Fecal microbiota transplantation: present and future

Article information

Clin Endosc. 2025;58(3):352-359

Publication date (electronic) : 2025 March 25

doi : https://doi.org/10.5946/ce.2024.270

Ra Ri Cha^1,2, Irene Sonu^,2

¹Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Jinju, Korea

²Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA

Correspondence: Irene Sonu Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 430 Broadway Pavilion C 3rd Floor, Redwood City, CA, 94063, USA E-mail: isonu@stanford.edu

Received 2024 October 8; Revised 2024 December 14; Accepted 2024 December 15.

Abstract

INTRODUCTION

Fecal microbiota transplantation (FMT) is an emerging treatment for regulating the gut microbiota. Biomass excreted in feces, commonly called the gut microbiome, plays an important role in the maintenance of health and the development of diseases. Research on the gut microbiome has expanded in the past decade, in addition to the role that FMT plays in its modification. FMT is now a routine procedure for treating specific infections, such as recurrent Clostridioides difficile infections (CDI).1 In addition, FMT may also be effective in treating inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), and disorders of gut-brain interaction (DGBI), such as irritable bowel syndrome (IBS), as well as improving the response to chemotherapy in patients with underlying malignancies.2 In this review, we discuss clinical applications, advanced therapeutic strategies, and emerging research on FMT.

FUNCTION OF THE GUT MICROBIOME

The term “microbiota” refers to the collection of all microbial taxa, including bacteria, archaea, fungi, and protists, that comprise the microbial community. When specifying a particular environment, the term is often preceded by its location; for example, “gut microbiota” refers to the microorganisms in the intestinal tract.3 The term “microbiome” refers to the collective genome of these microorganisms and is associated with various intestinal and extraintestinal disorders.4 Observational studies comparing the fecal microbiota of healthy participants with that of patients have shown that gut microbiota is involved in the pathogenesis of various diseases, such as IBD, IBS, colorectal cancer, and antibiotic-related diarrhea.5-9 Additionally, the gut microbiota has been extensively investigated in obesity and related diseases, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease.10-13

Dysbiosis is characterized by a decrease in microbial diversity and an increase in the abundance of pathogenic organisms that can trigger inflammation and produce genotoxins or carcinogenic metabolites. Antibiotic treatment is one of the most common causes of gut dysbiosis, which results in the disruption of healthy gut microbiota. This dysbiosis leads to the overgrowth of pathogens. Additionally, homeostatic mechanisms, such as bile salt synthesis, are perturbed in patients with dysbiosis. In healthy gastrointestinal (GI) tracts, the gut microbiome effectively suppresses the abundance of C. difficile. However, when antibiotics are administered, C. difficile becomes pathogenic and causes colitis.14 A growing number of studies have shown that the gut microbiota is strongly correlated with, and influences, the onset and progression of human health and disease.15,16

FECAL MICROBIOTA TRANSPLANTATION

FMT involves the administration of a solution of fecal matter from healthy donors into the GI tract of recipients to directly change their microbial composition and treat disease-associated gut dysbiosis.17 Fecal microbiota-based therapies include conventional FMT and United States (US) Food and Drug Administration (FDA)-approved therapies, fecal microbiota live-jslm, and fecal microbiota spores live-brpk.18 The recent approval by the FDA in 2022 and 2023 for agents derived from the human gut microbiome represents significant progress in the treatment of recurrent CDI in the US. These new drugs are classified as live biotherapeutic products or microbiome-based therapeutics. This development signifies a promising shift towards more refined and standardized treatments for gut-related disorders. REBYOTA (fecal microbiota live-jslm) and VOWST (fecal microbiota spores live-brpk) are both approved for prevention of recurrent CDI based on clinical trial data demonstrating safety and efficacy.19,20 REBYOTA is a live biotherapeutic product composed of a broad consortium of microorganisms derived from human stool and delivered via enema. In a phase 3 trial, statistical modeling showed that 71% of the participants treated with REBYOTA were free of CDI recurrence 8 weeks after administration. VOWST is an oral live microbiome therapeutic composed of live purified Firmicutes bacterial spores administered via orally ingested capsules. CDI recurrence was significantly lower with VOWST than with placebo at 8 weeks (12% vs. 40%, respectively; p<0.001) (Table 1).18,19,21

Table 1.

Comparison of live biotherapeutic products and classical FMT

THE METHODOLOGY OF FMT

The use of FMT has rapidly gained acceptance, largely due to the success of recurrent CDI treatment, and its scope of use is gradually expanding. The indications for FMT include immunocompetent adults and mildly, moderately, or severely immunocompromised adults with recurrent CDI. Recent US guidelines suggest the use of fecal microbiota-based therapies upon completion of standard-of-care antibiotics over non-fecal microbiota-based therapies.18 The European consensus guidelines recommend FMT for both mild and severe recurrent CDI.22 Korean guidelines suggest FMT for at least three episodes of CDI, including the initial episode, 2nd time recurrence.23 In addition to treating recurrent CDI, FMT has been investigated for other disorders, such as IBD, DGBI, metabolic disorders, and colorectal cancer; however, fully established guidelines are limited, and the level of recommendation or evidence is low.

No standardized guidelines exist for screening FMT recipients. Although not standardized, baseline recipient testing for infectious diseases, such as viral hepatitis, human immunodeficiency virus, and syphilis, is recommended. This precaution minimizes the risk of the transmission of new diseases diagnosed after FMT. Additional screening of the recipient should include evaluating comorbidities, such as immunocompromised status, which may increase the risk of adverse events.24,25

Most current practices for selecting fecal donors are based on expert opinions.26-28 Although the protocols differ, donor screening has been established to reduce the risk of transmitting infections from the donor to the recipient.24,25 The correct recruitment of healthy donors is essential for standardized and safe FMT.

FMT can be delivered via the upper GI route through upper endoscopy or nasogastric, nasoduodenal, or nasojejunal tube infusion; orally through capsules; or via the lower GI route through flexible sigmoidoscopy or colonoscopy with lavage or enema.29-32 The risk factors for aspiration may favor colonoscopy, whereas patients with difficulty undergoing colonoscopy may prefer the upper GI route.

FMT preparation varies across institutions; however, recent advancements include the use of frozen feces, capsules, and new methodological guidelines.30,33,34 For VOWST, capsules should be taken on an empty stomach after a bowel preparation of ten ounces of magnesium citrate is administered the night before treatment initiation to limit spore inactivation.35 With the increasing interest in FMT, standardizing and improving access to donor fecal suspensions is essential, and stool banks, such as OpenBiome, can help meet this need. The primary goal of a stool bank is to supply high-quality, ready-to-use fecal suspensions from a screened donor pool for safe, efficient, and cost-effective FMT.28

All recipients of FMT should undergo follow-up to assess treatment efficacy, disease recurrence, and possible side effects.36 Symptom resolution and short-term side effects must be monitored in the first week after FMT, particularly in patients with CDI.37 The primary outcomes in most studies were assessed at least 8 weeks after FMT.38 In a long-term follow-up study with a mean follow-up of 34 months to evaluate the efficacy and safety of FMT for the treatment of CDI, 75.8% of patients reported a sustained cure at the time of follow-up, and no procedure-related deaths were identified.39

CLOSTRIDIOIDES DIFFICILE INFECTION

C. difficile is a spore-forming, gram-positive bacterium that causes infectious diarrhea and colitis.40 CDI commonly recurs, affecting 15% to 20% after the first episode and up to 60% in subsequent cases,41,42 with a 40% risk of further recurrence.43 FMT has been used to successfully treat recurrent CDI; an approximately 90% cure rate in patients with recurrent CDI has been observed.44-47 FMT should be considered in cases of multiple relapses or when there is no response to standard antibiotics. FMT has been established in the clinical guidelines for the treatment of recurrent and refractory CDI. Previous studies have used various methodologies, reflecting the lack of detailed protocols or clear guidelines addressing issues related to the technical aspects of processing stool for FMT, the mode of administration to patients, and most importantly, the definition of cure and relapse. However, as treatment outcomes for recurrent CDI have improved and gained recognition, various guidelines have established clearer treatment methods and protocols, making them easier to apply in clinical practice.18,22,23 The human gut microbiome is a complex microbial community; however, antibiotics reduce microbial diversity. In patients with recurrent CDI, the gut microbiota showed significantly reduced ecological diversity and lower species richness compared to those without CDI. This reflects a microbial imbalance in which beneficial bacteria are diminished and pathogenic bacteria dominate, thereby increasing the risk of CDI recurrence. FMT restores these changes in the bacterial composition and improves CDI symptoms.48 Recent systematic reviews and meta-analyses have provided high-quality evidence supporting repeated FMT for recurrent CDI, demonstrating its superiority over vancomycin.49-51 In immunocompetent adults with recurrent CDI, fecal microbiota-based therapies should be considered upon completion of standard-of-care antibiotics over no fecal microbiota-based therapies. Patients randomized to receive fecal microbiota-based therapies were more likely to develop recurrent CDI than controls (overall, 74.2% vs. 51.7%; relative risk, 1.59).18 In addition, The American Gastroenterological Association guidelines suggest conventional FMT for patients hospitalized with severe or fulminant C. difficile infections who do not respond to antimicrobial therapy.18 For hospitalized patients who do not respond to standard antibiotic treatment, FMT should be considered, usually within 2 to 5 days of initiating CDI treatment. In mildly or moderately immunocompromised adults with recurrent C. difficile infections, FMT is recommended upon completion of standard-of-care antibiotics. However, in severely immunocompromised adults with recurrent C. difficile infections, fecal microbiota-based therapies should not be administered upon completion of standard antibiotic treatment.18

INFLAMMATORY BOWEL DISEASE

Gut microbiota dysbiosis is associated with IBD, marked by reduced microbial diversity and loss of anaerobic bacteria, and may be an important target for treatment strategies.52 The therapeutic application of FMT in IBD is currently in the early stages of development. Many randomized controlled trial (RCT) and observational studies have investigated FMT as a novel treatment option for IBD.21 However, the guidelines recommend against the use of conventional FMT in patients with IBD, including those with UC and CD, except in the context of clinical trials.18 No guidelines recommend FMT for IBD treatment, and further studies are needed before FMT can be used as therapy. The British Society of Gastroenterology guidelines note that there is no place for FMT in the management of IBD unless complicated with CDI.53 Although FMT may effectively induce remission in patients with mild-to-moderate UC, the evidence is insufficient to recommend it as a standard treatment for UC in routine clinical practice. FMT has shown promising results for the induction of remission in patients with moderate UC.54-56 However, these studies were performed in cohorts of patients with UC, with relatively small sample sizes and variations among study designs. However, limited evidence exists to recommend FMT as a treatment for CD than for UC in clinical practice. To date, FMT use has been limited to research settings. Therefore, larger and more consistent studies are needed to evaluate FMT in patients with IBD.

OBESITY AND METABOLIC SYNDROME

With the increasing number of patients with obesity and metabolic syndrome worldwide, research on these conditions has become an important area of study. Studies suggest that gut microbiota may influence obesity development, and microbial analysis has shown significant differences in the gut microbiota between lean and obese individuals.57 Therefore, obesity and diabetes can potentially be treated by modulating gut microbiota. A recent meta-analysis included nine studies with 303 participants. In terms of short-term outcomes (less than 6 weeks after FMT), compared to the placebo group, patients in the FMT group had lower fasting blood glucose (HbA1c and insulin levels) and higher high-density lipoprotein cholesterol levels.58 However, no significant differences in weight reduction were observed between the FMT and placebo groups. Although the weight loss effects were not significant, these results indicated that FMT is effective for glycemic control and improves insulin sensitivity. However, further high-quality studies are required to understand the role of FMT in glucose and lipid metabolism.

DISORDERS OF GUT-BRAIN INTERACTION

DGBIs are common with a prevalence of approximately 40%, and their pathophysiology is complex.59 A growing body of research suggests that gut microbiota plays a central role in the development and symptom regulation of DGBIs.60,61 Studies have indicated that up to 10% of the patients with IBS experience gut microbiota dysbiosis after gastroenteritis, leading to post-infectious IBS.62 Therefore, FMT may be a useful treatment option for DGBIs. However, the existing studies are limited and prone to bias, which makes them inconclusive. Well-designed studies are needed to determine whether there is indeed a link between the gut microbiota and DGBIs and whether FMT has a real effect on DGBIs, such as IBS.

SAFETY

FMT is generally considered safe and well-tolerated. With the expansion of its clinical use, legitimate concerns regarding its short- and long-term safety have arisen. Common side effects of FMT include transient diarrhea, abdominal cramps or pain, low-grade fever, bloating, flatulence, and constipation.63 The safety of FMT is an important aspect of its clinical application. The risk of infection transmission from FMT is of great concern, as highlighted by a FDA report on two cases of extended-spectrum beta-lactamase-producing Escherichia coli infections believed to have been transmitted through donor feces.64 Rigorous donor screening has significantly reduced the short-term infection risk; however, the long-term consequences of FMT remain unclear.41 Studies have indicated that the long-term adverse effects of donor microbe engraftment may include host susceptibility to diseases, such as obesity and immune-mediated disorders, such as immune thrombocytopenia, rheumatoid arthritis, and IBD.54,65,66 Larger, long-term follow-up studies are needed to determine the potential long-term adverse effects that influence FMT donor selection.

FUTURE DIRECTIONS

Considering the numerous studies and guidelines mentioned above, it is evident that FMT is highly effective and reliable for the treatment of recurrent CDI. However, as highlighted in various guidelines and studies, FMT has mostly been applied and recommended for patients with recurrent CDI after experiencing two or more episodes, and its effectiveness has been validated.

Nevertheless, some patients are at an increased risk of recurrence or severe recurrence, and may benefit from fecal microbiota-based therapy after the initial CDI episode or first recurrence. Severe and fulminant CDI, although uncommon, is associated with significant morbidity and mortality risks.67 Future studies should provide more data on the timing benefits of FMT, management of concomitant CDI antibiotics, number of FMT treatments, routes of FMT administration, and biomarkers to determine improvements in patients with severe or fulminant CDI. This will help to achieve better clinical outcomes. To improve access to conventional FMT, researchers and clinicians must continuously and accurately diagnose CDI and personalize the risk of recurrence. Patients who may benefit from early preventive therapy include those who have recovered from severe, fulminant, or refractory CDI. Patients with significant comorbidities who have recovered from CDI may also benefit from early fecal microbiota-based therapies. Therefore, RCT results for early treatment of patients diagnosed with recurrent or fulminant CDI are needed, and subsequent recommendations should be based on these findings.

As mentioned earlier, FMT has not received strong recommendation grades for indications other than recurrent CDI. Furthermore, there is a great interest in other applications of FMT, specifically in UC. Although more studies are being conducted, comparisons with existing treatment methods and recommended grades remain unclear. In addition, the positioning of the FMT along with the standard-of-care medications needs to be addressed. However, it remains unclear whether FMT is more suitable for inducing or maintaining remission. Further research is required to better define the role of FMT and its treatment characteristics. Factors such as dosage, frequency, and route of administration should be considered both as stand-alone treatments for IBD and in combination with currently available treatment modalities. Additionally, long-term patient follow-up plans should be established to assess the side effects.

As research on expanded indications for FMT progresses, finding the optimal donor will become crucial owing to the increasing demand. Donors can be optimized through diet, medication, or pretreatment. Currently, donors are not biologically matched with recipients, and this requires further exploration. The single strains were selected based on their mechanisms of action. However, fecal microbiota is a highly complex starting material, and it is necessary to understand how microbial communities in the sample interact and elucidate their mechanisms of action. Therefore, the discovery and clinical use of optimal microbial combinations may take considerable time. Until then, physicians and researchers focused on the safety and effectiveness of FMT by adhering to consensus guideline recommendations and supporting research on FMT interventions. Emerging therapies involve specific non-pathogenic strains. VE303 (Vedanta), a novel bacterial consortium composed of eight strains of commensal clostridia, is undergoing phase 3 trial.68 Therefore, detailed mechanistic and biomarker studies are required to achieve this goal.

CONCLUSIONS

FMT is highly effective for treating recurrent CDI, and new data are emerging regarding its use in other conditions. Based on these findings and the results of several ongoing studies, FMT may be a treatment option for patients with additional indications. Ongoing research and clinical trials are required to provide insight into this continually growing field.

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