for recurrent C difficile infection after antibiotic treatment, other potential clinical applications are being extensively investigated.30 Currently, 2 live biotherapeutic products have received FDA approval, and other investigational products are in development (Table 3).6,7,21,31,32
Live biotherapeutic products
Rebyota
Rebyota (fecal microbiota, live-jslm; formerly RBX2660) in November 2022 became the first live biotherapeutic product approved by the FDA for the prevention of recurrent C difficile infection in individuals 18 years or older.6,21 It is a rectal suspension administered as a single 150-mL enema, typically 24 to 72 hours after antibiotic therapy is completed.6 Rebyota includes a minimum of 1 × 105 colony-forming units (CFU) of Bacteroides per milliliter, and between 1 × 108 and 5 × 1010 CFU of total fecal microbes per milliliter from a single donor, ensuring a standardized formulation.6
The PUNCH (Microbiota Restoration Therapy for Recurrent Clostridium difficile–Associated Diarrhea) studies were 2 randomized, double-blind clinical trials and 3 open-label studies, with a total population of 978, conducted to evaluate efficacy and safety of Rebyota.33,34 The most recent trial—PUNCH CD3—was a phase 3, double-blind, placebo-controlled study that compared a single dose of Rebyota with placebo in patients 18 years or older who were previously treated with standard-of-care antibiotics and had 2 or more episodes of recurrent C difficile infection.34 Hierarchal Bayesian analysis revealed a 70.4% success rate for Rebyota vs 58.1% for placebo, an estimated 12.3% efficacy rate difference.34
Rebyota is generally considered safe and well tolerated, with treatment-emergent adverse events occurring in 66.4% of patients compared with 60.2% in the placebo group.33 The most commonly reported adverse events were mild gastrointestinal symptoms, with statistically significant differences observed only in abdominal pain, nausea, and flatulence.33
Vowst
Vowst (fecal microbiota spores, live-brpk; formerly SER-109) was the second live biotherapeutic product approved by the FDA, in April 2023, and the first approved for oral administration.7,21 Vowst is given as 4 capsules taken before the first meal of the day for 3 consecutive days, and each capsule contains 1 × 106 to 3 × 107 CFU of Firmicutes spores obtained from donors.7 It is administered 48 to 96 hours after completing antibiotic treatment, preceded by a single 296-mL dose of oral magnesium citrate the night before the first Vowst dose to minimize residual antibiotic effects.7
The 4 ECOSPOR (Randomized, Double Blind, Placebo Controlled, Parallel Group Study of SER 109 to Prevent Recurrent Clostridium difficile Infection) clinical trials, highlighted by the phase 3, double-blind, randomized, placebo-controlled ECOSPOR III trial,35 demonstrated that, in patients with 3 or more episodes of C difficile infection, the use of Vowst after standard antibiotic treatment was associated with an infection recurrence rate of 12% compared with 40% in the placebo group (relative risk 0.32, 95% confidence interval 0.18–0.58, P < .001 for a relative risk of < 1.0, P < .001 for a relative risk of < 0.833). A recent trial showed that Vowst is not only effective but also safe, with no deaths or serious treatment-emergent adverse events related to treatment, and reported adverse events were mild to moderate gastrointestinal symptoms.36
Investigational products
Additional live biotherapeutic products are being developed but have yet to receive FDA approval.
VE303 is an orally administered capsule composed of 8 × 109 CFUs (high dose) from 8 different strains of Clostridia manufactured from clonal cell banks.31 Unlike products that depend on donor stool, VE303 is produced from cultured bacteria, ensuring greater consistency and standardization in both production and clinical applications.31 A recent phase 2, randomized, double-blind, placebo-controlled, dose-ranging study showed C difficile infection recurrence rates of 13.8% (4 of 29) in the high-dose group, 37% (10 of 27) in the low-dose group, and 45.5% (10 of 22) in the placebo group (P = .006, high dose vs placebo).31
RBX7455 is an oral capsule developed by Rebiotix as another formulation of Rebyota.32 RBX7455 distinguishes itself from other live biotherapeutic products by its unique storage capabilities. Although initially stored at 2°C (36.5°F) to 8°C (46.4°F), it can be thawed to room temperature (23°C–27°C [73.4°F–81.6°F]) and remain stable, making it appropriate to self-administer in a home setting.32 An initial phase 1 study of 30 patients showed an overall 90% efficacy rate in preventing recurrent C difficile infection across 3 treatment groups with different dosing regimens.32
THE FUTURE OF FMT
Our improved understanding of a restored gut microbiome has opened the door to examine other therapeutic applications, but the use of FMT and live biotherapeutic products to treat diseases other than C difficile infection remains largely investigational. Research continues to assess potential applications across a range of conditions, including additional gastrointestinal issues, autoimmune disorders, neurologic and psychiatric conditions, and metabolic disorders (Table 4).8,29,37–41
Other potential applications for fecal microbiota transplantation
Microbiota restorative therapy shows the most encouraging results in treating irritable bowel syndrome and inflammatory bowel disease,29,40 and the AGA17 recommended further evaluation in clinical trials in its recent guidelines. Initial trials on inflammatory bowel disease in particular are promising. Patients with mild-to-moderate ulcerative colitis who received FMT were more likely to achieve remission induction than remission maintenance.17 Furthermore, aggregate data from 9 randomized controlled trials noted that those who received FMT were more likely to have clinical remission (32.8%) compared with control groups (16.3%; relative risk 1.95, 95% confidence interval 1.17–3.26), and the risk of serious adverse events remained low.17 However, there was significant variability in the administration route, number of treatments, and treatment duration,17 underscoring the need for additional trials to evaluate and establish the most optimal therapeutic delivery methods.
Using FMT to address disease states with limited therapeutic options or after failure of first-line treatments is increasingly compelling. A recent study of a small cohort of 5 patients with immune-related colitis that was refractory to both steroid and biologic anti-inflammatory therapy showed clinical improvement in 4 of the patients after FMT.41 Dysfunction in gut microbiota and its metabolites have been theorized as contributing factors of autoimmune conditions, and FMT has shown positive results in ongoing clinical studies.8 FMT is also gaining recognition as a potential treatment for major depressive disorder by modulating the expression of anti-inflammatory markers and production of serotonin, and clinical trials are evaluating its efficacy.37,42 Dysbiosis may be linked to obesity and metabolic syndrome, and restoring a healthy gut microbiome can improve insulin sensitivity.38
How dysbiosis may contribute to various diseases remains under investigation.9
CONCLUSION
FMT has demonstrated significant efficacy in managing recurrent C difficile infection, and emerging evidence suggests it can be used for other gastrointestinal and extraintestinal conditions. Although previous studies have highlighted that FMT can effectively correct dysbiosis, particularly when compared with standard antibiotic therapy, these findings should be interpreted with caution due to variability in methodologies and patient populations. FMT appears to be relatively safe in properly selected recipients. Most adverse events are mild, and severe events are primarily associated with specific risk factors such as immunosuppression. The development of standardized live biotherapeutic products like Rebyota and Vowst has enhanced the consistency and safety of FMT delivery. However, further research through large-scale randomized controlled trials is necessary to establish its broader therapeutic role and long-term outcomes. Clinicians should continue to view FMT as a validated treatment for recurrent or refractory C difficile infection, and remain cautiously optimistic about its future applications in other disease states.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2025 The Cleveland Clinic Foundation. All Rights Reserved.
REFERENCES
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.