Fecal Bacteriotherapy

Number: 0844

Table Of Contents

Applicable CPT / HCPCS / ICD-10 Codes


Scope of Policy

This Clinical Policy Bulletin addresses fecal bacteriotherapy for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

  1. Medical Necessity

    1. Oral suspension fecal bacteriotherapy

      Aetna considers fecal bacteriotherapy, including capsulized, frozen fecal microbiota transplantation, medically necessary for persons with Clostridium difficile infection (CDI), confirmed by a positive stool test for C. difficile toxin, that has recurred following at least 1 course of adequate antibiotic therapy (10 or more days of vancomycin at a dose of greater than or equal to 125 mg 4 times per day or 10 or more days of metronidazole at a dose of 500 mg 3 times per day);

    2. Rectal suspension fecal microbiota, live-jslm (Rebyota)

      1. Exclusions

        Treatment of Clostridioides difficile infection (CDI) is considered an exclusion for Rebyota.

      2. Criteria for Initial Approval

        Aetna considers a one-time dose of fecal microbiota, live-jslm (Rebyota) medically necessary for the prevention of CDI when all of the following criteria are met:

        1. Member is 18 years of age and older; and
        2. Member has recurrent CDI including either of the following:

          1. At least one recurrence after a primary episode and has completed at least 1 round of standard-of-care oral antibiotic therapy (e.g., metronidazole, fidaxomicin); or
          2. Has had at least 2 episodes of severe CDI resulting in hospitalization within the last year; and
        3. Member has a positive stool test for the presence of C.difficile toxin or toxigenic C. difficile within 30 days prior to treatment; and
        4. A single, one-time 150 mL dose will be administered rectally 24 to 72 hours after the last dose of antibiotics.

        Aetna considers all other indications for Rebyota as experimental, investigational, or unproven.

  2. Experimental, Investigational, or Unproven

    Aetna considers fecal bacteriotherapy experimental, investigational, or unproven for all other indications including the following (not an all-inclusive list) because the effectiveness of  this approach has not been established:

    1. Alcoholic hepatitis
    2. Alzheimer's disease
    3. Amyotrophic lateral sclerosis
    4. Attention-deficit hyperactivity disorder
    5. Autism spectrum disorder
    6. Autoimmune cholangiopathies (e.g., primary biliary cholangitis and primary sclerosing cholangitis)
    7. Colon cancer
    8. Crohn's disease
    9. D-lactic acidosis
    10. Diabetes
    11. Diabetic neuropathy
    12. Epilepsy
    13. Functional gastro-intestinal disorders (e.g., functional constipation, functional diarrhea, and functional dyspepsia)
    14. Gastro-intestinal dysbiosis
    15. Graft-versus-host disease of the gut
    16. Guillain-Barre syndrome
    17. Hepatic steatosis
    18. HIV infection
    19. Idiopathic thrombocytopenic purpura
    20. Inflammatory bowel diseases
    21. Irritable bowel syndrome
    22. Insulin resistance
    23. Intestinal multidrug-resistant bacterial decolonization
    24. Long COVID
    25. Metabolic syndrome
    26. Migraine
    27. Multiple sclerosis
    28. Non-alcoholic fatty liver disease
    29. Obesity
    30. Parkinson's disease
    31. Post-operative cognitive dysfunction
    32. Pouchitis
    33. Slow transit constipation
    34. Stroke
    35. Tourette syndrome
    36. Ulcerative colitis
    37. Urinary tract infection.


CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met :

0780T Instillation of fecal microbiota suspension via rectal enema into lower gastrointestinal tract
44705 Preparation of fecal microbiota for instillation, including assessment of donor specimen

HCPCS codes covered if selection criteria are met:

G0455 Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen
J1440 Fecal microbiota, live - jslm, 1 ml

Other HCPCS codes related to the CPB:

Fidaxomicin - no specific code

ICD-10 codes covered if selection criteria are met:

A04.71-A04.72 Enterocolitis due to Clostridium difficile

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

A04.9 Bacterial intestinal infection, unspecified [gastrointestinal dysbiosis]
C18.0 - C18.9 Malignant neoplasm of colon
D69.3 Immune thrombocytopenic purpura [idiopathic thrombocytopenic purpura]
D89.810 - D89.813 Acute, chronic, acute on chronic, and unspecified graft-versus-host disease
E08.00 - E13.9 Diabetes mellitus
E66.0 - E66.9 Overweight and obesity
E87.20, E87.21, E87.22, E87.29 Acidosis [D-lactic acidosis]
E88.81 Metabolic syndrome [insulin resistance]
F84.0 – F84.9 Autistic disorder
F90.0 – F90.9 Attention-deficit hyperactivity disorders
F95.2 Tourette syndrome
G12.21 Amyotrophic lateral sclerosis
G20 Parkinson’s disease
G30.0 - G30.9 Alzheimer’s disease
G31.84 Mild cognitive impairment, so stated [post-operative cognitive dysfunction]
G35 Multiple sclerosis
G40.001 – G40.C19 Epilepsy and recurrent seizures
G43.001 – G43.E19 Migraine
G61.0 Guillain-Barre syndrome
I63.00 – I63.9 Cerebral infarction
K30 Functional dyspepsia
K50.00 - K50.919 Crohn's disease [regional enteritis]
K51.00 - K51.919 Ulcerative colitis
K52.0 - K52.9 Other and unspecified noninfectious gastroenteritis and colitis [inflammatory bowel diseases]
K58.0 - K58.9 Irritable bowel syndrome
K59.0 - K59.09 Constipation
K59.1 Functional diarrhea
K70.10 - K70.11 Alcoholic hepatitis
K74.3 Primary biliary cirrhosis [autoimmune cholangiopathy]
K76.0 Fatty (change of) liver, not elsewhere classified
K83.01 Primary sclerosing cholangitis [autoimmune cholangiopathy]
K91.850 Pouchitits
N39.0 - N39.9 Other disorders of urinary system [urinary tract infection]
U09.9 Post COVID-19 condition, unspecified
Z16.24 Resistance to multiple antibiotics[intestinal multidrug-resistant bacterial decolonization]
Z16.30 Resistance to unspecified antimicrobial drugs[intestinal multidrug-resistant bacterial decolonization]
Z16.35 Resistance to multiple antimicrobial drugs[intestinal multidrug-resistant bacterial decolonization]
Z21 Asymptomatic human immunodeficiency virus [HIV] infection status


Fecal bacteriotherapy (FT, also known as fecal microbiota transplantation [FMT], fecal transplant, fecal transfusion, stool transplant and probiotic infusion) is the transfer of a liquid suspension of stool from a healthy donor to the patient and is proposed for the treatment of Clostridium difficile infection (CDI). CDI can result in mild diarrhea to life-threatening fulminant pseudomembraneous colitis. It most often affects older adults and may occur as a result of antibiotic therapy which disrupts the normal bacterial flora in the gastro-intestinal (GI) tract. Treatment involves discontinuation of the offending antibiotic. If the cessation of antibiotic therapy does not restore normal colonic flora, patients are treated with oral administration of metronidazole or vancomycin.  In some cases, patients non-responsive to medical management are treated by surgical colectomy which has a mortality rate of 35 % to 57 %. The introduction of healthy bacterial flora via FT is suggested as a treatment for persons with Clostridium difficile not responding to management with antibiotics. One of the risks with FT is the transfer of contagious agents (e.g., fungi, parasites, and viruses) from the donor (You et al, 2008; Bakken et al, 2009). 

FT is generally performed by a gastroenterologist. After testing blood and stool for common viral and bacterial pathogens and parasites, donor fecal material is combined with sterile saline to form a suspension (liquid) that can be instilled via several different methods: colonoscope, endoscope, nasoduodenal/jejunal tube, nasogastric tube, retention enema, sigmoidoscopy or a combination (upper and lower) approach. A pill form of this treatment is currently being studied. 

A randomized controlled clinical trial by van Nood and colleagues (2013) found that infusion of donor feces was significantly more effective for the treatment of recurrent CDI than the use of vancomycin.  Included in the study were patients who were at least 18 years of age and who had a life expectancy of at least 3 months and a relapse of CDI after at least 1 course of adequate antibiotic therapy (greater than or equal to 10 days of vancomycin at a dose of greater than or equal to 125 mg 4 times per day or greater than or equal to 10 days of metronidazole at a dose of 500 mg 3 times per day).  C. difficile infection was defined as diarrhea (greater than or equal to 3 loose or watery stools per day for at least 2 consecutive days or greate than or eqaul to 8 loose stools in 48 hours) and a positive stool test for C. difficile toxin.  Available isolates were characterized by PCR.  These investigators randomly assigned patients with recurrent CDI to receive 1 of 3 therapies
  1. an initial vancomycin regimen (500 mg orally 4 times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a naso-duodenal tube;
  2. a standard vancomycin regimen (500 mg orally 4 times per day for 14 days); or
  3. a standard vancomycin regimen with bowel lavage. 
The primary end-point was the resolution of diarrhea associated with CDI without relapse after 10 weeks.  The study was stopped after an interim analysis.  Of 16 patients in the infusion group, 13 (81 %) had resolution of C. difficile-associated diarrhea after the first infusion.  The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients.  The investigators reported that resolution of CDI occurred in 4 of 13 patients (31 %) receiving vancomycin alone and in 3 of 13 patients (23 %) receiving vancomycin with bowel lavage (p < 0.001 for both comparisons with the infusion group).  No significant differences in adverse events among the 3 study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day.  After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in bacteroidetes species and clostridium clusters IV and XIVa and a decrease in proteobacteria species.  An accompanying editorial (Kelly, 2013) stated that the study by van Nood et al is an important confirmation of the efficacy of fecal microbiota transplant for recurrent CDI.

Baddour (2013) commented that the findings of this study by van Nood et al will garner much attention and will likely increase the use of fecal transplantation (FT) in the treatment of recurrent CDI.  These happenings, coupled with our increasing understanding of the gut microbiome, should markedly advance our understanding of the pathogenesis and treatment of CDI.

This clinical trial is consistent with the results of earlier studies of fecal bacteriotherapy.  Guo et al (2012) critically appraised the clinical research evidence on the safety and effectiveness of FT compared with standard care in the treatment of patients with clostridium difficile-associated disease (CDAD).  A comprehensive literature search was conducted by a research librarian to identify relevant studies published between 2000 and 2011.  The Cochrane Library, PubMed, EMBASE, CINAHL, Biological Abstracts, BIOSIS Previews and Web of Science were searched.  Methodological quality of the included case series studies was assessed in terms of patient selection criteria, consecutive recruitment, prospective data collection, reporting of lost to follow-up, and follow-up rates.  No controlled studies were found.  Based on the weak evidence from 7 full-text case series studies of 124 patients with recurrent/refractory CDAD, FT appears to be a safe and effective procedure.  In most cases (83 %) symptoms improved immediately after the first FT procedure, and some patients stayed diarrhea-free for several months or years.  The authors concluded that although these results appear to be promising, the treatment effects of FT can not be determined definitively in the absence of a control group.  Results from randomized controlled trials (RCTs) that compare FT to oral vancomycin without or with a taper regimen will help to better define the role of FT in the management of recurrent CDAD.

Guidelines on Clostridium difficile infection from the American College of Gastroenterology (Surawicz, et al., 2013) state that, if there is a third recurrence of Clostridium difficile after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. This is a conditional recommendation based upon moderate-quality evidence. 

Brandt and Reddy (2011) stated that with the increasing prevalence of recurrent/refractory CDI, alternative treatments to the standard antibiotic therapies are being sought.  One of the more controversial of such alternative treatments is fecal microbiota transplantation (FMT).  Although the notion of FMT is foreign -- even startling -- and not esthetic to most people, the concept has been around for many decades.  Its benefit and effectiveness dated back more than 50 years to its use for staphylococcal pseudomembranous colitis, and now FMT is showing a great promise as an inexpensive, safe, and highly efficient treatment for recurrent and refractory CDI.  Moreover, with a better understanding of the intricacies of the colonic microbiome and its role in colonic pathophysiology, FMT has the potential to become the standard of care for CDI treatment, and a potential answer to other intestinal disorders in years to come.

Smits et al (2013) stated that there has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastro-intestinal infections and inflammatory bowel diseases (IBD).  Lately, there has also been interest in its therapeutic potential for cardio-metabolic, autoimmune, and other extra-intestinal conditions that were not previously considered to be associated with the intestinal microbiota.  Although it is not clear if changes in the microbiota cause these conditions, these researchers reviewed the most current and best methods for performing FMT and summarized clinical observations that have implicated the intestinal microbiota in various diseases.  They also discussed case reports of FMT for different disorders, including CDI, irritable bowel syndrome, IBD, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura.  There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardio-metabolic diseases, and these investigators explored these relationships and the potential roles of different microbial strains. 

Kump et al (2013) examined if patients with ulcerative colitis (UC) would benefit from FMT and if dysbiosis can be reversed.  A total of 6 patients with chronic active UC non-responsive to standard medical therapy were treated with FMT by colonoscopic administration.  Changes in the colonic microbiota were assessed by 16S rDNA-based microbial community profiling using high-throughput pyro-sequencing from mucosal and stool samples.  All patients experienced short-term clinical improvement within the first 2 weeks after FMT.  However, none of the patients achieved clinical remission.  Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT.  In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response.  On phylum level, there was a significant reduction of proteobacteria and an increase in bacteroidetes after FMT.  The authors concluded that FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy-refractory UC.  Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis.  They stated that the results of this small study suggested that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.

Zhang et al (2013) stated that the concept of FMT has been used in traditional Chinese medicine at least since the 4th century.  Evidence from recent human studies strongly supports the link between intestinal bacteria and IBD.  These investigators proposed that standardized FMT might be a promising rescue therapy for refractory IBD.  However, there were no reports of FMT used in patients with severe Crohn's disease (CD).  These researchers reported the successful treatment of standardized FMT as a rescue therapy for a case of refractory CD complicated with fistula, residual barium sulfate and formation of intra-peritoneal large inflammatory mass.  The authors concluded that this was the first case of severe CD treated using FMT through mid-gut.

In a pilot study, Cui and colleagues (2015) evaluated the safety, feasibility and effectiveness of FMT through mid-gut for refractory CD.  These researchers established standardized laboratory protocol and clinical work-flow for FMT.  Only refractory CD patients with Harvey-Bradshaw Index (HBI) score greater than or equal to 7 were enrolled for this study.  All included patients were treated with single FMT through mid-gut and assessed during follow-up.  Meta-genomics analysis showed a high concordance between feces sample and purified fecal microbiota from same donors.  Standardized fecal microbiota preparation and clinical flow significantly simplified the practical aspects of FMT.  A total of 30 patients were qualified for the present analysis.  The rate of clinical improvement and remission based on clinical activity at the 1st month was 86.7 % (26/30) and 76.7 % (23/30), respectively, which was higher than other assessment points within 15-month follow-up.  Patients' body weight increased after FMT, and the lipid profile improved as well.  Fecal microbiota transplantation also showed a fast and continuous significant effect in relieving the sustaining abdominal pain associated with sustaining CD.  The authors concluded that these findings demonstrated that FMT through mid-gut might be a safe, feasible, and efficient rescue therapy for refractory CD.

van Nood et al (2014) reviewed the current evidence on FMT for recurrent CDIs, metabolic syndrome and IBD.  These investigators noted that recently, a randomized trial confirmed the effectiveness of this treatment strategy in patients with recurrent CDI.  For other disorders, evidence is still limited.  To-date, studies have been performed to try and influence the course of metabolic syndrome and IBD.  The authors concluded that there is increasing interest in the role of altered microbiota in the development of a myriad of diseases.  Together with new insights comes an interest in influencing this altered microbiota as a potential target for therapy.  Fecal microbiota transplantations are effective against recurrent CDI.  Restoration of intestinal flora and thereby restoration of colonization resistance is thought to be the mechanism responsible for cure.  With the developments in FMT and the extension of this treatment modality to both intestinal and extra-intestinal diseases, a new field of targeted therapy awaits.  The authors concluded that currently, FMT should only be given in a strict experimental setting for other conditions than CDI.

Colman and Rubin (2014) conducted a systematic review and meta-analysis to evaluate the effectiveness of FMT as treatment for patients with IBD.  A systematic literature search was performed through May 2014.  Inclusion criteria required FMT as the primary therapeutic agent.  Clinical remission (CR) and/or mucosal healing were defined as primary outcomes.  Studies were excluded if they did not report clinical outcomes or included patients with infections.  A total of 18 studies (9 cohort studies, 8 case studies and 1 RCT) were included.  A total of 122 patients were described (79 UC; 39 CD; 4 IBD unclassified).  Overall, 45 % (54/119) of patients achieved CR during follow-up.  Among the cohort studies, the pooled proportion of patients that achieved CR was 36.2 % (95 % confidence interval [CI]: 17.4 % to 60.4 %), with a moderate risk of heterogeneity (Cochran's Q, p = 0.011; I2 = 37 %).  Subgroup analyses demonstrated a pooled estimate of CR of 22 % (95 % CI: 10.4 % to 40.8 %) for UC (p = 0.37; I2 = 0 %) and 60.5 % (95 % CI: 28.4 % to 85.6 %) for CD (p = 0.05; I2 = 37 %); 6 studies performed microbiota analysis.  The authors concluded that this analysis suggested that FMT is a safe, but variably effective treatment for IBD.  They stated that more RCTs are needed and should investigate frequency of FMT administration, donor selection and standardization of microbiome analysis.

Almeida and colleagues (2016) stated that as knowledge of the composition and function of the intestinal microbiota continues to expand, there is new interest in using these developments to tailor FMT and microbial ecosystem therapeutics (MET) for a variety of diseases. The potential role of FMT and MET in the treatment of CDI -- currently the leading nosocomial gastro-intestinal infection -- has proven highly effective for recurrent CDI, and has emerged as a paradigm shift in the treatment of this disease. These investigators summarized the key aspects of CDI, and introduced the essential frame-work and challenges of FMT, as is currently practiced. Microbial ecosystem therapeutics represents the progression of conventional bacteriotherapy that fundamentally capitalizes on the restorative properties of intestinal bacterial communities and may be viewed as the culmination of a rationally designed therapeutic modality. The authors concluded that as the understanding of the composition and function of the intestinal microbiota evolves, it will likely drive next-generation microbiota therapies for a range of medical conditions, such as IBD, metabolic syndrome, and obesity.

Oral, Capsulized, Frozen Fecal Microbiota Transplantation

In an open-label, single-group, preliminary feasibility study, Youngster et al (2014) evaluated the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from pre-screened unrelated donors to patients with recurrent CDI. This study was conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. A total of 20 patients (median age of 64.5 years; range of 11 to 89 years) with at least 3 episodes of mild-to-moderate CDI and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe CDI requiring hospitalization were enrolled. Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80° C (-112° F). Patients received 15 capsules on 2 consecutive days and were followed-up for symptom resolution and adverse events for up to 6 months. The primary end-points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end-points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70 %; 95 % CI: 47 % to 85 %) after a single capsule-based FMT. All 6 non-responders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90 % (95 % CI: 68 % to 98 %) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR] of 3 to 6) the day prior to administration to 2 (IQR of 1 to 3) at day 3 (p = 0.001) and 1 (IQR of 1 to 2) at 8 weeks (p < 0.001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR of 5 to 7) for overall health and 4.5 (IQR of 3 to 7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR of 7 to 9) after FMT administration for both overall and gastro-intestinal health (p = 0.001). Patients needing a second treatment to obtain resolution of diarrhea had lower pre-treatment health scores (median of 6.5 [IQR of 5 to 7.3] versus 5 [IQR of 2.8 to 5]; p = 0.02). The authors concluded that this preliminary study among patients with relapsing CDI provided data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. They stated that larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness. The main drawbacks of this study were its small sample size and the lack of placebo or active comparator.

Commenting on the study by Youngster et al, Rex (2014) noted that “The oral use of frozen encapsulated fecal material for FMT seems to be a major improvement over current methods of treating relapsing C. difficile infection -- for a number of obvious reasons. The major risks seem to be vomiting and aspiration, which did not occur in this small, non-placebo-controlled trial. Pending commercialization of frozen encapsulated fecal material, or development of safe, reliable protocols for institutions to create their own frozen encapsulated feces, colonoscopy will likely remain the primary means of FMT administration”.

An UpToDate review on “Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection” (broody et al, 2015) states that “In an open label, single group feasibility study, 20 patients with at least three episodes of mild to moderate C. difficile infection and failure of a six- to eight-week taper with vancomycin taper or at least two episodes of severe C. difficile infection requiring hospitalization were treated with up to 30 frozen FMT capsules on two consecutive days. Diarrhea resolved following initial treatment in 14 of 20 patients and 4 of 6 non-responders who were retreated. No serious adverse events were noted during six months follow-up. However, larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness”.

In a randomized, double-blind, non-inferiority clinical trial, Lee and colleagues (2016) examined if frozen-and-thawed (frozen, experimental) FMT is non-inferior to fresh (standard) FMT in terms of clinical effectiveness among patients with recurrent or refractory CDI and evaluated the safety of both types of FMT. A total of 232 adults with recurrent or refractory CDI were enrolled in this study, which was conducted between July 2012 and September 2014 at 6 academic medical centers in Canada.  Patients were randomly allocated to receive frozen (n = 114) or fresh (n = 118) FMT via enema.  The primary outcome measures were clinical resolution of diarrhea without relapse at 13 weeks and adverse events; non-inferiority margin was set at 15 %.  A total of 219 patients (n = 108 in the frozen FMT group and n = 111 in the fresh FMT group) were included in the modified intention-to-treat (mITT) population and 178 (frozen FMT: n = 91, fresh FMT: n = 87) in the per-protocol population.  In the per-protocol population, the proportion of patients with clinical resolution was 83.5 % for the frozen FMT group and 85.1 % for the fresh FMT group (difference, -1.6 % [95 % CI: -10.5 % to ∞]; p = 0.01 for non-inferiority).  In the mITT population the clinical resolution was 75.0 % for the frozen FMT group and 70.3 % for the fresh FMT group (difference, 4.7 % [95 % CI: -5.2 % to ∞]; p < 0.001 for non-inferiority).  There were no differences in the proportion of adverse or serious adverse events between the treatment groups.  The authors concluded that among adults with recurrent or refractory CDI, the use of frozen compared with fresh FMT did not result in worse proportion of clinical resolution of diarrhea.  Moreover, they stated that given the potential advantages of providing frozen FMT, its use is a reasonable option in this setting. 

In an editorial that accompanied the afore-mentioned study, Malani and Rao (2016) stated that “The current collective understanding of the microbiome remains incomplete, but given demonstrated associations between the gut microbiota and conditions such as obesity, inflammatory bowel disease, diabetes, and colon cancer, there is also increased interest in expanding the therapeutic scope of FMT”.

Fecal Microbiota, Live-jslm (Rebyota)

U.S. Food and Drug Administration (FDA)-Approved Indications

  • Rebyota is indicated for the prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 years of age and older, following antibiotic treatment for recurrent CDI.
  • Limitations of Use: Rebyota is not indicated for the treatment of CDI.

Fecal microbiota, live-jslm (Rebyota) (Ferring Pharmaceuticals, Inc.) is a live biotherapeutic suspension consisting of a broad consortium of microbes prepared from human stool for rectal use for reduction of recurrent Clostridioides difficile (CDI) infection (Khanna et al, 2022). Rebyota was FDA-approved November 2022 for the prevention of recurrence of CDI in individuals 18 years of age and older, following antibiotic treatment for recurrent CDI. FDA-approval is based on results from the "clinical program including the randomized, double-blind, placebo-controlled Phase 3 PUNCH CD3 trial in which a single dose of Rebyota demonstrated superiority to placebo as a treatment to reduce recurrence of CDI after standard-of-care antibiotic treatment. Two hundred sixty-two (262) trial participants received blinded treatment [Rebyota, n=177; placebo, n=85] and the primary endpoint was treatment success, defined as the absence of CDI diarrhea within 8 weeks after completing study treatment. The Bayesian model-estimated treatment success rate at eight weeks for Rebyota was 70.6% versus 57.5% for placebo, with a 99.1% posterior probability that Rebyota was superior to placebo in reducing recurrent CDI after standard-of-care antibiotic treatment. More than 90% of study participants who achieved treatment success remained free of CDI recurrence through six months" (Ferring Pharmaceuticals, 2022a).

Khanna et al (2022) conducted a prospective, multicenter, randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, to evaluate the safety and efficacy of RBX2660 (Rebyota) for the prevention of recurrent CDI. Adults who had one or more CDI recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of CDI diarrhea within 8 weeks of study treatment. Two hundred eighty-nine (289) patients were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events. The authors concluded that RBX2660 is a safe and effective treatment to reduce recurrent CDI following standard-of-care antibiotics with a sustained response through 6 months. 

Rebyota is indicated as a single dose of 150 mL administered rectally 24 to 72 hours after the last dose of antibiotics for CDI. The most commonly reported (3% or more) adverse reactions occurring in adults following a single dose of Rebyota were abdominal pain, (8.9%), diarrhea (7.2%), abdominal distention (3.9%), flatulence (3.3%), and nausea (3.3%).

Other Indications

Alcoholic Hepatitis

Philips and colleagues (2017) noted that patients with severe alcoholic hepatitis (SAH) have high mortality in the presence of steroid unresponsiveness in the absence of clear treatment recommendations.  Liver transplantation (LT) is the curative option in such cases but is controversial in the wake of severe infections, post-transplant recidivism and long waiting on deceased donor listing.  Animal and human studies have shed light on the beneficial effects of gut microbiota modulation in alcoholic liver disease.  These researchers presented the first report of FMT in a steroid non-responder in whom, clinical, biochemical and liver disease severity scores improved post-FMT and demonstrated distinct bacterial population changes pre-FMT and post-FMT.  The authors concluded that healthy donor FMT could be safe and effective in SAH not responding to corticosteroid treatment, as a bridge to LT or in candidates who are unwilling or not ideal for LT for improvement in short-term transplant free survival.  They stated that larger controlled studies are needed for confirmation.

Philips and co-workers (2018) stated that alcohol-induced intestinal dysbiosis is central to the development of the severe alcoholic liver disease.  These researchers presented the first study to compare outcomes in patients with SAH on nutritional therapy, corticosteroids, pentoxifylline, and healthy donor FMT and discussed distinct microbial community and microbiome metabolic functional changes after FMT.  Of 1,271 liver disease patients, 809 (63.7 %) were diagnosed to have the alcoholic liver disease, of which 51 patients (8 treated with corticosteroids, 17 with nutritional support only, 10 with pentoxifylline, 16 receiving FMT were included.  Clinical, biochemical parameters, liver disease, and alcoholic hepatitis severity scores at baseline and mortality at the end of 1 and 3 months were analyzed between groups.  Stool microbiota (SM) analysis was performed for healthy controls (HC) and respective recipients after FMT.  All the patients were male.  The proportions of patients surviving at the end of 1 and 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 63 %, 47 %, 40 % and 75 % [p = 0.179] and 38 %, 29 %, 30 %, and 75 % [p = 0.036], respectively.  When compared with FMT, RR and hazard ratios (HRs) for death were higher in all the other groups.  Following FMT, distinct and beneficial modulation of SM and pathways of dysregulated metabolism, infections, inflammation, and oxidative stress in SAH patients were noted in tandem with improved clinical outcomes.  The authors concluded that healthy donor FMT for SAH improved survival beyond what is offered by current therapies and could function as a cost-effective bridge to LT or for improving transplant-free survival.  Moreover, these investigators stated that larger studies and randomized trials are needed.

Alzheimer's Disease

Sun and colleagues (2019) noted that Alzheimer's disease (AD) is the most common dementia in the elderly; and AD is associated with abnormal gut microbiota.  However, little is known about the role of FMT in AD.  These researchers evaluated the efficacy of FMT for the treatment of AD.  They used an APPswe/PS1dE9 transgenic (Tg) mouse model.  Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed.  Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (NMR).  The results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice . These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42.  These investigators observed an increases in synaptic plasticity in the Tg mice, showing that post-synaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT.  These researchers also observed the decrease of COX-2 and CD11b levels in Tg mice following FMT.  They also found that FMT treatment reversed the changes of gut microbiota and SCFAs.  The authors concluded that FMT might be a potential therapeutic strategy for AD.

Autoimmune Cholangiopathies (e.g., Primary Biliary Cholangitis and Primary Sclerosing Cholangitis)

Gerussi and co-workers (2020) stated that primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited therapeutic options.  A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs.  For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and anti-inflammatory action.  Conversely, different pathogenetic models have been proposed in PSC such as the "leaky gut" hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity.  Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, FMT or new biliary acids (BAs) with possible immunomodulatory potential.  Finally, for both diseases, anti-fibrotic agents are under investigation.

Allegretti and colleagues (2019) noted that PSC is a cholestatic liver disease with no effective medical therapies.  A perturbation of the gut microbiota has been described in association with PSC, and FMT has been reported to restore the microbiome in other disease states.  In an open-label, pilot study, these researchers examined the safety, change in liver enzymes, microbiota, and metabolomic profiles in patients with PSC after FMT.  This trial included patients with PSC with concurrent IBD and alkaline phosphatase (ALP) of greater than 1.5× the upper limit of normal.  Patients underwent a single FMT by colonoscopy.  Liver enzyme profiles and stool microbiome and metabolomic analysis were conducted at baseline and weeks 1, 4, 8, 12, and 24 post-FMT.  The primary outcome was safety, and the secondary outcome was a decrease in ALP levels of greater than or equal to 50 % from baseline by week 24 post-FMT; stool microbiota (by 16S rRNA gene profiling) and metabonomic dynamics were assessed.  A total of 10 patients underwent FMT; 9 patients had UC, and 1 had Crohn's colitis.  The mean baseline ALP level was 489 U/L.  There were no related AEs.  Overall, 30 % (3/10) experienced a greater than or equal to 50 % decrease in ALP levels.  The diversity increased in all patients post-FMT, as early as week 1 (p < 0.01).  More importantly, abundance of engrafter operational taxonomic units in patients post-FMT correlated with decreased ALP levels (p = 0.02).  The authors concluded that to their knowledge, this was the 1st study to demonstrate that FMT in PSC was safe.  Furthermore, increases in bacterial diversity and engraftment may correlate with an improvement in ALP among patients with PSC.

Little and associates (2020) stated that PSC is a chronic cholestatic liver disease characterized by biliary inflammation and stricture.  Exploration of the pathogenesis of PSC in light of its association with IBD and the "gut-liver" axis is an emerging area of interest.  A growing number of studies have begun to examine the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSC-IBD.  Studies of the fecal microbiota have high-lighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others.  A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated.  For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses.  Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites, including BAs, which function as signaling molecules with important gut and hepatic effects.  An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and FMT.  Some of these have already shown some preliminary evidence of benefit.  The authors concluded that despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations.  Moreover, these researchers stated that further investigation is needed to definitively establish the utility of the above strategies and agents.  Key limitations to existing data include their short-term (12 to 24 weeks) nature and the absence of good surrogate end-points that have been shown to correlate with clinically meaningful outcomes.  This latter limitation is a significant hindrance to the study of PSC in general.

Crohn Disease

In a prospective, open-label, single-center study, Gutin and colleagues (2019) examined if single-dose FMT improves clinical and endoscopic outcomes in CD patients and identified meaningful changes in the microbiome in response to FMT.  A total of 10 CD patients underwent FMT and were evaluated for clinical response (defined as decrease in Harvey-Bradshaw Index score greater than or equal to 3 at 1 month post-FMT and microbiome profile (16S ribosomal RNA sequencing) at 1 month post-FMT; 3 of 10 patients responded to FMT; 2 of 10 patients had significant AEs requiring escalation of therapy.  On microbiome analysis, bacterial communities of responders had increased relative abundance of bacteria commonly found in donor gut microbiota.  The authors concluded that single-dose FMT in this cohort of CD patients showed modest effect and potential for harm.  Responders tended to have lower baseline alpha diversity, suggesting baseline perturbation of microbiota may be an indicator of potential responders to FMT in this patient population.  These researchers stated that controlled trials are needed to further evaluate the safety and efficacy of FMT in CD and examine if FMT is a viable option in this patient population.

In a systematic review, Fehily et al (2021) examined the effectiveness of FMT in the treatment of patients with CD.  These investigators carried out a systematic literature search through August 2020 (Medline; Embase).  Studies were included if they reported FMT administration in patients with CD and reported on clinical outcomes.  A total of 15 studies published between 2014 and 2020, comprising 13 cohort studies and 2 RCTs, were included in the analysis.  The majority of studies examined FMT for induction of remission, with follow-up duration varying from 4 to 52 weeks.  One RCT (1-dose in 21 patients) of FMT versus placebo, following steroid-induced remission, showed a higher rate of steroid-free clinical remission in the FMT group compared to the control group: 87.5 % versus 44.4 % at week 10 (p = 0.23).  Another RCT (2-dose FMT in 31 patients) showed an overall clinical remission rate of 36 % at week 8, however, with no difference in clinical or endoscopic endpoints between FMT administered by gastroscopy and colonoscopy.  Considering all studies, the clinical response rates in early follow-up were higher following multiple FMT than with single FMT.  FMT dose did not appear to influence clinical outcomes, nor did whether FMT was fresh or frozen.  FMT delivered via upper GI route demonstrated higher early effectiveness rates of 75 % to 100 % compared with lower delivery route rates of 30 % to 58 %, but on follow up beyond 8 weeks, this difference was not maintained.  Whether pre-FMT antibiotic administration was beneficial was not able to be determined due to the limited number of patients receiving antibiotics and varying antibiotic regimens; no serious AEs were reported.  The authors concluded that preliminary studies suggested that FMT may be an effective therapy in the treatment of CD.  Moreover, these researchers stated that large, controlled studies are needed to validate these findings.

Zhou et al (2023) noted that FMT has been found to be a potential treatment for CD.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of FMT in patients with CD.  They carried out electronic databases searches for studies until January 2023.  Clinical remission was established as the primary outcome.  The secondary outcome was clinical response, endoscopic remission, minor AEs, serious AEs, and changes in disease activity indices, biochemical indicators, and microbial diversities.  Pooled effect sizes and 95 % CIs were calculated under the random effects model.  A total of 11 cohort studies and 1 RCT involving 228 patients were included. In a meta-analysis, the pooled proportion of adult patients with active CD that achieved clinical remission 2 to 4 weeks after FMT was 57 % (95 % CI: 49 % to 64 %) with a low risk of heterogeneity (I2 = 37 %).  In addition, these findings showed that FMT significantly (standardized mean difference = -0.66; 95 % CI: -1.12 to -0.20; I2 = 0) reduced CD activity index scores 4 to 8 weeks after FMT.  Subgroup analyses showed no difference between FMT methodologies, except for pre-FMT treatment with antibiotics (p = 0.02).  Most AEs were self-limiting and disappeared spontaneously within hours or days after FMT.  Microbiota analysis showed an increased Shannon diversity and a shift toward donor-like microbiome after FMT.  The authors concluded that FMT could be a promising therapy in the short-term treatment of active CD; however, these researchers stated that more placebo-controlled randomized trials with a long-term follow-up treatment are needed.

Diabetes / Obesity

He and colleagues (2015) stated that the incidence of diabetes has increased rapidly across the entire world in the past 20 years. Accumulating evidence suggested that gut microbiota contribute to the pathogenesis of diabetes.  Several studies have demonstrated that patients with diabetes are characterized by a moderate degree of gut microbial dysbiosis.  However, there are still substantial controversies regarding altered composition of the gut microbiota and the underlying mechanisms by which gut microbiota interact with the body's metabolism.  These researches reviewed the association between gut microbiota and diabetes.  They performed an electronic search of studies published in English from January 2004 to the November 2014 in the National Library of Medicine, including the original studies that addressed the effects of gut microbiota on diabetes, energy metabolism, inflammation, the immune system, gut permeability and insulin resistance.  They discussed the possible mechanisms by which the gut microbiota are involved in the development of diabetes, including energy metabolism, inflammation, the innate immune system, and the bowel function of the intestinal barrier.  The compositional changes in the gut microbiota in type 2 and type 1 diabetes were also discussed.  The authors introduced the new findings of fecal transplantation, and use of probiotics and prebiotics as new treatment strategies for diabetes.  They stated that future research should be focused on defining the primary species of the gut microbiota and their exact roles in diabetes, potentially increasing the possibility of fecal transplants as a therapeutic strategy for diabetes.

Napolitano and Covasa (2020) stated that a wealth of evidence has revealed the critical role of the gut microbiota in health and disease.  Many chronic diseases have been associated with gut microbiota imbalance in its composition, diversity and functional capacity.  Several types of interventions have been shown to correct microbiota imbalance and restore the beneficial metabolic outcomes of a normal microbiota.  Among them, FMT is an emergent, promising technology employed to improve clinical outcomes of various pathological conditions via modifications in the gut microbiota composition.  FMT has been used successfully as a therapeutic option in recurrent Clostridium difficile infection; however, the potential usage of FMT in other microbiota-associated conditions different from C. difficile such as metabolic syndrome or obesity that are also marked by gut dysbiosis is still under investigation.  In addition, the contribution of the gut microbiota as a cause or consequence in metabolic disease is still largely debated.  The authors concluded that with the potential for negative side effects, the use of FMT for conditions other than recurrent C. difficile infections is ill-advised at this time.  However, the evidence from studies showing remedial effects such as weight loss and better glycemic control are promising and warrant the need for further research into the role of FMT in the pathophysiology of metabolic syndrome.

D-Lactic Acidosis

Davidovics and associates (2017) stated that D-lactic acidosis (D-LA) can occur in patients with short bowel syndrome (SBS) when excessive mal-absorbed carbohydrate (CHO) enters the colon and is metabolized by colonic bacteria to D-lactate.  D-lactate can be absorbed systemically, and increased serum levels are associated with central nervous system toxicity manifested by confusion, ataxia, and slurred speech.  Current therapy, usually directed toward suppressing intestinal bacterial overgrowth and limiting ingested CHO, is not always successful.  Fecal microbiota transplantation has been used for decades to treat recurrent Clostridium difficile infection, and case reports document its use in the successful treatment of constipation, diarrhea, and abdominal pain.  The exact mechanism of action is unknown, but it is surmised that the alteration of the intestinal microbiome, as well as the re-introduction of potential beneficial microbes, helps mediate disease.  The authors presented the case of a child with SBS and recurrent, debilitating D-LA, which was successfully treated with FMT.

Bulik-Sullivan and colleagues (2018) noted that although used primarily for recurrent Clostridium difficile infection, FMT is increasingly being attempted as an experimental therapy for other illnesses, including metabolic disorders; D-LA is a metabolic disorder that may occur in individuals with SBS when lactate-producing bacteria in the colon overproduce D-lactate.  This results in elevated systemic levels of D-lactate, metabolic acidosis, and encephalopathy.  In this single-case study, these investigators reported the successful use of FMT for the treatment of recurrent D-LA in a child who was unresponsive to conventional therapies.  They also presented profiles of the enteric microbiota, as well as fecal D-/L-lactic acid metabolites, before and longitudinally after FMT.  These data provided valuable insight into the putative mechanisms of D-LA pathogenesis and its treatment.  These preliminary findings need to be validated by well-designed studies.

Functional Gastro-Intestinal Disorders

Pinn and associates (2015) stated that despite its high prevalence and significant effect on quality of life, the etiology of functional gastro-intestinal disorders (FGID), and specifically irritable bowel syndrome (IBS), has yet to be fully elucidated. While alterations in immunity, motility, and the brain-gut axis have been implicated in disease pathogenesis, the intestinal microbiota are increasingly being shown to play a role and numerous studies have demonstrated significant differences from normal in the intestinal flora of patients with FGID, and between types of FGID.  It is well established that FMT is a curative therapy for CDI; and FMT is now being explored as a means to also restore intestinal homeostasis in FGID.  The authors examined the role of intestinal microbiota in the pathogenesis of FGID, the implications of FMT for the treatment of FGID, and the challenges encountered in measuring response to a specific intervention in patients with FGID.

Rossen and colleagues (2015) examined the safety and effectiveness of FMT. These investigators systematically reviewed FMT used as clinical therapy.  They searched Medline, Embase, the Cochrane Library and Conference proceedings from inception to July, 2013.  Treatment effect of FMT was calculated as the percentage of patients who achieved clinical improvement per patient category, on an intention-to-treat basis.  These researchers included 45 studies; 34 on CDI, 7 on IBD, 1 on metabolic syndrome, 1 on constipation, 1 on pouchitis and 1 on irritable bowel syndrome (IBS).  In CDI 90 % resolution of diarrhea in 33 case series (n = 867) was reported, and 94 % resolution of diarrhea after repeated FMT in a RCT (n = 16).  In UC remission rates of 0 % to 68 % were found (n = 106).  In CD (n = 6), no benefit was observed.  In IBS, 70 % improvement of symptoms was found (n = 13); 100 % reversal of symptoms was observed in constipation (n = 3).  In pouchitis, none of the patients (n = 8) achieved remission.  One RCT showed significant improvement of insulin sensitivity in metabolic syndrome (n = 10).  Serious adverse events were rare.  The authors concluded that FMT is highly effective in CDI, and holds promise in UC.  As for CD, chronic constipation, pouchitis and IBS data are too limited to draw conclusions.  FMT increases insulin sensitivity in metabolic syndrome.

Gupta and colleagues 92016) stated that there has been increasing interest in understanding the role of the human gut microbiome to elucidate the therapeutic potential of its manipulation.  Fecal microbiota transplantation has been used to successfully treat recurrent CDI.  There are preliminary indications to suggest that it may also carry therapeutic potential for other conditions such as IBD, obesity, metabolic syndrome, and functional gastro-intestinal disorders.

Fang and colleagues (2021) noted that functional constipation is a prevalent, burdensome GI disorder whose treatment remains challenging.  Combined therapy uniting multiple treatments may be promising; FMT that tends to be an etiological treatment has been increasingly examined in its management.  Meanwhile, laxatives are widely used to relieve constipation temporarily; however, their overall efficacy is poor.  These researchers carried out a meta-analysis of RCTs to examine the efficacy of FMT combined with laxatives in the treatment of functional constipation.  They conducted a systematic literature search of 6 electronic databases as of August 11, 2020; RCTs of FMT together with laxatives versus laxatives alone in functional constipation in adults were included.  Two reviewers independently performed the screening, data extraction, and bias assessment.  Dichotomous outcome data were synthesized by RR, and measurement data by weighted mean difference (WMD).  A total of 1,400 records were identified, of which 5 were eligible (409 patients).  Overall, compared to laxatives alone, combined therapy of FMT and laxatives more significantly improved total effective rate (RR: 1.35; 95 % CI: 1.14 to 1.60; I2 = 13 %), Bristol stool form scale score (WMD: 1.04; 95 % CI: 0.57 to 1.51; I2 = 76 %), reduce Wexner score (WMD: -3.25; 95 % CI: -5.58 to -0.92; I2 = 92 %), Knowles-Eccersley-Scott-Symptom (KESS) score (WMD: -5.65; 95 % CI: -7.62 to -3.69; I2 = 0 %) and patient assessment of constipation quality of life (QOL) score (WMD: -18.56; 95 %; CI: -26.43 to -10.68; I2 = 78 %).  No serious adverse events (AEs) were reported.  The majority of included studies had poor methodological quality.  The authors concluded that combined therapy of FMT and laxatives may be a reasonably safe and effective treatment for individuals with functional constipation; however, caution is needed with the interpretation of these data due to the small sample size, high heterogeneity, and low quality of the studies.  Furthermore, these researchers expect that more studies will be carried out to examine the safety and efficacy of combined therapy for the treatment of functional constipation.

Gastro-Intestinal Dysbiosis

Cohen and Maharshak (2017) examined the evidence regarding the use of FMT in conditions other than IBD and CDI.  These researchers performed a PubMed search using the terms "fecal microbiota transplantation" or "FMT" or "bacteriotherapy".  A total of 26 articles describing the use of FMT in a variety of both intra-and extra-intestinal disease conditions including gastro-intestinal, hematologic, neurologic, metabolic, infectious, and autoimmune disorders have been included in this review and have demonstrated some positive results.  The studies included were case reports, case series, controlled trials, and cohort studies.  The authors concluded that the findings of these studies demonstrated that FMT, particularly in conditions associated with GI dysbiosis, showed promise to provide another effective tool in the therapeutic armament of the practicing physician.  They noted that FMT was found to be possibly effective in various diseases, mostly associated with enteric dysbiosis or with immune dysfunction.  Moreover, they stated that randomized clinical studies on large populations should be performed to explore the effectiveness of this therapy, and basic research studies should be designed to gain understanding of the mechanisms through which impact these disorders.

Graft-Versus-Host Disease of the Gut

Kakihana and colleagues (2016) stated that increasing evidence indicates that the gut microbiota is closely associated with acute graft-versus-host disease (aGVHD) in stem cell transplantation (SCT). Fecal microbiota transplantation could represent an alternative treatment option for aGVHD.  However, FMT for SCT patients carries a potential risk of infection by infused microbiota because of the severely immunosuppressed status.  In a pilot study, these researchers evaluated the safety of FMT in SCT.  A total of 4 patients with steroid-resistant (n = 3) or steroid-dependent gut aGVHD (n = 1) received FMT.  No severe adverse events (SAEs) attributed to FMT were observed.  All patients responded to FMT, with 3 complete responses and 1 partial response.  Temporal dynamics of microbiota appeared to be linked to the gut condition of patients and peripheral effector regulatory T cells also increased during response to FMT.  The authors concluded that FMT was safely performed in these patients and might offer a novel therapeutic option for aGVHD.

Kakihana (2017) conducted a feasibility study of FMT for acute GVHD of the gut in four human transplant recipients.  No SAEs that were obviously attributable to FMT were observed.  All patients responded to FMT: 3 patients showed a complete response (CR) and 1 a partial response (PR).  The author concluded that these findings indicated that FMT could be a new therapeutic option for acute GVHD of the gut.  However, the use of FMT in treating acute GVHD is in the initial stages of clinical application.  They noted that FMT has limitations that need to be addressed, such as safety and determination of the optimal donor screening or the treatment protocol; further evaluation is needed.

Qiao et al (2023) examined the safety and effectiveness of FMT in the treatment of GVHD following hematopoietic SCT (HSCT).  These investigators carried out a systematic literature search to conduct a meta-analysis constructed of studies involving GVHD patients treated with FMT.  A total of 23 studies were included, among which 2 prospective cohort studies, 10 prospective single-arm studies, 2 retrospective single-arm studies, 2 case-series, and 7 case-reports.  These studies comprised a total of 242 patients with steroid-resistant or steroid-dependent GVHD secondary to HSCT who were treated with FMT.  A total of 100 cases achieved CRs, while 61 cases showed PRs, and 81 cases presented no effect after FMT treatment.  The estimate of clinical remission OR was 5.51 (95 % CI: 1.49 to 20.35) in cohort studies, and the pooled clinical remission rate was 64 % (51 % to 77 %) in prospective single-arm studies; and 81 % (62 % to 95 %) in retrospective studies, case-series, and case-reports.  A total of 5 (2.1 %) patients had FMT-related infection events; however, all recovered after treatment.  Other adverse effects were mild and acceptable.  Microbiota diversity and composition, donor type, and other related issues were also analyzed.  The authors concluded that these findings indicated that FMT is a promising therapeutic modality of GVHD; however, further validation of its safety and effectiveness is still needed with prospective, control trials.

HIV Infection

Kang and Cai (2019) noted that HIV infection progressively destroys CD4+ mononuclear cells, leading to profound cellular immune deficiency that manifests as life-threatening opportunistic infections and malignancies (i.e., AIDS).  Gut microbiota plays key roles in the modulation of host metabolism and gene expression, maintenance of epithelial integrity, and mediation of inflammatory and immunity.  Hence, the normal intestinal microbiota plays a major role in the maintenance of health and disease prevention.  In fact, a large number of studies have shown that the alteration of the gut microbiota contributes to the pathogenesis of several diseases, such as IBD, IBS, metabolic diseases, anorexia nervosa, autoimmune diseases, multiple sclerosis, cancer, neuropsychiatric disorders, and cardiovascular diseases.  Recently, accumulating evidence has shed light on the association of dysbiosis of gut microbiota with HIV infection.  Hence, the modification of gut microbiota may be a potential therapeutic tool.  The authors concluded that FMT may improve the conditions of patients with HIV infection by manipulating the human intestinal bacteria.  However, the relevant research is very limited, and a large amount of scientific research work needs to be done in the near future.

Inflammatory Bowel Diseases

Weingarden and Vaughn (2017) stated that “With increasing numbers of studies, including randomized trials, of FMT for IBD (39 registered studies on clinicaltrials.gov as of this writing), we will be faced with more clinical data in an area where a mechanistic understanding is lacking.  At the moment, FMT cannot be considered a consistent therapy across trials.  In fact, trials to date vary on the method of FMT delivery, bacterial dose, method of stool filtration, frequency of administration, and do not control for other donor factors such as diet.  This diversity may ultimately be beneficial for deriving a mechanistic underpinning for FMT in IBD, though currently it limits our interpretation of FMT as a clinical success or failure … Continued clinical trials of FMT in IBD without teasing out these underlying mechanisms will continue to result in variable and difficult-to-interpret results.  Beyond the potential therapeutic application, microbial patterns may allow us to identify those at risk for IBD, predict phenotypes or disease courses, and perhaps even predict complications of IBD, such as PSC or dysplasia”.  The authors concluded that IBD is clearly associated with dysbiosis, and the available data suggested there may be a role for manipulating the intestinal microbiota in the treatment of these devastating diseases.

In a systematic review and meta-analysis, Paramsothy and colleagues (2017) examined the safety and effectiveness of FMT in IBD.  A systematic review was conducted until January 2017.  Studies were excluded if patients had co-infection or data were pooled across disease subtypes (UC, CD, pouchitis).  Clinical remission was established as the primary outcome.  Pooled effect sizes and 95 % CIs were obtained using the random effects model.  A total of 53 studies were included [41 in UC, 11 in CD, 4 in pouchitis].  Overall, 36 % [201/555] of UC, 50.5 % [42/83] of CD, and 21.5 % [5/23] of pouchitis patients achieved clinical remission.  Among cohort studies, the pooled proportion achieving clinical remission was 33 % (95 % CI: 23 % to 43 %] for UC and 52 % [95 % CI: 31 % to 72 %] for CD, both with moderate risk of heterogeneity.  For 4 RCTs in UC, significant benefit in clinical remission (pooled odds ratios [[P-OR] = 2.89, 95 % CI: 1.36 to 6.13, p = 0.006) with moderate heterogeneity [Cochran's Q, p = 0.188; I2 = 37 %] was noted.  Sub-analyses suggested remission in UC improved with increased number of FMT infusions and lower GI tract administration.  Most AEs were transient GI complaints.  Microbiota analysis was performed in 24 studies, with many identifying increased diversity and a shift in recipient microbiota profile towards the donor post-FMT.  The authors concluded that FMT appeared effective in UC remission induction, but long-term durability and safety remain unclear.  These researchers stated that additional well-designed controlled studies of FMT in IBD are needed, especially in CD and pouchitis.

Intestinal Multidrug-Resistant Bacterial Decolonization

Manges and colleagues (2016) stated that therapeutic options for multidrug-resistant (MDR) bacterial infections are limited and often less effective.  Non-pharmacologic approaches to preventing or treating MDR infections are currently restricted to improved anti-microbial stewardship and infection control practices.  Fecal microbiota transplantation has emerged as a promising therapy for intestinal MDR bacterial decolonization.  A total of 8 case reports have been published showing FMT resulted in intestinal decolonization of extended spectrum β-lactamase (ESBL)-producing and carbapenemase-producing Enterobacteriaceae, vancomycin-resistant enterococci, or methicillin-resistant staphylococcus aureus.  The procedure has been shown to work even in immunocompromised patients and those experiencing medical crises without any AEs.  These researchers noted that 5 trials are currently underway to further examine the use of FMT for MDR bacterial decolonization.  The authors concluded that FMT is a novel approach to eradicate drug-resistant bacteria from the intestinal reservoir and should be further investigated to address the global problem of difficult-to-treat, MDR bacterial infections.

Bilinski and associates (2016) stated that colonization of the GI tract with MDR bacteria is a consequence of gut dysbiosis.  These investigators described the successful utilization of FMT to inhibit Klebsiella pneumoniae MBL(+) and Eecherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms  The authors concluded that there have been few descriptions of FMT intentionally used to eradicate colonization with antibiotic-resistant bacteria from the GI tract and this report confirmed its utility.  They stated that more systematic evaluation of efficacy of this treatment modality requires a prospective study, which is currently conducted in the authors’ institution.

Davido and co-workers (2017) stated that carbapenem-resistant enterobacteriaceae (CRE) or vancomycin-resistant Enterococci (VRE) carriage present a major public health challenge. Decolonization strategies are lacking.  These researchers evaluated the impact of FMT on a cohort of patients (n = 8) with digestive tract colonization by CRE (n = 6) or VRE (n = 2).  One month after FMT, 2 patients were free from CRE carriage, and another patient was free from VRE after 3 months.  The authors concluded that in their experience, this strategy was safe.  The effectiveness of this approach needs to be further investigated in well-designed studies.

Tavoukjian (2019) stated that antibiotic resistance is a growing global problem associated with increased morbidity and mortality, and presents a significant financial and economic burden on healthcare.  Fecal microbiota transplantation (FMT) has been proven effective for curing recurrent Clostridium difficile infections, however no systematic review to-date has addressed its effectiveness for decolonization of antibiotic-resistant bacteria (ARB) from the gut.  These researchers examined if FMT decolonizes ARB from the gut of colonized adults.  They carried out a systematic review by performing a comprehensive search on Medline, Embase, CENTRAL, PubMed and CINAHL databases for evidence up until May 2018.  Randomized and non-randomized studies evaluating the effects of FMT on gut colonization of ARB in adults were eligible.  Studies were assessed using the Joanna Briggs Institution critical appraisal checklists.  Quality of reporting was assessed using PROCESS and CARE checklists.  Data were synthesized narratively, along with a meta-analysis of proportions for the primary outcome.  A total of 5 studies with 52 subject were included.  Evidence of low quality showed that decolonization was achieved in 50 % of the cases 1 month after FMT with higher response noted in Pseudomonas aeruginosa, and lower response in Klebsiella pneumoniae with New Delhi metallo-beta-lactamase 1 (NDM-1) and extended-spectrum β-lactamase (ESBL) mechanisms of resistance.  In successful cases, 70 % of decolonization cases occurred within the 1st week following FMT; few temporary AEs were identified.  The author concluded that despite the limitations of the included studies, evidence from this review indicated a potential benefit of FMT as a decolonization intervention for ARB, which can only be confirmed by future well-designed RCTs.

Davido and colleagues (2019) noted that spontaneous decolonization of ARB takes time: approximately 25 % after 30 days for carbapenem-producing Enterobacteriaceae or extended-spectrum beta-lactamase-producing Enterobacteriaceae.  Fecal microbiota transplantation (FMT) has been proposed as a new strategy to promote decolonization in order to reduce the risk of super-infection due to these ARB.  These investigators discussed the literature on the use of FMT for this indication, and the improvement levers available to promote its efficacy.  They reviewed the literature available to-date concerning the use of FMT to eradicate ARB, and the different factors that may have influenced the efficacy of decolonization were evaluated.  Four factors that could have played major roles in the efficacy of FMT were identified: bowel preparation before FMT; donor; dose; and thermal conditioning of feces.  The positive or negative impact of each on the outcome of FMT was discussed.  The authors concluded that although FMT is very efficient for the eradication of Clostridium difficile, the same “recipe” could not be used for the eradication of ARB.  These researchers stated that working together with expert centers may help to improve the efficacy of FMT for this indication, and enable the reduction of in-hospital isolation precautions.

In a systematic review and meta-analysis, Dharmaratne et al (2021) examined the effectiveness of FMT for the decolonization of antimicrobial-resistant (AMR) bacteria from the gut.  A total of 4 databases (Embase, Medline, SCOPUS, and Web of Science) were searched up until September 2020; 14 studies (in-vivo (n = 2), case-reports (n = 7), case-series studies without control arm (n = 3), RCT (n = 2)) were reviewed.  Data were synthesized narratively for the case reports, along with a proportion meta-analysis for the case series studies (n = 102 subjects) without a control arm followed by another meta-analysis for case-series studies with a defined control arm (n = 111 subjects) for their primary outcomes.  A total of 7 non-duplicate case reports (n = 9 subjects) were narratively reviewed and found to have broad AMR remission events at the 1-month time-point.  Proportion meta-analysis of case-series studies showed an overall 0.58 (95 % CI: 0.42 to 0.74) AMR remission.  Furthermore, a significant difference in AMR remission was observed in FMT versus treatment naïve (RR = 0.44; 95 % CI: 0.20 to 0.99) and moderate heterogeneity (I2 = 65 %).  A subgroup analysis of RCTs (n = 2) revealed FMT with further benefits of AMR remission with low statistical heterogeneity (RR = 0.37; 95 % CI: 0.18 to 0.79; I2 = 23 %).  The authors concluded that existing studies in this subject are limited and of low quality with moderate heterogeneity, and do not allow definitive conclusions to be drawn.  These researchers stated that more rigorous RCTs with larger sample size and standardized protocols on FMTs for gut decolonization of AMR organisms are needed.

Bilsen et al (2022) noted that antimicrobial resistance is a rising threat to global health and is associated with increased mortality.  Intestinal colonization with multi-drug-resistant organisms (MDRO) can precede invasive infection and facilitates spread within communities and hospitals.  Novel decolonization strategies, such as FMT, are being studied.  In a systematic review, these investigators provided an update on how the field of FMT for MDRO decolonization has developed during the past year and to examine the effectiveness of FMT for intestinal MDRO decolonization.  Since 2020, a total of 7 highly heterogenous, small, non-randomized cohort studies and 5 case-reports have been published.  In line with previous literature, decolonization rates ranged from 20 % to 90 % between studies and were slightly higher for carbapenem-resistant Enterobacteriaceae (CRE) than vancomycin-resistant Enterococcus (VRE).  Despite moderate decolonization rates in 2 studies, a reduction in MDRO bloodstream and urinary tract infections (UTIs) was observed.  The authors concluded that although a number of smaller cohort studies showed some effect of FMT for MDRO decolonization, questions remain regarding the effectiveness of FMT (taking spontaneous decolonization into account), the optimal route of administration, the role of antibiotics pre- and post-FMT and the effectiveness in different patient populations.  Moreover, these researchers stated that despite modest decolonization rates, FMT reduced the number of MDRO infections, a finding warranting further investigation.

The authors stated that next to the low number of controlled studies, the evidence included in this systematic review was limited by small samples sizes.  Furthermore, these investigators noted that their review process had several methodological limitations.  Although title/abstract and full-text screening were carried out by 2 reviewers independently, data extraction and risk of bias assessment was performed by 1 reviewer.  However, a 2nd reviewer was always consulted in case of doubt.  In case of missing data, these researchers did not contact study authors.  These researchers stated that future research should include sufficiently powered RCTs with an adequate duration of follow-up to account for spontaneous decolonization.  The protocol for FMT should be standardized with 1 or more treatments, including the use of different donors to study donor effects.  It is possible that different strategies should be applied to CRE and VRE gut eradication.  Moreover, more stringent definitions of (de)colonization should be applied and different pre- and post-treatments and routes of administration should be compared to optimize effectiveness.  Next to decolonization, the number of MDRO infections post-FMT should be assessed.  These investigators stated that several large RCTs, including both immunocompromised and immunocompetent patients, are currently recruiting.  At least one RCT (NCT04188743) is using a more stringent definition of colonization, requiring at least 2 positive rectal swabs before FMT.  The same RCT is comparing the effectiveness of donor stool to autologous FMT.  Another RCT (NCT04181112) is pre-treating one group with antibiotics, while not pre-treating the other group.  Different routes of administration are being examined, although they are not being compared head-to-head within a single upcoming trial.

Macareno-Castro et al (2022) stated that the prevalence of CRE has increased dramatically in recent years and has become a global public health issue.  Since carbapenems are considered the last drugs of choice, infections caused by these pathogens are difficult to treat and carry a high risk of mortality.  Several antibiotic combination regimens have been employed for the management of CRE infections or to eradicate colonization in CRE carriers with variable clinical responses.  Furthermore, recent studies have examined the use of FMT to eradicate CRE infections.  These investigators carried out a systematic review of publications in which FMT was used to eliminate CRE colonization in infected individuals.  They searched the PubMed, Cochrane, and Medline databases up to November 30, 2021.  A total of 10 studies (209 patients) met the inclusion criteria for this review with 3 articles describing retrospective cohorts (n = 53 patients) and 7 reporting prospective data (n = 156 patients), including 1 open-label, randomized clinical trial.  All studies were published between 2017 and 2021 with 8 from Europe and 2 from South Korea.  There were substantial variations in terms of outcome measurements and study endpoint among these trials.  Among the 112 FMT recipients with confirmed CRE colonization, CRE decolonization was reported in 55/90 cases at 1 month after FMT and at the end of the study follow-up (6 to 12 months), decolonization was documented in 74/94 (78.7 %) patients.  The predominant CRE strains reported were Klebsiella pneumoniae and Escherichia coli and the most frequently documented carbapenemases were KPC, OXA-48, and NDM.  In general, FMT was well-tolerated, with no severe complications reported even in immunosuppressed patients and in those with multiple underlying conditions.  The authors concluded that FMT appeared to be safe and effective in eradicating CRE colonization; however, more studies, especially randomized trials, are needed to validate the safety and effectiveness of FMT for CRE eradication.

Irritable Bowel Syndrome

Maharshak and colleagues (2018) noted that IBS has been associated with changes in the intestinal microbiota.  Only a few studies have explored differences in the mucosa-associated microbiota between IBS patients and healthy controls (HC).  These researchers characterized and compared the microbiota in mucosal and fecal samples from carefully selected patients with IBS-D and HC.  The cohort was composed of 23 diarrhea-predominant IBS (IBS-D) patients and 24 HC.  Fresh stool samples were collected from participants prior to the collection of colonic mucosal samples from an un-prepped bowel.  After DNA extraction, 16S rRNA genes were sequenced by 454 pyrosequencing and analyzed using the QIIME pipeline.  The fecal microbiota (luminal niche) of IBS-D patients was found to have reduced enteric richness compared to HC (p < 0.05), whereas no differences were observed between the 2 groups within the mucosal microbiota.  Within the luminal niche, the relative proportions of Faecalibacterium genus were found to be lower in IBS-D than in HC and the Dorea genus was higher in IBS-D.  None of the taxa proportions were significantly different in IBS-D patients versus HC using an FDR of less than or equal to 0.1 when analyzing samples that appeared in greater than 25 % samples of either niche.  The authors concluded that fecal and mucosal microbiota of IBS-D patients and HC were very similar and were not sufficient to explain the reported altered physiology and symptomatology of IBS-D.  They stated that future studies should investigate intestinal microbiome-dependent functional activity in addition to the fecal and mucosal-associated microbial composition.

In a Cochrane review, Imdad and colleagues (2018) examined the safety and efficacy of FMT for the treatment of IBD.  The authors concluded that FMT may increase the proportion of participants achieving clinical remission in UC.  However, the number of identified studies was small and the quality of evidence was low.  There is uncertainty regarding the rate of SAEs.  As a result, no solid conclusions could be drawn at this time.  These researchers stated that additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity.  No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants.  In addition, no studies assessed long-term maintenance of remission in UC or CD.  These investigators stated that future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.

In a systematic review and meta-analyses of available RCTs, Xu and colleagues (2019) evaluated the efficacy of FMT in IBS.  These researchers performed a systematic literature search of Medline, Embase, Cochrane Central Register of Controlled Trials, and Web of Science.  Selection criteria included RCTs of FMT versus placebo using FMT excipients or autologous FMT in IBS.  Meta-analyses were conducted to evaluate the summary RR and 95 % CIs of combined studies for primary outcome of improvement in global IBS symptoms as measured by accepted integrative symptom questionnaires or dichotomous responses to questions of overall symptom improvement.  Among 742 citations identified, 7 were deemed to be potentially relevant, of which 4 studies involving 254 participants met eligibility.  No significant difference in global improvement of IBS symptoms was observed at 12 weeks in FMT versus placebo (RR = 0.93; 95 % CI: 0.48 to 1.79).  Heterogeneity among studies was significant (I = 79 %).  Subgroup analyses revealed benefits of single-dose FMT using colonoscopy and naso-jejunal tubes in comparison with autologous FMT for placebo treatment (number needed to treat = 5, RR = 1.59; 95 % CI: 1.06 to 2.39; I = 0 %) and a reduction in likelihood of improvement of multiple-dose capsule FMT RCTs (number needed to harm = 3, RR = 0.54; 95 % CI: 0.34 to 0.85; I = 13 %).  Placebo response was 33.7 % in non-oral FMT RCTs and 67.8 % in capsule FMT RCTs.  The Grading of Recommendations Assessment, Development and Evaluation (GRADE) quality of the body of evidence was very low.  The authors concluded that current evidence from RCTs does not suggest a benefit of FMT for global IBS symptoms.  There remain questions regarding the efficacy of FMT in IBS as well as the lack of a clean explanation on the discrepant results among RCTs in subgroup analyses.

Ianiro and associates (2019) noted that increasing evidence supports the role of the gut microbiota in the etiology of IBS.  Fecal microbiota transplantation is a highly effective treatment against recurrent Clostridioides difficile infection in RCTs, and may be beneficial in UC.  However, its efficacy in IBS is uncertain.  These researchers performed a systematic review and meta-analysis to examine this issue.  They searched Medline, Embase, Embase Classic, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov through to March 2019; RCTs recruiting adults with IBS, which compared FMT with placebo, were eligible.  Dichotomous symptom data were pooled to obtain a RR of remaining symptomatic after therapy, with a 95 % CI.  The search strategy identified 322 citations; 5 RCTs were eligible for inclusion, containing 267 patients.  Overall, 92.2 % of included patients had IBS with diarrhea (IBS‐D) or IBS with mixed stool pattern (IBS‐M), and only 7.8 % IBS with constipation (IBS‐C).  When data were pooled for all patients, irrespective of stool type, the RR of IBS symptoms not improving was 0.98 (95 % CI: 0.58 to 1.66).  Placebo capsules administered orally were superior to capsules containing donor stool in 2 pooled trials (RR = 1.96; 95 % CI: 1.19 to 3.20); FMT from donor stool delivered via colonoscopy was superior to autologous stool in 2 pooled RCTs (RR = 0.63; 95 % CI: 0.43 to 0.93); FMT from donor stool via naso-jejunal tube showed a trend towards a benefit over autologous stool in 1 trial (RR = 0.69; 95 % CI: 0.46 to 1.02).  The authors concluded that fresh or frozen donor stool delivered via colonoscopy or naso-jejunal tube may be beneficial in IBS.  Moreover, these researchers stated that larger, more rigorously conducted trials of FMT in IBS are needed.

In a meta-analysis, Myneedu and colleagues (2020) examined if FMT is successful in the treatment of IBS.  These researchers carried out a systematic review to find trials on FMT in IBS. Ratios and RR of improvement for single-arm trials (SATs) and RCTs were calculated, respectively.  Changes in IBS Severity Scoring System (IBS-SSS) and IBS Quality of Life (IBS-QOL) instrument compared to baseline in FMT versus placebo groups were pooled.  In SATs, 59.5 % (95 % CI: 49.1 to 69.3) of IBS patients showed significant improvement.  In RCTs, there were no differences between FMT and control in improvement (RR = 0.93 (95 % CI: 0.50 to 1.75)) or changes in the IBS-SSS and IBS-QOL.  The authors concluded that FMT was not effective in IBS.  Variations in FMT methods and patient factors may contribute to the heterogeneous results of the trials.

El-Salhy et al (2021) noted that although IBS is a benign condition, it reduces the QOL considerably.  While there is currently no effective treatment for this disorder, FMT appears to be promising.  These investigators examined the possible factors affecting the success or failure of RCTs of FMT for IBS and highlighted the gaps in the knowledge that need to be filled and described a possible model for successful FMT in IBS patients.  They carried out a systematic search of literature published in English from January 2015 to December 2020 using the keywords: fecal microbiota transplantation, randomized trials, and IBS.  A total of 7 RCTs on the effectiveness of FMT for IBS were found in the literature; 4 of the 7 RCTs found various positive effects, while the other 3 did not find any effect.  The authors concluded that FMT appeared to be a promising treatment for IBS . The outcome of FMT is donor-dependent, indicating the need for care when selecting donors.  Clinical criteria that are associated with a favorable microbiota signature have been proposed.  However, it is still unclear if some of these criteria are more important than others or if all of the criteria should be satisfied in an effective (super) donor.  These researchers stated that future studies should examine the reliability of these criteria and also compare the microbial signatures between the donor and healthy subjects.  Moreover, these investigators stated that the dose of the fecal transplant is important to the success of FMT, with doses lower than 30 g not showing any effect.  Administering the fecal transplant to either the small or large intestine is effective; however, further studies are needed to establish which route is optimal.  Whether the effectiveness differs between single and repeated FMT also remains to be determined.

Wu et al (2022) stated that RCTs have examined the effectiveness of FMT in IBS with conflicting results.  In a meta-analysis, these researchers examined both the short- and long-term effectiveness of FMT in IBS.  They searched Medline, Embase, and the Cochrane Central Register through September 2021.  RCTs recruiting adult patients with IBS that compared FMT with placebo with dichotomous data of response to therapy were eligible.  Dichotomous data were pooled to obtain a RR of symptom not improving after therapy; RR was also pooled for AEs.  Continuous data were calculated using a mean difference (MD) for IBS-QOL (IBS-QOL).  GRADE methodology was used to evaluate quality of evidence.  The search strategy generated 658 citations; 7 RCTs comprising 472 patients with IBS were included.  FMT was not associated with a significant improvement in global symptom in IBS at 12 weeks in comparison with placebo (RR 0.75, 95 % CI: 0.43 to 1.31) with high heterogeneity between studies (I2 = 87 %).  Subgroup analyses showed that FMT was superior to placebo when administered via colonoscopy or gastroscope (RR 0.70, 95 % CI: 0.51 to 0.96; RR 0.37, 95 % CI: 0.14 to 0.99, respectively, while FMT was inferior to placebo when administered via oral capsules (RR 1.88, 95 % CI: 1.06 to 3.35).  FMT induced a significant improvement in IBS-QOL compared to placebo (MD 9.39, 95 % CI: 3.86 to 14.91) at 12 weeks.  No significant difference in the total number of AEs was observed between FMT and placebo (RR 1.20, 95 % CI: 0.59 to 2.47).  FMT did not significantly improve global symptom in IBS at 1-year follow-up compared with placebo (RR 0.90, 95 % CI: 0.72 to 1.12).  The GRADE quality evidence to support recommending FMT in IBS was very low.  The authors concluded that IBS patients may benefit from FMT when administered via colonoscopy or gastroscope; FMT may improve the QOL of patients with IBS.  Moreover, these researchers stated that the long-term use of FMT in IBS warrants further investigation; and there is very-low-quality evidence to support recommending FMT in IBS.

Rokkas and Hold (2023) noted that treatment is a challenge in IBS, and FMT has attracted significant interest.  Network meta-analysis (NWM) has been established as an evidence-synthesis tool that incorporates direct and indirect evidence in a collection of RCTs comparing therapeutic intervention competing for similar therapeutic results.  No NWM exists concerning the comparative effectiveness and safety of various FMT modalities for IBS.  These investigators updated pair-wise meta-analyses published in the past and examined the comparative safety and effectiveness of various FMT delivery modalities for IBS.  Pair-wise meta-analyses and Bayesian NWM were carried out; heterogeneity, consistency of results and publication bias were examined.  Of 510 titles raised by initial search, 7 RCTs were entered into meta-analyses and NWM.  They included 470 patients and controls, in whom 4 FMT delivery modalities were employed (i.e., via colonoscopy, naso-jejunal tube, duodenoscope, and capsules per os).  In the pair-wise meta-analysis, the pooled results showed that overall FMT was not superior to placebo, whereas the subgroup analyses showed that FMT via duodenoscope and naso-jejunal tube was superior.  The NWM showed that 60-g FMT via duodenoscope had the highest effectiveness (OR, 26.38; 95 % CI: 9.22 to 75.51) and was by far the highest in the effectiveness ranking (SUCRA, 98.8 %).  The authors concluded that pooled results showed no overall advantage of FMT over placebo in IBS; however, upper GI delivery (via duodenoscopy or naso-jejunal tube) proved to be effective.  Moreover, these researchers stated that well-designed RCTs are needed to ensure the safety and effectiveness profile before FMT can be applied in everyday clinical practice for IBS patients.

Neurological Disorders

Vendrik et al (2020) noted that several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy.  FMT is currently the most effective gut microbiota intervention and an accepted treatment for recurrent Clostridioides difficile infections.  To examine indications of FMT for patients with neurological disorders, these investigators examined the available evidence on FMT.  Furthermore, they provided suggestions for future directions.  In July 2019, a total of 5 main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models.  Additionally, the ClinicalTrials.gov website was consulted for registered planned and ongoing trials.  Of 541 identified studies, 34 were included in the analysis.  Clinical trials with FMT have been carried out in patients with autism spectrum disorder (ASD) and showed beneficial effects on neurological symptoms.  For MS and PD, several animal studies suggested a positive effect of FMT, supported by some human case reports.  For epilepsy, Tourette syndrome, and diabetic neuropathy, some studies suggested a beneficial effect of FMT; however, evidence was restricted to case reports and limited numbers of animal studies.  For AD, and Guillain-Barre syndrome (GBS),and stroke, only studies with animal models were identified.  These studies suggested a potential beneficial effect of healthy donor FMT.  In contrast, 1 study with an animal model for stroke showed increased mortality following FMT. For GBS, only 1 study was identified.  Whether positive findings from animal studies could be confirmed in the treatment of human diseases awaits to be seen.  Several trials with FMT as treatment for the afore-mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis (ALS).  The authors concluded that preliminary literature suggested that FMT may be a promising therapeutic option for several neurological disorders; however, available evidence is still scanty and some contrasting results were observed.  These researchers stated that a limited number of studies in humans have been carried out or are ongoing, while for some disorders only animal experiments have been performed.  The authors concluded that large, well-designed double-blinded RCTs in human patients are needed to ascertain the effect of FMT in neurological disorders.

Pasokh et al (2022) stated that FMT is a novel microbiota-based therapeutic method that transfers stool from donor into a recipient and its use is under investigations for the treatment of neurological disorders such as stroke.  In a systematic review, these investigators examined the effect of FMT in progression and treatment of stroke and recovery of post-stroke complications.  Preliminary studies were searched in Medline via PubMed, Scopus, Cochrane library and Google Scholar, databases up to February 2022 were used.  The search strategy was restricted to studies regarding FMT in stroke.  The initial search yielded 4,570 articles, of which 19 publications were included in this systematic review.  Based on outcomes transferring microbiome from healthy or ischemic donor to other ischemic recipient could affect brain infarct volume and survival rate, neurological and behavioral outcomes, and inflammatory pathways.  The authors concluded that this systematic review on pre-clinical studies showed that manipulating gut microbiota via FMT could be a possible therapeutic approach for the treatment of stroke and recovery of post-stroke complications.

Matheson and Holsinger (2023) noted that neurodegenerative diseases are highly prevalent but poorly understood, and with few therapeutic options despite decades of intense research, attention has recently shifted toward other mediators of neurological disease that may present future targets for therapeutic research.  One such mediator is the gut microbiome, which communicates with the brain via the gut-brain axis and has been implicated in various neurological disorders.  Alterations in the gut microbiome have been associated with numerous neurological and other diseases, and restoration of the dysbiotic gut has been demonstrated to improve disease conditions.  One method of restoring a dysbiotic gut is via FMT, re-colonizing the "diseased" gut with normal microbiome.  The authors concluded that FMT is a treatment traditionally used for Clostridium difficile infections; however, it has recently been used in neurodegenerative disease research as a potential therapeutic approach.  These investigators presented a summary of neurodegenerative research that has employed FMT, whether as a treatment or to examine how the microbiome influences pathogenesis.  They stated that the available evidence suggested that gut microbiome modification via FMT may be a novel treatment for AD, PD, MS, and ALS that should be examined in more depth.  At the very least, this approach appeared to provide some relief from symptoms with minimal (if any) adverse side effects; this is valuable in an area where treatments are either missing or limited in their long-term effectiveness; thus, these researchers eagerly await the emergence of further research, especially, clinical trials.

The authors concluded that it is important to note that this specific area of research is still in its infancy; and there are still several drawbacks regarding the current pool of research.  For example, while case studies are valuable for providing inspiration for future studies, and animal studies can provide further insight, clinical trials are still either very limited or lacking entirely.  Furthermore, FMT protocols are rarely standardized across multiple studies; thus, it is difficult to make meaningful inferences on a meta scale.  In addition, different delivery routes (e.g., naso-duodenal tube or colonic delivery) could produce significantly different outcomes.  Some studies may administer antibiotics beforehand, others might not; some studies may use a single FMT infusion, others may use multiple.  Guidelines do exist to aid researchers in selecting donors; however, standardized protocols are still not available.  Given this absence, it would be beneficial for future research to either establish standard procedures or examine the impact of factors such as those mentioned, so that comparison between studies may become possible.

Uceda et al (2023) addressed the complex mechanism involved in the microbiota-gut-brain axis as well as the implications of alterations in the microbial composition of patients with neurodegenerative diseases.  The pathophysiology of neurodegenerative diseases with neuronal loss or death was analyzed, as well as the mechanisms of action of the main metabolites involved in the bi-directional communication via the microbiota-gut-brain axis.  Furthermore, interventions targeting gut microbiota restructuring via FMT and the use of psycho-biotics, prebiotics, and probiotics, were examined as an opportunity to reduce the symptomatology associated with neurodegeneration in these pathologies.  The authors concluded that the future research focusing on the role of the host microbiota in neuropsychiatric disorders offers significant promise for elucidating the complex relationships between the microbiota in various tissues and the brain.  This research has the potential to open new avenues for diagnostic methodologies and innovative therapeutic strategies for these disorders.

Bicknell et al (2023) stated that the human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically.  There is an established link between a healthy, balanced, and diverse microbiome and overall health.  When the gut microbiome becomes unbalanced (dysbiosis) via dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on health, and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, as well as neurological diseases.  While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated.  The link between the gut and the brain is especially important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases.  This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as AD, ASD, MS, PD, and attention-deficit hyperactivity disorder (ADHD), among others.  There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease.  These investigators discussed the role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as FMTs and photo-biomodulation.

These researchers stated that while conventional methods of altering the microbiome, such as diet, prebiotics, and probiotics, have demonstrated some potential in animal models, results in human trials have been less convincing.  Long-term modification of the diet to encourage a healthier microbiome has been shown to reduce the risk of developing neurodegenerative diseases, but the use of these techniques to change the disease trajectory following diagnosis has been less promising.  There is perhaps more opportunity to make a positive change to the microbiome with less established techniques, such as targeted medications, FMT, traditional Chinese medicine (TCM), and photobiomodulation (PBM).  In particular, FMT and PBM showed promise not only in altering the microbiome but also in improving the symptoms of neurogenerative and neurodevelopmental diseases.  What is unclear, is the permanency of any changes that can be made to the microbiome, namely, whether these changes are transient, semi-permanent, or permanent, and how often these treatments might need to be repeated to maintain a healthy microbiome.  Perhaps, a fruitful area of future research is a combination of these novel therapies to target neurodegenerative and neurodevelopmental diseases.

Non-Alcoholic Fatty Liver Disease

Craven and colleagues (2020) stated that non-alcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome (MS).  The gut microbiome plays a role in metabolism and maintaining gut barrier integrity.  Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD; and FMT have been used to alter the gut microbiome.  These researchers hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability.  In a RCT, a total of 21 patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum; IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test.  Additional markers of MS and the gut microbiota were examined.  Patient visits occurred at baseline, 2, 6 weeks, and 6 months post-FMT.  There were no significant changes in HOMA-IR or hepatic PDFF in patients who received the allogenic or autologous FMT.  Allogenic FMT patients with elevated small intestinal permeability (greater than 0.025 lactulose:mannitol, n = 7) at baseline had a significant reduction 6 weeks after allogenic FMT.  The authors concluded that FMT did not improve IR as measured by HOMA-IR or hepatic PDFF; but did have the potential to reduce small intestinal permeability in patients with NAFLD.

Obesity and Metabolic Syndrome

In a double-blind, placebo-controlled pilot trial (FMT-TRIM), Yu and associates (2020) examined the safety of weekly oral FMT capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity.  This trial was carried out at a single U.S. academic medical center.  Between August 2016 and April 2018, these researchers randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks.  The primary outcome, assessed by ITT, was change in insulin sensitivity between 0 and 6 weeks as measured by hyper-insulinemic euglycemic clamps.  Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry (DEXA), and resting energy expenditure by indirect calorimetry.  Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing.  The study population was 71 % female, with an average baseline body mass index (BMI) of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively.  There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+ 5 % ± 12 % in FMT group versus -3 % ± 32 % in placebo group, mean difference 9 %, 95 % CI: -5 % to 28 %, p = 0.16).  There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95 % CI: -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95 % CI: -0.6 to 3.0 kg, p = 0.18) over the 12-week study.  These investigators observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study.  There were no significant differences in AEs (10 versus 5, p = 0.09), and no SAEs related to FMT.  The authors concluded that weekly administration of FMT capsules in adults with obesity resulted in gut microbiota engraftment in most recipients for at least 12 weeks.  Despite engraftment, no clinically significant metabolic effects were observed during the study.  These researchers stated that it appeared unlikely that FMT-induced microbiome compositional changes alone would be sufficient to treat or prevent metabolic disorders in humans.  Future research should examine if pre-selection of donors and/or recipients or specifically designed microbial compositions could optimize beneficial microbiota changes, and whether use of a microbiome intervention in conjunction with a dietary/exercise intervention may lead to synergistic metabolic improvements in adults with obesity.

The authors stated that limitations of this study included the small sample size (n = 24) of this pilot trial and the heterogeneous study population, and inclusion of participants with only mild insulin resistance, perhaps hampering the ability to detect improvements in insulin sensitivity.  Furthermore, these researchers did not evaluate hepatic insulin sensitivity based upon prior studies that only found FMT effects on peripheral insulin resistance.  Although they used sophisticated microbiome analysis tools, they were mostly limited to the taxonomic resolution available from the 16S V4 region, such that roughly 25 % to 75 % of reads in each participant’s baseline sample could not be differentiated from donor sequences.  Nevertheless, results from shotgun sequencing performed on a subset of samples were consistent with their 16S V4 data suggesting engraftment.  As noted earlier, metabolic and microbiome responses were highly variable, and this study was not sufficiently powered to characterize subgroups of responders or outcomes specific to individual donors.  Finally, these investigators did not introduce a dietary intervention to this study design, and the study participants consumed typical high-fat, low-fiber “Western” diets.  Given that a previous study in germ-free mice found that the obese or lean phenotype was only transmissible via FMT in the presence of a low-fat, high-fiber diet, it was possible that pairing gut microbiota modulation with a dietary intervention may be needed to enhance metabolic response.

Zhang and colleagues (2020) noted that FMT is a gut microbial-modulation strategy that has been examined for the treatment of a variety of human diseases, including obesity-associated metabolic disorders. These researchers evaluated current literature and provided an overview of the effectiveness and limitations of FMT as a potential therapeutic strategy for obesity and MS.  A total of 5 electronic data-bases and 2 gray literature sources were searched up to December 10, 2018.  All interventional and observational studies that contained information on the relevant population (adult patients with obesity and MS), intervention (receiving allogeneic FMT) and outcomes (metabolic parameters) were eligible.  From 1,096 unique citations, 3 randomized, placebo-controlled studies (76 patients with obesity and MS, BMI = 34.8 ± 4.1 kg/m2, fasting plasma glucose = 5.8 ± 0.7 mmol/L) were included for review.  Studies reported mixed results with regards to improvement in metabolic parameters; 2 studies reported improved peripheral insulin sensitivity (rate of glucose disappearance, RD) at 6 weeks in patients receiving donor FMT versus patients receiving the placebo control.  Furthermore, 1 study observed lower HbA1c levels in FMT patients at 6 weeks.  No differences in fasting plasma glucose, hepatic insulin sensitivity, BMI, or cholesterol markers were observed between 2 groups across all included studies.  The authors concluded that while promising, the influence of FMT on long-term clinical end-points needs to be further investigated.  Moreover, these researchers stated that future studies are also needed to better understand the mechanisms through which changes in gut microbial ecology and engraftment of microbiota affect metabolic outcomes for patients with obesity and MS.  They noted that further research is also needed to better-define the optimal fecal microbial preparation, dosing, and method of delivery.

The authors stated that their systematic review findings were limited by the small number of studies and the small trial sample sizes.  Furthermore, the studies were conducted primarily by 1 research group and may not reflect expected outcomes across global populations.  More importantly, only 1 study published the raw microbiome data, making it impossible to perform meta-analyses across the individual microbiome data-sets.  These investigators advocated for FMT studies to publish gut microbiome sequencing data to allow for future high-quality aggregate bioinformatic analysis.

Parkinson’s Disease

Huang and colleagues (2019) noted that FMT is recognized as an emerging treatment through reconstruction of gut microbiota.  Parkinson's disease (PD) is a neurodegenerative disorder, which is accompanied by constipation.  These researchers reported a patient with PD and constipation that were relieved following FMT.  A 71-year old man presented with 7 years of resting tremor, bradykinesia (first inflicted the upper limbs and subsequently spread to lower limbs), and intractable constipation (more than 3 years; defecation needing more than 30 mins).  The patient had used madopar, pramipexole, and amantadine for anti-Parkinson and showed partially mitigation while laxative therapy for constipation failed.  Finally FMT was performed.  The patient successfully defecated within 5 mins and maintained daily unobstructed defecation until the end of follow-up.  The patient's tremor in legs almost disappeared at 1 week after FMT; but recurred in the right lower extremity at 2 months following FMT.  The authors concluded that gut microbiota reconstruction may have therapeutic effects for PD patients, especially those who have GI symptoms and limited treatment choices.


In a prospective, open-label, pilot study, Selvig and colleagues (2020) examined the safety, efficacy, and microbiome dynamics of FMT for patients with chronic pouchitis.  This trial was carried out at an academic center among pouchitis patients undergoing FMT.  Patients received a minimum of a single FMT by pouchoscopy from healthy, screened donors.  The primary outcome was clinical improvement in pouchitis assessed by patient survey at week 4.  Secondary outcomes included decrease in total Pouchitis Disease Activity Index (PDAI) Score of greater than or equal to 3 at week 4, bowel movement frequency, ESR, CRP, fecal calprotectin, abdominal pain, and PDAI sub-scores including endoscopic and histologic changes.  Stool samples were collected at baseline and 4 weeks post-FMT to assess bacterial microbiota using V4 16S rRNA sequencing.  A total of 19 patients were enrolled; however, 1 patient was lost to follow-up.  No patients had a major AE or escalation of therapy related to FMT.  Total PDAI scores, endoscopic scores, and histologic scores did not decrease significantly post-FMT.  However, there was a statistically significant improvement in bowel movement (BM) frequency (9.25 to 7.25 BM/day, p = 0.03) and trend for improvement in abdominal pain to improve post-FMT (p = 0.05).  Bacterial microbiota profiling revealed no distinct community-level changes post-FMT, though a small number of specific bacterial taxa significantly differed in relative abundance.  The authors concluded that a single FMT had a tolerable short-term safety profile and may be associated with a decrease in BMs in patients with chronic pouchitis; however, no robust endoscopic or histologic changes were observed.

Trang-Poisson and associates (2020) noted that there is currently no established effective treatment for chronic antibiotic-dependent pouchitis; FMT is a novel therapy involving the transfer of normal intestinal flora from a healthy donor to a patient with a medical condition potentially caused by the disrupted homeostasis of intestinal microbiota or dysbiosis.  These researchers presented the study protocol for a prospective, multi-center, double-blind, randomized, controlled trial that compares the delay of relapse of chronic recurrent pouchitis after FMT versus sham transplantation.  A total of 42 patients with active recurrent pouchitis after having undergone an ileal pouch–anal anastomosis (IPAA) for UC will be enrolled at 12 French centers.  Subjects who respond to antibiotics will be randomized at a ratio of 1:1 to receive either FMT or sham transplantation.  The authors concluded that if the findings of this study are conclusive, FMT, which is less expensive than biologics, could become a routine treatment in the future.

Slow Transit Constipation

In a prospective study, Ding and colleagues (2018) evaluated the clinical outcomes and prognostic factors of FMT for the treatment of slow transit constipation (STC).  A total of 52 patients with STC received standardized FMT and were followed-up for 6 months.  Bowel habit, colonic transit time, constipation-related symptoms (PAC-SYM score), quality of life (PAC-QOL score), treatment satisfaction scores and AEs were monitored.  The primary efficacy end-point was the proportion of patients having on average 3 or more complete spontaneous bowel movements (CSBMs) per week.  The primary efficacy end-point was achieved in 50.0 %, 38.5 % and 32.7 % of patients over week intervals 3 to 4, 9 to 12 and 21 to 24, respectively (p < 0.01 for all comparisons).  Significant improvements were also observed in other bowel movement assessments, colonic transit time, constipation-related symptoms and QOL; but all improvements diminished at weeks 12 and 24.  Incompleteness of evacuation served as the only factor associated with efficacy.  No serious treatment-related AEs were observed.  The authors concluded that the findings of this study showed that FMT was safe and effective for STC.  Patients with a lower degree of sensation of incompleteness could achieve a better outcome.  However, an obvious diminution of efficacy was also observed, which called for regular supplements, such as frozen or freeze-dried FMT capsules.  Moreover, they stated that larger RCTs are needed to further evaluate the benefits and risks of FMT for constipation.

The authors stated that the main drawback of this study was the lack of a controlled group.  This study was a further investigation with larger sample size and longer follow-up based on their previous pilot studies.  As the long-term effects of microbiota manipulation were still unclear, a 6-month follow-up was elected in this study.  According to the available data regarding efficacy of placebo in previous RCTs, it would be difficult and inhumane for patients in the placebo group to complete the 6-month follow-up, considering the poor QOL for constipated patients.  A RCT with shorter follow-up is being conducted in the authors’ center, in which the changes of gut microbiota will be also evaluated.

Ulcerative Colitis

Narula and colleagues (2017) performed a systematic review and meta-analysis to evaluate FMT as a treatment for active UC.  A literature search was conducted to identify high-quality studies of FMT as a treatment for patients with UC.  The primary outcome was combined clinical remission and endoscopic remission or response.  Secondary outcomes included clinical remission, endoscopic remission, and SAEs; OR with 95 % CIs were reported.  Overall, 4 studies with 277 participants were eligible for inclusion.  Among 4 RCTs, FMT was associated with higher combined clinical and endoscopic remission compared with placebo (risk ratio [RR] UC not in remission was 0.80; 95 % CI: 0.71 to 0.89) with a number needed to treat of 5 (95 % CI: 4 to 10).  There was no statistically significant increase in SAEs with FMT compared with controls (RR for AE was 1.4; 95 % CI: 0.55 to 3.58).  The authors concluded that among RCTs, short-term use of FMT showed promise as a treatment to induce remission in active UC based on the observed safety and efficacy.  However, there remain many unanswered questions that require further research before FMT can be considered for use in clinical practice.

Nusbaum and associates (2018) noted that UC is a chronic inflammatory disease of the colon that carries a significant disease burden in children.  Therefore, new therapeutic approaches are being explored to help children living with this disease; FMT has been successful in some children with UC.  However, the mechanism of its therapeutic effect in this patient population is not well understood.  To characterize changes in gut microbial and metabolomic profiles after FMT, these investigators  performed 16S rRNA gene sequencing, shotgun metagenomic sequencing, virome analysis and untargeted metabolomics by gas chromatography-time of flight-mass spectrometry on stool samples collected before and after FMT from 4 children with UC who responded to this treatment.  Alpha diversity of the gut microbiota increased after intervention, with species richness rising from 251 (S.D. 125) to 358 (S.D. 27).  In responders, the mean relative abundance of bacteria in the class Clostridia shifted toward donor levels, increasing from 33 % (S.D. 11 %) to 54 % (S.D. 16 %).  Patient metabolomic and viromic profiles exhibited a similar but less pronounced shift toward donor profiles after FMT. The fecal concentrations of several metabolites were altered after FMT, correlating with clinical improvement. The authors concluded that larger studies using a similar multi-omics approach may suggest novel strategies for the treatment of pediatric UC.

In a systematic review with meta-analysis, Dang and colleagues (2020) compared the safety and efficacy of basic treatment combined with FMT or mixed probiotics therapy in relieving mild-to-moderate UC.  PubMed, Embase, and Cochrane libraries (updated September 2019) were searched to identify randomized, placebo-controlled, or head-to-head trials evaluating FMT or probiotic VSL#3 as induction therapy in active UC.  These researchers analyzed data using the R program to obtain evidence of direct comparison and to generate intermediate variables for indirect treatment comparisons.  A total of 7 randomized, double-blind, placebo-controlled trials were used as the sources of the induction data.  All treatments were superior to placebo.  In terms of clinical remission and clinical response to active UC, direct comparisons showed FMT (OR = 3.47, 95 % CI: 1.93 to 6.25) (OR = 2.48, 95 % CI: 1.18 to 5.21) and mixed probiotics VSL#3 (OR = 2.40, 95 % CI: 1.49 to 3.88) (OR = 3.09, 95 % CI: 1.53 to 6.25) to have better effects than the placebo.  Indirect comparison showed FMT and probiotic VSL#3 did not reach statistical significance either in clinical remission (RR = 1.20, 95 % CI: 0.70 to 2.06) or clinical response (RR = 0.95, 95 % CI: 0.62 to 1.45).  In terms of safety, FMT (OR = 1.15, 95 % CI: 0.51 to 2.61) and VSL #3 (OR = 0.90, 95 % CI: 0.33 to 2.49) showed no statistically significant increase in AEs compared with the control group.  In terms of SAEs, there was no statistical difference between the FMT group and the control group (OR = 1.29, 95 % CI: 0.46 to 3.57).  The probiotics VSL#3 appeared safer than FMT, because SAEs were not reported in the VSL#3 articles.  The authors concluded that FMT or mixed probiotics VSL#3 achieved good results in clinical remission and clinical response in active UC, and there was no increased risk of AEs.  There was no statistical difference between the therapeutic effect of FMT and that of mixed probiotics VSL#3.  However, the use of FMT and probiotics still has many unresolved problems in clinical applications, and more RCTs are needed to confirm its efficacy.

The authors stated that their research had several drawbacks.  First, when a head-to-head clinical trial was absent, the online meta-analysis appeared to be a reasonable tool for conducting comparative studies, but the level of evidence for indirect comparisons was lower than that for direct comparisons.  Second, a slightly different evaluation criterion could result in inaccurate results (e.g., through sensitivity analysis, these investigators concluded that Rossen’s experiments had a large impact on heterogeneity).  Third, the study was limited to patients with mild-t- moderate active UC during the induction period, and there were differences in follow-up time during induction.  The follow-up times ranged from 6 to 12 weeks, and there were large fluctuations, which had a great impact on the results of the experimentt.  Fourth, since the analysis began before registration, this meta-analysis was not registered online.

Liu and colleagues (2021) noted that increasing evidence supports the role of the gut microbiota in the etiology of UC.  While FMT is an effective treatment against recurrent Clostridium difficile infection; its effectiveness in the treatment of UC is still controversial.  In a systematic review and meta-analysis, these researchers examined the safety and efficacy of FMT for treatment of active UC.  They searched Cochrane, Medline, Web of Science, and Embase from inception to February 2020; RCTs recruiting adults with active UC, which compared FMT with controls, were eligible.  The primary outcome was combined clinical remission with endoscopic remission/response.  Secondary outcomes included clinical remission, endoscopic remission, and SAEs; RR with 95 % CI was reported.  A total of 5 RCTs with 292 subjects were eligible for inclusion.  When data were pooled for all patients, FMT was associated with a higher combined clinical remission with endoscopic remission/response; the RR of combined outcome not achieving after FMT versus control was 0.79 (95 % CI: 0.70 to 0.88).  FMT delivered via lower GI route was superior to upper GI route with regard to combined clinical remission with endoscopic remission/response (RR = 0.79, 95 % CI: 0.70 to 0.89).  FMT with pooled donor stool (RR = 0.69, 95 % CI: 0.56 to 0.85) and higher frequency of administration (RR = 0.76, 95 % CI: 0.62 to 0.93) may be more effective with regard to clinical remission.  There was no statistically significant difference in SAEs with FMT compared with controls (RR = 0.98, 95 % CI: 0.93 to 1.03).  The authors concluded that FMT showed a promising perspective with comparable safety and favorable clinical efficacy for the treatment of active UC in the short-term.  Moreover, these researchers stated that future larger, more rigorous RCTs are still needed to address questions regarding donor selection, treatment prior to FMT, ideal stool or microbiota dosage, frequency of administration, predictors of patients most likely to respond, the most effective delivery route in different conditions, and cost-effectiveness, which remain controversial.  Moreover, these researchers stated that there were drawbacks of the included studies in this meta-analysis.  All the included RCTs recruited patients with mild-moderate active UC, instead of serious conditions.  However, patients with severely active UC were difficult to treat in clinic, and FMT was generally used to resolve these serious conditions.  Most of patients with severely active UC were not suitable for RCT.  As a result, further studies should pay more attention to these patients.

Huang et al (2022) stated that FMT as a promising therapy for the treatment of UC remains controversial.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of FMT as a treatment for UC.  The target studies were identified by searching PubMed, Embase, the Cochrane Library, Web of Science, and ClinicalTrials and by manual supplementary retrieval.  These researchers carried out a general review and quantitative synthesis of included studies.  They used the RevMan and Stata programs in the meta-analysis.  The outcomes were total remission, clinical remission, steroid-free remission, and serious AEs.  They also performed subgroup analyses based on different populations.  A total of 34 articles were included in the general review.  Only 16 articles, including 4 RCTs, 2 controlled clinical trials, and 10 cohort studies, were selected for the meta-analysis.  These investigators found that donor FMT might be more effective than placebo for attaining total remission (RR: 2.77, 95 % CI: 1.54 to 4.98; p = 0.0007), clinical remission (RR: 0.33, 95 % CI: 0.24 to 0.41; p < 0.05), and steroid-free remission (RR: 3.63, 95 % CI: 1.57 to 8.42; p = 0.003), but found no statistically significant difference in the incidence of serious AEs (RR: 0.88, 95 % CI: 0.34 to 2.31, p = 0.8).  The subgroup analyses revealed significant differences between the pooled clinical remission rates for different regions, degrees of severity of the disease, and patients with steroid- or nonsteroid-dependent UC.  The authors concluded that FMT could achieve clinical remission and clinical response in patients with UC.

The authors stated that this study had several drawbacks. First, if only high methodological quality studies were included in this meta-analysis, the sample size of the study would be relatively small; thus, moderate-methodological-quality cohort studies were also included in the meta-analysis, which may lead to potential outcome bias.  Second, these investigators only carried out subgroup analyses of populations and outcomes, and various other unreported factors may have affected the overall results, including donor selection, stool, and process conditions.  These researchers stated that clinical trials that clearly report these factors are urgently needed in the future to determine the best conditions for FMT.

Chehade et al (2023) stated that FMT has been examined as a therapeutic option for patients with IBD with controversial results.  In a systematic review and meta-analysis, these investigators examined the benefit of FMT in patients with UC.  Double-blind CTs including adult patients with active UC who received either FMT or placebo were eligible for inclusion.  Outcomes of interest included the rate of combined clinical and endoscopic remission, endoscopic remission or response, clinical remission or response, and specific AEs.  The results were pooled together using Reviewer Manager 5.4 software.  Publication bias was assessed using the Egger's test.  A total of 6 RCTs involving 324 patients were included.  The findings showed that compared with placebo, FMT exhibited significant benefit in inducing combined clinical and endoscopic remission (OR, 4.11; 95 % CI: 2.19 to 7.72; p < 0.0001).  Subgroup analyses of influencing factors showed no differences between pooled or single stool donors (p = 0.71), fresh or frozen FMT (p = 0.35), and different routes or frequencies of delivery (p = 0.80 and 0.48, respectively).  Pre-FMT antibiotics, bowel lavage, concomitant biologic therapy, and topical rectal therapy did not affect combined remission rates (p values of 0.47, 0.38, 0.28, and 0.40, respectively).  Clinical remission or response and endoscopic remission or response were significantly higher in patients who received FMT compared with placebo (p < 0.05) without any differences in serious or specific AEs.  The authors concluded that FMT showed a clinical and endoscopic benefit in the short-term treatment of active UC, with a comparable safety profile to placebo.   Future RCTs are needed to standardize study protocols and examine data on maintenance therapy.

Imdad et al (2023) noted that IBD is a chronic, relapsing disease of the GI tract that is thought to be associated with a complex interplay between the immune system, the GI tract lining, the environment, and the gut microbiome, resulting in an abnormal inflammatory response in genetically susceptible individuals.  An altered composition of the gut's native microbiota, known as dysbiosis, may play an important role in the pathogenesis of UC and CD, 2 subtypes of IBD.  There is growing interest in the correction of this underlying dysbiosis using FMT.  In a Cochrane review, these investigators examined the safety and benefits profile of FMT for the treatment of IBD in adults and children versus autologous FMT, placebo, standard medication, or no intervention.  They searched CENTRAL, Medline, Embase, 2 clinical trial registries, and the reference sections of published trials through December 22, 2022.  These researchers included RCTs that examined adults and children with UC or CD.  Eligible intervention arms used FMT, defined as the delivery of healthy donor stool containing gut microbiota to a recipient's GI tract, to treat UC or CD.  Two review authors independently screened studies for inclusion.  The primary outcomes were induction of clinical remission; maintenance of clinical remission; and serious AEs.  The secondary outcomes were any AEs; endoscopic remission; QOL; clinical response; endoscopic response; withdrawals; inflammatory markers; and microbiome outcomes.  They used the GRADE approach to evaluate the certainty of evidence.  They included 12 studies with 550 participants; 3 studies were carried out in Australia; 2 in Canada; and 1 in each of the following countries: China, the Czech Republic, France, India, the Netherlands, and the U.S., 1 study was carried out in both Israel and Italy.  FMT was administered in the form of capsules or suspensions and delivered by mouth, naso-duodenal tube, enema, or colonoscopy.  One study delivered FMT by both oral capsules and colonoscopy.  A total of 6 studies were at overall low risk of bias, while the others had either unclear or high risk of bias.  A total of 10 studies with 468 participants, of which 9 studies focused on adults and 1 focused on children, reported induction of clinical remission in patients with UC at longest follow-up (range o6 to 12 weeks) and showed that FMT may increase rates of induction of clinical remission in UC compared to control (RR 1.79, 95 % CI: 1.13 to 2.84; low-certainty evidence).  A total of 5 studies showed that FMT may increase rates of induction of endoscopic remission in UC at longest follow-up (range 8 to 12 weeks); however, the CIs around the summary estimate were wide and included a possible null effect (RR 1.45, 95% CI 0.64 to 3.29; low-certainty evidence). Nine studies with 417 participants showed that FMT may result in little to no difference in rates of any adverse events (RR 0.99, 95% CI 0.85 to 1.16; low-certainty evidence). The evidence was very uncertain about the risk of serious adverse events (RR 1.77, 95% CI 0.88 to 3.55; very low-certainty evidence) and improvement in quality of life (mean difference (MD) 15.34, 95% CI -3.84 to 34.52; very low-certainty evidence) when FMT was used to induce remission in UC. Two studies, of which one also contributed data for induction of remission in active UC, assessed maintenance of remission in people with controlled UC at longest follow-up (range 48 to 56 weeks). The evidence was very uncertain about the use of FMT for maintenance of clinical remission (RR 2.97, 95% CI 0.26 to 34.42; very low-certainty evidence) and endoscopic remission (RR 3.28, 95% CI 0.73 to 14.74; very low-certainty evidence). The evidence was also very uncertain about the risk of serious adverse events, risk of any adverse events, and improvement in quality of life when FMT was used to maintain remission in UC. None of the included studies assessed use of FMT for induction of remission in people with CD. One study with 21 participants reported data on FMT for maintenance of remission in people with CD. The evidence was very uncertain about the use of FMT for maintenance of clinical remission in CD at 24 weeks (RR 1.21, 95% CI 0.36 to 4.14; very low-certainty evidence). The evidence was also very uncertain about the risk of serious or any adverse events when FMT was used to maintain remission in CD. None of the studies reported data on use of FMT for maintenance of endoscopic remission or improvement in quality of life in people with CD.  The authors concluded that FMT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. The evidence was very uncertain about whether use of FMT in people with active UC impacted the risk of serious adverse events or improvement in quality of life. The evidence was also very uncertain about the use of FMT for maintenance of remission in people with UC, as well as induction and maintenance of remission in people with CD, and no conclusive statements could be made in this regard. Further studies are needed to address the beneficial effects and safety profile of FMT in adults and children with active UC and CD, as well as its potential to promote longer-term maintenance of remission in UC and CD.

Urinary Tract Infection

Biehl and colleagues (2018) reported on a kidney transplant recipient treated with FMT for recurrent urinary tract infections; FMT was administered via frozen capsulized microbiota.  Before and after FMT, urinary, fecal and vaginal microbiota compositions were analyzed.  The patient remained without symptoms after FMT.  The authors concluded that underlying mechanisms of action need to be addressed in depth by future research.

Bezlotoxumab as Adjunctive Therapy with Fecal Bacteriotherapy

Kaako and colleagues (2019) noted that Clostridium difficile is the most commonly reported pathogen to cause nosocomial infections in the U.S. with a high burden affecting morbidity, mortality and healthcare expenditure.  The use of FMT is one of the current standard therapies for recurrent C. difficile infection (CDIr).  One emerging promising approach is the use of monoclonal antibodies that bind to and neutralize C. difficile toxins such as bezlotoxumab (BEZ).  These researchers presented the 1st case report on combining the 3rd FMT with BEZ after the failure of standard-of-care antibiotics and 2 trials of FMT alone, with subsequent success in preventing the recurrence of refractory CDI for 12 weeks following treatment.  The authors concluded that this case highlighted the need for further studies and guidelines to recommend the best combination among different treatment options and modalities.


The above policy is based on the following references:

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