Fecal Microbiota Transplantation in 2025: Two Steps Forward, One Step Back

Abstract

Purpose of Review

This review summarizes the history and current landscape of fecal microbiota transplantation (FMT), with an emphasis on use of the therapy for Clostridioides difficile infection (CDI), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS). We clarify indications, evidence, and current recommendations for FMT—highlighting major advances and minor setbacks that have led to the state of FMT in 2025.

Recent Findings

After decades of steady progress, the U.S. Food and Drug Administration (FDA) approved the first FMT-based therapies: fecal microbiota, live-jslm and fecal microbiota spores, live-brpk—in 2022 and 2023, respectively. The 2024 American Gastroenterological Association (AGA) Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases made specific recommendations for conventional FMT and these FDA-approved therapies for multiple CDI presentations, as well as for IBD and IBS. Conventional FMT remains an option for CDI; however, OpenBiome’s halt of shipped, frozen FMT preparations on December 31, 2024, has made access more challenging in 2025.

Summary

Although first reported almost seventy years ago, extensive efforts over the last two decades have placed FMT in routine algorithms for many patients with CDI. While understanding of the intestinal microbiome’s role in other gastrointestinal conditions is expanding, and FMT may modulate these pathways, additional evidence is needed before FMT becomes routine outside CDI.

An Introduction to Fecal Microbiota Transplantation

In 2009, a thirty-four-year-old schoolteacher presented with her eighth recurrence of Clostridioides difficile, with diarrhea and weakness so severe that she struggled to rise from the couch. Her symptoms had become refractory to any taper of high-dose oral vancomycin. With limited options, advice from several national providers experienced in what was then termed fecal bacteriotherapy (FB) or fecal transplantation (FT) was sought. Within a month, she underwent colonoscopy with FT using her healthy, asymptomatic sister’s pre-screened stool. She noted immediate and lasting resolution of all symptoms.

Without national guidance, early experience with FT spread partly through case reports and small series and largely through word of mouth among providers and patients. The increasing burden of recurrent CDI led many to find a way to say “yes” to this novel therapy. After completing the first FT at a major academic medical center, we soon saw patients from multiple states, all hoping FT could address their severe illness—marking the start of a structured FT program. But how did we arrive here, and where are we going?

Fecal Microbiota Transplantation for Clostridioides difficile Infection

Pre-guideline Era

While the use of human or animal stool for health benefits dates to antiquity, the first modern report of fecal enemas as adjunctive therapy for pseudomembranous enterocolitis appeared in 1958 [1]. This preceded recognition of Clostridioides difficile as the causative organism, then attributed to Micrococcus pyogenes. The four patients in that initial series had profound responses, prompting Dr. Eiseman and colleagues to recommend further study. However, 23 years elapsed before the next publication - a case series describing 16 patients treated with healthy stool for pseudomembranous enterocolitis, including the first case utilizing an upper gastrointestinal route [2]. The first reported successful prevention of recurrent CDI (RCDI) by rectal infusion of fresh stool came in 1984, followed by colonoscopic delivery in 1998 (Norway) and 2000 (United States) [3–5].

At the time we had performed our first colonoscopic fecal transplantation in 2009, a review of all published cases of RCDI (including pseudomembranous enterocolitis cases) reported a 90% prevention of recurrence among 100 total patients, though there had yet to be any prospective or controlled evaluation of the therapy [6]. But patients were continuing to suffer from the often crippling effects of Clostridioides difficile recurrences, and providers were left with minimal options when the infection was refractory or recurrent to standard medical options. The medical community was slowly but steadily learning from the initial experiences with fecal transplantation, with a growing number of providers and medical centers developing protocols and offering FT for those patients who had no other options. For both patients and providers, it often felt like a leap of faith, but we were clearly taking two steps forward in our efforts to battle the worsening challenges Clostridioides difficile was presenting.

Developing a Standard of Care

While published experience of fecal transplantation initially took decades and then years to accumulate, its acceptance and use continued to accelerate. But without any prospective data or societal guidance, collaboration between providers and medical centers became even more essential. In 2011, thirteen international providers from multiple medical specialties formed the Fecal Microbiota Transplantation Workgroup (FMTW), formally coining the term Fecal Microbiota Transplantation (FMT) for the rapidly evolving therapy. FMT remains the most uniformly accepted term to date. The FMTW released the first FMT guideline, which offered recommendations in seven important categories including: indications, donor selection, recipient exclusion criteria, protocol for performing FMT, preparation of stool, means of administering stool, and evaluation of success [7].

Despite FMT becoming a trending topic in both top medical journals and mainstream media, providers were still relying on retrospective and batched observational data. Between 2011 and 2013, systematic reviews in the infectious diseases and gastroenterology literature documented a resolution rate of 92% in 317 patients and 89% in 273 patients respectively, the latter excluding any series with less than ten patients [8, 9]. The seminal randomized controlled trial (RCT) came in 2013, comparing FMT to oral vancomycin with or without bowel lavage. The study was ultimately stopped early due to the dramatically reduced CDI recurrence rates seen in the duodenal infusion of donor stool arm (83%) compared to vancomycin alone (31%) or vancomycin after bowel lavage (23%) [10]. With resolution rates of 90% in systematic reviews and now an RCT requiring early trial cessation given such an overwhelming benefit of the active treatment, FMT was positioned to become a standard of care for RCDI when other medical options failed. Success in treating RCDI and the growing acceptance of FMT in the medical community and public prompted a growing interest in FMT for new indications, including ulcerative colitis, Crohn’s disease, irritable bowel syndrome, chronic diarrhea, and metabolic syndrome, among others.

With burgeoning experience and interest in the use of FMT, the FDA held a public workshop entitled “Fecal Microbiota for Transplantation” in May 2013 to provide a forum for the medical and scientific communities to discuss regulatory and scientific issues associated with FMT. After announcing an intention to require an investigational new drug (IND) application for use or study of FMT, physicians and scientists expressed concern that FMT was not appropriate for study under the Agency’s IND regulations, and that applying IND requirements would make this critical therapy unavailable. The FDA acknowledged those concerns and exercised a policy of “enforcement discretion”, allowing ongoing use of FMT for individuals with CDI unresponsive to standard therapies, provided adequate informed consent be obtained from patients for the use of FMT products [11]. They emphasized acknowledgment that FMT products to treat CDI were investigational and mandated discussion of its potential and largely unknown risks. This policy did not extend to the use of FMT for indications outside of CDI.

The OpenBiome Era

While providers were still able to offer FMT to patients requiring the therapy, doing so continued to require significant administrative and clinical protocols. This could be burdensome for individual providers or smaller practices offering the therapy infrequently, and likely prevented many from adopting this therapeutic option. Fortunately, the independent nonprofit OpenBiome was founded in 2012 [12]. Devoted to increasing access to screened stool for investigational FMT and its study, OpenBiome made processed and frozen FMT preparations from extensively screened and tested donors widely available. OpenBiome shipped its first clinical FMT preparation in November 2013, successfully treating a ninety-one-year-old woman with three previous CDI recurrences. In the next 25 months, OpenBiome had shipped its 10,000th FMT preparation, and by 2021, its 60,000th. FMT had reached widespread acceptance, and now with OpenBiome, widespread availability as well.

Increased access and use of FMT was buttressed by a growing body of evidence. A 2015 trial comparing colonoscopic FMT to vancomycin for RCDI was stopped early because of FMT’s superiority (90% vs. 26% in the first thirty-nine patients) [13]. This was followed by a 46-patient double-blind RCT in 2016 showing the benefit of heterologous compared to autologous FMT via colonoscopy in patients with three or more CDI recurrences, 90.9% compared to 62.5% in intention-to-treat analysis [14]. A randomized, active-comparator trial found the combination of 4–10 days of vancomycin followed by FMT (71%) to be superior to standard 10-day courses of either vancomycin (19%) or fidaxomicin (33%) for a combined clinical and microbiological resolution of RCDI [15]. The trial, conducted in Denmark, showed the efficacy of FMT via both nasojejunal tube and colonoscopy with 88% meeting the secondary outcome of clinical resolution.

Developing a National Registry

Given innumerable clinical protocols and methods for FMT in CDI, wide variability in the source for fecal microbiota, and the challenging regulatory status, leaders from multiple adult and pediatric gastroenterology and infectious diseases societies proposed the creation of an FMT National Registry [16]. Initially introduced in 2016 as the AGA Fecal Microbiota Transplantation National Registry, the registry planned to collect clinical and patient-reported outcomes to assess the safety and track the effectiveness of FMT and other gut-related microbiota therapies. The inaugural publication of results from the FMT National Registry in 2021 reported one-month cure of RCDI in 90% of the first 228 patients, of which 98% received only one FMT [17]. Nine patients (4%) reported severe symptoms within one month of FMT and three patients had hospitalizations possibly related to FMT. As of August 2024, the renamed AGA Fecal Microbiota Transplantation (FMT) and Other Gut Microbial Therapies National Registry had enrolled its 1,000th patient [18].

Arrival of the Live Biotherapeutic Products -- FDA Approval of Fecal Microbiota, Live-jslm

A landmark shift in the delivery and management of fecal microbiota-based therapies arrived with the first FDA approved live biotherapeutic products (LBPs), signaling a move away from the so-called “conventional FMT” of OpenBiome era or singular practice protocols. An initial open-label study of RBX2660, a standardized microbiota suspension prepared from donor stool and delivered via enema bag, prompted a subsequent phase 2B randomized trial that demonstrated a single 150mL dose of the product to be superior to placebo for prevention of RCDI [19, 20]. This work culminated in the double blinded RCT PUNCH CD3 trial which found a treatment effect of 13.1% compared to placebo (70.6% vs. 57.5%, respectively) sustained through six months [21]. The FDA approved RBX2660 as the first LBP under the name fecal microbiota, live-jslm (Rebyota) in November 2022 for the prevention of RCDI following antibiotic treatment for the second recurrence of CDI.

Looking for an Oral Option -- FDA Approval of Fecal Microbiota spores, Live-brpk

With the advent of LBPs came the goal to further simplify administration of this clearly effective therapy via an oral encapsulated delivery route. In the first series, frozen, encapsulated healthy stool was shown to be 70% effective at resolution of RCDI with one course of thirty capsules over two days, and 90% effective with a second course [22]. A second series showed an efficacy of 88% for resolution of RCDI with freeze-dried, encapsulated fecal microbiota with some patients treated with as few as two to three capsules [23]. A noninferiority RCT comparing oral FMT (40 capsules taken under direct observation) to colonoscopy-delivered FMT after a full course of vancomycin found both treatments prevented further RCDI in 96.2% of patients with a single treatment [24].

The encouraging findings of these cohort and non-inferiority studies were followed by PRISM3, a double-blind, placebo-controlled study of CP101, a full-spectrum, oral, lyophilized microbiome therapeutic for RCDI [25]. The trial, conducted at 51 sites across the United States and Canada between 2017 and 2020 found CP101 to be statistically superior to placebo in prevention of CDI recurrence (74.5% vs. 61.5%). Despite the success of this large phase 2 trial, the manufacturer of CP101, halted the Phase 3 clinical trial (PRISM4) and discontinued its Clostridioides difficile program in January 2023 [26]. Two steps forward, one step back (Fig. 1).

Fig. 1.

Timeline of advances and setbacks in Fecal Microbiota Transplantation (FMT). Chronologic summary of major advances (green) and minor setbacks (red) which have led to the state of Fecal Microbiota Transplantation in 2025. Notable puplications corresponding to peer-reviewed publications are referenced below. Abbreviations: AGA, American Gastroenterological Association; CDI, Clostridioides difficile infection, CSP, colonoscopy; FDA, U.S. Food and Drug Administration; FT, fecal transplantation; IND, Investigational New Drug; RCDI, recurrent Clostridioides difficle infection; RCT, randomized controlled trial. (1) 1958 – First modern series of fecal enemas for pseudomembranous colitis (PMEC) [1]. (2) 1958–1981 – (setback) - No further report of fecal enemas for 23 years. (3) 1981 – Early case series of fecal transplantation (PMEC) including upper GI route [2]. 1984 – First cure of relapsing C.difficile infection with rectal infusion of healthy stool [3]. (4) 1998–2000 – First colonoscopic FMT delivery reported (Norway; United States) [4, 5]. (5) 2009 – Systematic review suggests ~ 90% cure in 100 patients with recurrent CDI [6]. (6) 2011 – FMT Workgroup (FMTW) form; first guideline and term “FMT” coined. (7) 2013 – First RCT of duodenal FMT vs. vancomycin stopped because of FMT benefit [10]. (8) 2013 – OpenBiome ships first frozen FMT preparation [12]. (9) 2013 – (setback) – FDA announces intention to require IND for any use of FMT [11]. (10) 2015 – FMT is superior to Vancomycin in prevention of CDI in patients with RCDI [13]. 11) 2016–2018 – RBX2660 is found to be safe and effective in phase 2/2B trials [19, 20]. 12) 2021 – AGA National Registry publishes first report [17]. 13) 2022 – FDA approves fecal microbiota, live-jslm (Rebyota). 14) 2022 – (setback) – FDA updates guidance; will end enforcement discretion in 2024 [27]. 15) 2023 – (setback) – PRISM4 trial (phase 3 study of CP101 oral FMT) is halted [26]. 16) 2023 – FDA approves fecal microbiota spores, live-brpk (Vowst). 17) 2024 – AGA Clnical Practice Guideline on Fecal Microbiota-Based Therapies released [28]. 18) 2024 – (setback) – OpenBiome ships last FMT, closing the primary U.S. stool bank. 19) 2025 – FMT is shown to be non-inferior to vancomycin for treatment of initial CDI [29]

Meanwhile, SER-109, another investigational, oral microbiome therapeutic composed of purified Firmicutes spores, was also in phase 3 trial between 2017 and 2020. The ECOSPOR III trial, a double-blind trial comparing SER-109 to placebo after standard of care antibiotics in patients with three or more courses of CDI, found SER-109 superior to placebo in reducing recurrence (12% recurrence compared to 40%) [30]. The FDA approved SER-109 under the name fecal microbiota spores, live-brpk (Vowst) in April 2023, giving patients and providers a second FDA approved option for reducing risk of recurrence in patients already suffering from RCDI.

Though direct comparison of the FDA approved LBPs to conventional FMT for prevention of RCDI has not been performed, initial clinical data shows encouraging real-world efficacy. A 2025 multi-center retrospective cohort study showed a significant reduction of RCDI at 24 weeks in patients treated with LBPs (12.5% to 18.9%) compared to conventional FMT (36.7%) [31]. An additional 2025 single-center retrospective cohort study also showed a non-significant reduction in RCDI with use of fecal microbiota spores, live-bprk compared to conventional FMT (7% compared to 18%), though two patients treated with spores developed fulminant CDI compared to none treated with conventional FMT [32]. 2025 also brought the first trial of off-label use of fecal microbiota live-jslm delivered via colonoscopy. The phase 3b, multicenter, single-arm trial entitled CDI-SCOPE, showed 92.7% of 41 patients had no CDI recurrence up to six months after receiving the treatment via colonoscopy [33].

FMT in Severe or Fulminant Clostridioides Difficile Infection

Despite the very first case series highlighting the successful use of FMT in patients with severe CDI (hospitalized patients with pseudomembranous colitis), the majority of subsequent observational studies and trials focused on the prevention of RCDI. However, patients with severe or fulminant CDI (SFCDI) continued to face significant morbidity and mortality. Among patients with SFCDI refractory to antibiotics, especially those who were poor surgical candidates, FMT became an ever more attractive option of last resort. Retrospective cohort studies in patients with SFCDI showed significant mortality benefit of FMT over standard of care with numbers needed to treat as low as two to three to prevent one death [34, 35]. In a single-center retrospective analysis of 30-day mortality in patients hospitalized for SFCDI before (2009–2012) and after (2013–2016) implementation of an inpatient FMT program, mortality from refractory SFCDI dropped from 43.2% to 12.1% [36]. Because of the profound benefit of FMT in this patient population and despite no prospective trials, FMT was suggested for patients with SFCDI refractory to antibiotics in the 2021 American College of Gastroenterology (ACG) Clostridioides difficile guideline as well as the 2024 AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases [28, 37].

FMT in Early Clostridioides Difficile Infection

Evidence was also accumulating that FMT could be used earlier in a patient’s course, before they had suffered multiple recurrences or severe disease. An RCT in Denmark comparing FMT to placebo following a 10-day course of oral vancomycin for an initial or second CDI was stopped at interim analysis due to a significantly lower rate of 8-week resolution in the placebo group (33% vs. 90%) [38]. Effective at prevention of recurrence, FMT was now positioned to possibly be an alternative to an initial course of antibiotics. Though changes in the intestinal microbiome were the aim of the first trial comparing fecal donor-unrelated donor mix (FMT-FURM) transplantation to a 10–14 day course of high dose vancomycin for primary CDI, the trial showed a symptom resolution rate of 71.4% with one to two doses of FMT compared to 88.9% with vancomycin [39]. A small Norwegian trial comparing a 60-mL enema of aerobically cultivated human microbiota to a standard 10-day course of metronidazole showed similar rates of cure for initial CDI (56% vs. 45%) [40]. A larger Norwegian trial, recently published in 2025, comparing FMT to a 10-day course of vancomycin showed non-inferiority of FMT for clinical cure (66.7% vs. 61.2%) and no disease recurrence within 60 days of FMT [29]. While it’s premature to declare FMT an alternative to standard of care antibiotics for an initial CDI, early FMT is clearly an option to be further explored in the management of this challenging disease.

FMT for CDI in Patients with Comorbidities

Proven effective for many presentations of CDI, one of the main reasons for continued clinical and research momentum for FMT was its overall safety. While adverse events (AEs) were reported in most studies and frequently outnumbered AEs associated with placebo, severe AEs were infrequent. As a byproduct of its use as a therapy for patients with RCDI and SFCDI, FMT and LBPs were often utilized in patient populations that tended to have severe co-morbidities and/or required high-risk medical therapies. A 2014 sixteen-center retrospective series examined outcomes of FMT for recurrent, refractory, and severe CDI among 80 patients with immunocompromising conditions including HIV/AIDS, solid organ transplant, cancer, and immunosuppressive therapies [41]. In this high risk population, the CDI cure rate for a single FMT was 78% and rose to 89% when including patients receiving a second FMT. Twelve patients had a severe adverse effect including ten hospitalizations, and one death related to aspiration during a colonoscopy. Additional retrospective series in patients with cancer, solid organ and hematopoietic stem cell transplants, and inflammatory bowel disease reported successful reductions in RCDI post-FMT at similar rates to patients without those comorbidities [42–45]. Based on both efficacy and safety, the 2024 AGA Fecal Microbiota-Based Therapies guideline suggests the use of conventional FMT upon completion of standard care antibiotics in mildly to moderately immunocompromised adults with RCDI but not in severely immunocompromised adults (Table 1).

Table 1.

Current recommendations for the use of conventional fecal microbiota transplantation (FMT) and FDA-approved live biotherapeutic products (LBPs) in different presentations of Clostridioides difficile infection (CDI) and other gastrointestinal conditions. These recommendations are based on the 2024 AGA Clinical Practice Guideline on Fecal Microbiota-Based Therapies for Select Gastrointestinal Diseases.

The Status of Conventional FMT for CDI in 2025

With two FDA-approved LBPs available for the prevention of further recurrence after an appropriate course of antibiotics in patients with RCDI, and conventional FMT available for patients with recurrent, severe or fulminant CDI, most providers and patients now had an option for these challenging illnesses. However, the FDA released a Guidance for Industry in November 2022, finalizing draft guidance from March 2016 [27]. This guidance required stool banks to maintain an Investigational New Drug (IND) to provide their FMT product for continued clinical use, and ended FDA enforcement discretion. This ultimately forced the main stool bank in the United States, OpenBiome, to announce that their donor FMT material would not be available after October 31, 2024, eventually extended to December 31, 2024. After shipping their 72,507th FMT treatment, the closure of the OpenBiome stool bank eliminated the main national source for conventional FMT, which had been utilized by over 1,300 facilities over the prior twelve years.

Because hospitals and clinics are not considered stool banks under this guidance, physicians may still perform conventional FMT by identifying and screening an individual donor and do not need an IND. However, this effectively returns programs to the pre-OpenBiome model (pre-2013), reintroducing substantial logistical barriers—donor identification, comprehensive laboratory screening, specimen processing, storage, documentation, and quality assurance. One giant step backward. Even so, accumulated clinical experience, supportive evidence, and ongoing advocacy mean FMT remains available for patients who need it. Practical resources from professional societies (including the AGA FMT and Other Gut Microbial Therapies National Registry) and the newly formed OpenBiome Foundation can help clinicians and institutions reestablish compliant workflows, maintain safety monitoring, and navigate this transition.

Fecal Microbiota Transplantation for Other Gastrointestinal Conditions

FMT for Ulcerative Colitis

Early pioneers in the field of FMT noted clear efficacy in many patients with Clostridioides difficile infection, but with an established role of the intestinal microbiome in other digestive diseases such as inflammatory bowel disease, and a possibility of modifying the microbiome with FMT, it was postulated that FMT could benefit many of these conditions as well. First reported in 1989 as a single case of clinical and histologic remission of ulcerative colitis (UC) in a patient treated with FMT, the first case series (2003) described the complete reversal of clinical symptoms in six patients with UC who were treated with retention enemas of healthy fecal suspensions for five consecutive days [46, 47]. The treatments, then termed human probiotic infusions, led to clinical, endoscopic and histologic remission of UC for one to 13 years follow-up after treatment. Eight years later, attempts to treat five patients with UC refractory to medical therapies with daily FMT by nasojejunal tube and enema resulted in clinical response for one patient and remission in none [48].

In July 2015, the first two randomized controlled trials of FMT in patients with UC were published in the same journal. The first, an RCT of six weekly retention enemas of healthy stool compared to placebo enemas found the active treatment led to clinical and endoscopic remission of mild to moderate UC in 24% (compared to 5% in the placebo group) [49]. Of note, this trial allowed other medical treatments for UC as long as they were at a stable dose for at least 12 weeks. The second, an RCT comparing two doses of donor FMT delivered via nasojejunal tube three weeks apart to autologous FMT in mild to moderate UC showed no statistical difference between the treatments [50]. A subsequent trial also comparing pooled donor to autologous FMT for mild to moderate UC, this time delivered by colonoscopy and followed by two enemas over seven days, resulted in 32% clinical remission at 8 weeks and 13% at 12 months [51]. A larger RCT of 85 patients in Australia compared FMT delivered by colonoscopy followed by enemas five days per week for eight weeks to placebo [52]. Each FMT preparation was derived from between three and seven unrelated donors. This more intensive regimen led to eight-week steroid-free clinical remission and endoscopic response in 27% compared to 8% with placebo. This study also showed increased and sustained microbial diversity with FMT.

While most studies compared FMT to placebo, a small RCT showed non-inferiority of a five-week regimen of FMT enemas in inducing clinical remission in active left-sided UC when compared to mesalamine enemas [53]. As oral therapy became an option for FMT treatment of RCDI, this was also an obvious target for UC. A single-center RCT evaluated 12-weeks of daily administration of frozen, encapsulated oral FMT after initial FMT induction by colonoscopy compared to placebo [54]. Patients were allowed to be on other UC medications as long as doses were stable for at least six weeks. Two patients in the treatment group and none in the placebo group achieved clinical remission at 12 weeks, a not statistically significant result based on only 12 patients completing the study protocol. A second and larger RCT, this time in 35 patients, found oral lyophilized FMT capsules for eight weeks following two weeks of systemic antibiotics, to be superior to placebo in inducing corticosteroid-free clinical remission and endoscopic remission or response at week eight (53% compared to 15%) [55]. The ten patients who achieved a clinical or endoscopic response to oral FMT, were randomly assigned to continue open-label FMT or withdraw therapy. Impressively, all four patients who continued FMT were in clinical, endoscopic, and histologic remission at week 56 compared to none of the patients who had FMT withdrawn.

As compared to recurrent Clostridioides difficile infection (RCDI)—where disease manifestations and prior treatments are generally similar between patients—ulcerative colitis (UC) presents with substantial variability in disease severity, duration, and treatment history. There are also many treatment options for both induction and maintenance of remission in ulcerative colitis, whereas treatment options in RCDI and SFCDI are very limited. These factors are coupled with substantial trial variance in timing, route, and frequency of FMT delivery, number and status of donors, and lack of uniformity in comparison groups and trial design. While there is evidence that FMT has the potential to be effective in select patients with UC, more progress will be needed before it has a role in standard UC treatment algorithms. Currently, FMT is not recommended for primary induction treatment of UC per the 2025 ACG Ulcerative Colitis Clinical Guideline Update, and is recommended only in the context of clinical trials in the 2024 AGA Fecal Microbiota-Based Treatments guideline [28, 56]. Limited trial data in chronic pouchitis also show no benefit of FMT over placebo and it is currently also recommended only in the context of a clinical trial [57, 58].

FMT for Crohn’s Disease

While evidence of a potential role of FMT in ulcerative colitis is limited, there is even less trial evaluation of FMT for Crohn’s disease. A single-center series of fourteen patients with medically-refractory IBD treated with FMT through a nasojejunal or rectal tube included eight patients with UC and six with Crohn’s disease [59]. Though FMT led to endoscopic remission at eight weeks (and sustained for over two years) in two of eight of the UC patients, there was no significant improvement in any of the six patients with Crohn’s disease. One RCT evaluated a single FMT via colonoscopy compared to sham for patients in clinical remission of Crohn’s disease after treatment of a disease flare with systemic corticosteroids [60]. The primary aim was implantation of donor microbiota, and was not met by any of the eight patients treated with FMT, and there was not a statistically significant difference in steroid-free remission at week ten. A recently published RCT of FMT via colonoscopy followed by once-weekly oral FMT for induction of remission in mild to moderate Crohn’s Disease showed no benefit over placebo [61]. With no current trial evidence of efficacy in Crohn’s disease, FMT is not addressed in the 2025 ACG Crohn’s Disease Management guideline, and the 2024 AGA Fecal Microbiota-Based Therapies guideline suggests against the use of FMT in adults with Crohn’s disease, except in the context of a clinical trial [62].

FMT for Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is a commonly diagnosed condition without a specific mechanism. Alterations in the intestinal microbiota are thought to play a role in its pathogenesis, making IBS another target for attempts at treatment with FMT. A 2014 retrospective case series of 13 IBS patients receiving a fecal suspension infused into the distal duodenum or jejunum during upper endoscopy reported resolution or improvement of symptoms in 70% [63]. A 2018 single-center, placebo-controlled RCT found symptom response three months after colonoscopic-delivered active FMT in 65% compared to autologous transplant (43%) [64]. While a few additional trials noted some symptoms benefit with FMT, five additional RCTs published between 2018 and 2021 showed no sustained benefit [65–71]. These results led to a recommendation against the use of FMT for IBS in the 2021 ACG IBS Treatment guideline and to only consider its use in the context of a clinical trial in the 2024 AGA Fecal Microbiota-Based Therapies guideline [72].

Conclusion

Almost seventy years after the initial series of four hospitalized patients treated with healthy fecal enemas for pseudomembranous enterocolitis, FMT has become indispensable for recurrent and severe Clostridioides difficile infection. National guidelines recommend conventional FMT or FDA-approved live biotherapeutic products after standard antibiotics in immunocompetent patients with RCDI; conventional FMT is also suggested for mildly to moderately immunocompromised patients with RCDI and for hospitalized patients with antibiotic-refractory SFCDI. After 11 years and over 70,000 shipped FMT treatments, the December 2024 closure of the national stool bank, OpenBiome, has hampered the use of conventional FMT. Fortunately, conventional FMT can still be pursued by treating physicians without an IND, and the near 90% cure rates noted in systematic reviews and publication of the AGA’s National Registry, can still be expected with conventional FMT. Though FMT is currently only recommended in the context of clinical trials for IBD and IBS, with over 200 active trials in FMT including 35 in IBD and seven in IBS, we would expect to keep taking two steps forward with each small step back.

Key References

• Feuerstadt P, Louie TJ, Lashner B, Wang EEL, Diao L, Bryant JA, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022 Jan 20;386(3):220–9.

  • ○The phase 3 placebo-controlled RCT of SER-109, an investigational therapeutic composed of purified Firmicutes spores, showing reduction of recurrent CDI from 40% (placebo) to 12% with the active treatment. This trial led to the FDA approval of SER-109 as fecal microbiota spores, live-brpk (Vowst) in April 2023.

• Juul FE, Bretthauer M, Johnsen PH, Samy F, Tonby K, Berdal JE, et al. Fecal Microbiota Transplantation Versus Vancomycin for Primary Clostridioides difficile Infection : A Randomized Controlled Trial. Ann Intern Med. 2025 July;178(7):940–7.

  • ○An open-label, randomized trial showing non-inferiority of FMT compared to a standard course of vancomycin for an initial C. difficile infection. 66.7% of patients treated with FMT experienced clinical cure and no disease recurrence within 60 days, compared to 61.2% with vancomycin.

• Kelly CR, Yen EF, Grinspan AM, Kahn SA, Atreja A, Lewis JD, et al. Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry. Gastroenterology. 2021 Jan;160(1):183-192.e3.

  • ○Results of the first 259 participants enrolled in the American Gastroenterological Association FMT National Registry, showing FMT led to a cure of CDI in 90% of patients. These patients had enrolled in the registry from 20 different North American sites between 2017 and 2019.

• Khanna S, Assi M, Lee C, Yoho D, Louie T, Knapple W, et al. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs. 2022 Oct;82(15):1527–38.

  • ○The phase 3 placebo-controlled RCT of RBX2660, a live biotherapeutic product consisting of a broad mix of microbes from human stool, showing prevention of CDI recurrence in 70.6% in the treatment group, compared to 58.1% (placebo). This trial led to the FDA approval of RBX2660 as fecal microbiota, live-jslm (Rebyota) in November 2022.

• Peery AF, Kelly CR, Kao D, Vaughn BP, Lebwohl B, Singh S, et al. AGA Clinical Practice Guideline on Fecal Microbiota–Based Therapies for Select Gastrointestinal Diseases. Gastroenterology. 2024 Mar;166(3):409–34.

  • ○Comprehensive guideline covering the use of conventional fecal microbiota transplantation (FMT) and fecal microbiota-based therapies for several different presentations of Clostridioides difficile infection, inflammatory bowel disease, and irritable bowel syndrome.

• Van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, De Vos WM, et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407–15.

  • ○The seminal open-label RCT stopped at interim analysis due to efficacy of duodenal infusion of donor feces (81%) compared to a standard vancomycin regimen (31%) and a standard vancomycin regimen after bowel lavage (23%) in preventing further RCDI. This trial contributed to increased acceptance of FMT as standard treatment for RCDI.

Author Contributions

C.B.M. conceived the review, wrote the initial manuscript draft, and created the table and figure. G.A.B. and C.L.K. contributed to content development, literature review, and critical manuscript revisions. All authors reviewed and approved the final manuscript.

Data Availability

No datasets were generated or analyzed during the current study.

Declarations

Disclaimer

The views expressed are those of the author(s) and do not necessarily reflect the official policy or position of the Defense Health Agency, the Department of Defense, nor any agencies under the U.S. Government.

Competing interests

The authors declare no competing interests.