Fecal Bacteriotherapy

Number: 0844

Policy

Aetna considers fecal bacteriotherapy, including capsulized, frozen fecal microbiota transplantation, medically necessary for persons with Clostridium difficile infection, with infection 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).

Aetna considers fecal bacteriotherapy experimental and investigational for all other indications including the following (not an all-inclusive list):

  • Alcoholic hepatitis
  • Alzheimer's disease
  • Autoimmune cholangiopathies (e.g., primary biliary cholangitis and primary sclerosing cholangitis)
  • Colon cancer
  • Crohn's disease
  • D-lactic acidosis
  • Diabetes
  • Functional gastro-intestinal disorders (e.g., functional constipation, functional diarrhea, and functional dyspepsia)
  • Gastro-intestinal dysbiosis
  • Graft-versus-host disease of the gut
  • Hepatic steatosis
  • HIV infection
  • Idiopathic thrombocytopenic purpura
  • Inflammatory bowel diseases
  • Irritable bowel syndrome
  • Insulin resistance
  • Intestinal multidrug-resistant bacterial decolonization
  • Metabolic syndrome
  • Multiple sclerosis
  • Non-alcoholic fatty liver disease
  • Obesity
  • Parkinson's disease
  • Pouchitis
  • Slow transit constipation
  • Ulcerative colitis
  • Urinary tract infection.

Background

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 motality 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”.

Other Indications

Diabetes:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Fecal Bacteriotherapy for 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.

Fecal Bacteriotherapy for 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.

Fecal Bacteriotherapy for 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.

Fecal Bacteriotherapy for 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.

Fecal Bacteriotherapy for 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.

Fecal Bacteriotherapy for Pouchitis:

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.

Bezlotoxumab as Adjunctive Therapy with Fecal Bacteriotherapy:

Kaako and colleagues (2019) noted that Costridium 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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met :

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

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
E87.2 Acidosis [D-lactic acidosis]
E88.81 Metabolic syndrome [insulin resistance]
G20 Parkinson’s disease
G30.0 - G30.9 Alzheimer’s disease
G35 Multiple sclerosis
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]
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

The above policy is based on the following references:

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