Conventional FMT is the administration of minimally processed stool and distal gut microbiota from healthy donors to restore a healthy gut microbiome in recipients.^7,21 Although microbiota-based therapies have come into vogue in recent years, the use of fresh or processed stool for the treatment of digestive diseases dates to the fourth century CE in China.²² The first modern case series was published in 1958 by Eiseman and colleagues,²³ demonstrating the use of FMT to treat pseudomembranous enterocolitis.

The most compelling indication for FMT is the prevention of CDI recurrences in people with rCDI.^22,24 The evidence for use of FMT in rCDI is longstanding, with the first case report in contemporary medical journals being published in 1983²⁵ and the first randomized control trial published 30 years later.²⁶ Meta-analyses have demonstrated FMT is effective for treating rCDI in immunocompetent adults²¹ with reported efficacy of 80% to 90%.^22,27–29 The benefits of FMT can be sustained over multiple years.^30–32

Guidelines recommend consideration of FMT after at least 2 recurrences of CDI (ie, at least 3 episodes; Table 1). The evidence regarding use of FMT after the first or second episode of CDI is mixed.^33,34 The number of FMT doses, timing of FMT after initial CDI treatment, and need for laboratory confirmation differ between studies,^33,34 reflecting the heterogeneity of FMT trials and the potential requirement of multiple FMT courses for disease resolution.³⁵

FMT is also used in the treatment of severe or refractory CDI. Guidelines propose the use of FMT in cases unresponsive to standard-of-care antibiotics, especially for unsuitable surgical candidates, in an interdisciplinary setting with multiple specialists.^16,36

FMT recipient registries have been created to track real-world efficacy and adverse events. The FMT National Registry, managed by the American Gastrointestinal Association (AGA), plans to follow North American FMT recipients for up to 10 years to compile more long-term safety and efficacy data.^37,38

“FMT” is not a singular procedure or product but instead a spectrum of diverse interventions³⁹ using minimally processed donor stool procured from stool banks or academic medical centers.^6,13 Early FMT programs used donors selected by the recipient; however, with increasingly strict donor screening requirements,⁴⁰ among other ethical and practical concerns, the use of anonymous stool donors has proliferated.⁶

FMT comes in several formulations: encapsulated, fresh, or frozen. Oral capsules, frozen or lyophilized, have demonstrated efficacy in preventing rCDI,^27,29,33 although the quantity of capsules ingested varies substantially by study protocol.²⁹ Oral liquid formulations are an option for patients who cannot swallow capsules.⁴¹ Fresh stool products can be used, but frozen FMT products are equally effective.^24,42 Frozen FMT products offer the convenience of prolonged storage⁴³ and may increase safety by allowing FMT product destruction if the donor becomes ill in the interval between donation and product use.²⁴

Administration of FMT varies by route (eg, upper or lower gastrointestinal [Gl] tract) and method of delivery (eg, administration via feeding tube, enema, or instillation during endoscopy). There is insufficient evidence to recommend a specific route of FMT delivery^{14,15,17–19,24}; however, there are clinical conditions and patient factors that influence FMT administration. Upper GI administration should be avoided in patients at elevated risk for aspiration or regurgitation.^17–19,24 FMT via enema has lower efficacy but does not require feeding tube placement or the procedural costs and risks of colonoscopy.^19,24 If patients fail initial FMT by oral capsule or enema, subsequent FMT via colonoscopy is recommended¹⁹; lower GI endoscopy also allows for confirmation of CDI diagnosis and severity.¹⁷

The most common side effects of FMT are abdominal discomfort/cramping, flatulence, diarrhea, vomiting, belching, and fever,⁴⁴ although rates of diarrhea may be overestimated (Table 2). Serious adverse events can include injury from FMT delivery methods (eg, aspiration of fecal contents, bowel perforation during endoscopy, or anesthesia-related complications). There are rare reports of inflammatory bowel disease exacerbation and development of autoimmune diseases.^44,45 Patients should be followed for a minimum of 8 weeks after FMT to evaluate for adverse events and late treatment failure.^19,24

The largest safety concern is transmission of infectious pathogens through FMT. Enteric bacteria producing extended-spectrum β-lactamases (ESBL) have been transmitted by FMT⁴⁶ as well as viral infections like cytomegalovirus (CMV) and norovirus.^47,48 The Food and Drug Administration (FDA) has also issued safety alerts communicating the risk of potential transmission of SARS-CoV-2 or mpox with FMT.^49,50 Seronegative immunocompromised patients at increased risk of disseminated infection from CMV or Epstein-Barr virus should be informed about the rare possibility of viral transmission through FMT.^19,24

Donor screening programs mitigate the risk of donor-derived infection through FMT, although there remains a need for standardized screening protocols.^51,52 Generally, donor blood and stool are screened for transmissible diseases, and prospective donors undergo risk assessment of behaviors linked to infectious diseases.^24,45,53 After a donor-derived ESBL Escherichia coli strain was linked to invasive infections and one death in 2 immunocompromised FMT recipients,^40,54 the FDA recommended the addition of multidrug-resistant organism screening.⁴⁰ Given the possible contribution of recipient neutropenia to the invasive infections and death, FMT is generally avoided in neutropenic patients.¹⁷

Although serious adverse events have been associated with FMT,⁴⁵ these events have been very rare. A review of longitudinal studies found zero FMT-attributable deaths, autoimmune diseases, or GI disorders during a 10-year follow-up period.³⁰

Logistical and regulatory challenges in maintaining safe, consistent supplies of stool from healthy donors to meet clinical demand for microbiota-based therapy led to the commercial development of FMPs.¹³ FMPs are manufactured from human donor stool using standardized processes, offering improved ease of distribution and reimbursement over conventional FMT.^4,7,67 Like FMT, these products aim to correct deficiencies in the gut microbiome, mainly by replacing key phyla (ie, Bacteroidetes and Firmicutes) to prevent C difficile recurrence.⁶⁸ FMPs are manufactured using Good Manufacturing Practice^63,69 and undergo sampling before administration to ensure minimum thresholds of bacterial species are met.⁶⁸ Two FMPs have received FDA approval for the prevention of rCDI in adults undergoing treatment of rCDI (Tables 3 and 4).

Rebyota (Fecal microbiota, Live-jsIm; Ferring Pharmaceuticals, Parsippany, NJ) was the first FMP to receive FDA approval in 2022. Rebyota is a liquid suspension of fecal microbiota (including 1 × 10⁵ colony-forming units of Bacteroides spp) administered rectally.⁷⁰ Rebyota can be stored in an ultracold freezer (−60°C to −90°C) or refrigerated (2°C to 8°C) for 5 days (Fig. 1).

Vowst (Fecal microbiota spores, Live-brpk; Nestle HealthScience, Hoboken, NJ) was the first oral FMP to receive FDA approval. Vowst is a purified suspension of fecal bacterial spores (Firmicutes spp) in oral capsules that can be stored at room temperature (up to 25°C).⁷¹

Both products should be administered 1 to 3 days after the completion of C difficile antibiotics.^70,71 Like conventional FMT, most side effects associated with either drug were mild to moderate GI symptoms.³⁷ Both products are available by prescription in the United States, generally covered by commercial insurance.

Given the novelty of FMPs, there are minimal safety data regarding use in pediatrics, pregnancy, and breastfeeding.^70,71 There is insufficient evidence supporting the use of FMPs in immunosuppressed patients,¹⁷ although patients considered immunocompromised were enrolled in trials for both products.^71,73