Key Points

Description and history of FMT

FMT is the currently accepted term to describe the “infusion of a fecal suspension from a healthy individual into the gastrointestinal tract of an individual with colonic disease.” Although the notion of FMT is at first unpalatable and inconceivable to some, the concept has existed for many decades and has been used successfully clinically. Historically, the first recorded case of enteric flora transplantation was described by the Italian anatomist, Fabricius Acquapendente, in the seventeenth century, when he reported, “I have heard of animals which lost the capacity to ruminate, which, when one puts into their mouth a portion of the materials from the mouth of another ruminant which that animal has already chewed, they immediately start chewing and recover their former health.” Since that time, transfaunation has been used in veterinary practice for cattle, horses, sheep, and various other animals suffering from rumination disorders and colitis. The first recorded use in humans dates back more than 50 years to its use for antibiotic-induced staphylococcal pseudomembranous colitis (PMC), where it resulted in rapid recovery of previously moribund patients. In the face of the rapidly worsening current CDI epidemic, this therapy has shown great promise as an inexpensive, safe, and highly efficient treatment for recurrent and refractory CDI, which achieves results current pharmaceuticals cannot achieve.

The first published case of FMT in humans was by Eiseman and colleagues in 1958, when they reported the successful treatment of 4 patients with severe PMC using fecal enemas ( Table 1 ). At the time, the investigators were unaware they were treating CDI because C difficile was not recognized as a cause of PMC until 1978. Three of 4 patients were suffering with life-threatening fulminant PMC, which then carried a 75% mortality rate. The patients had failed all available therapies and in desperation the physicians resorted to fecal retention enemas, which resulted in prompt recovery of all patients and facilitated their discharge from hospital within days. At the time, the investigators expressed their hope that a “more complete evaluation of this simple therapeutic measure can be given further clinical trial by others.”

Since FMT’s first introduction into medical practice in 1958, more than 500 patients have been treated for CDI in 35 publications with a cumulative cure rate of 95%. The results are summarized in Table 2 . At the authors’ center alone, approximately 100 patients have been treated for CDI, spanning 24 years.

Description and history of FMT

FMT is the currently accepted term to describe the “infusion of a fecal suspension from a healthy individual into the gastrointestinal tract of an individual with colonic disease.” Although the notion of FMT is at first unpalatable and inconceivable to some, the concept has existed for many decades and has been used successfully clinically. Historically, the first recorded case of enteric flora transplantation was described by the Italian anatomist, Fabricius Acquapendente, in the seventeenth century, when he reported, “I have heard of animals which lost the capacity to ruminate, which, when one puts into their mouth a portion of the materials from the mouth of another ruminant which that animal has already chewed, they immediately start chewing and recover their former health.” Since that time, transfaunation has been used in veterinary practice for cattle, horses, sheep, and various other animals suffering from rumination disorders and colitis. The first recorded use in humans dates back more than 50 years to its use for antibiotic-induced staphylococcal pseudomembranous colitis (PMC), where it resulted in rapid recovery of previously moribund patients. In the face of the rapidly worsening current CDI epidemic, this therapy has shown great promise as an inexpensive, safe, and highly efficient treatment for recurrent and refractory CDI, which achieves results current pharmaceuticals cannot achieve.

The first published case of FMT in humans was by Eiseman and colleagues in 1958, when they reported the successful treatment of 4 patients with severe PMC using fecal enemas ( Table 1 ). At the time, the investigators were unaware they were treating CDI because C difficile was not recognized as a cause of PMC until 1978. Three of 4 patients were suffering with life-threatening fulminant PMC, which then carried a 75% mortality rate. The patients had failed all available therapies and in desperation the physicians resorted to fecal retention enemas, which resulted in prompt recovery of all patients and facilitated their discharge from hospital within days. At the time, the investigators expressed their hope that a “more complete evaluation of this simple therapeutic measure can be given further clinical trial by others.”

Since FMT’s first introduction into medical practice in 1958, more than 500 patients have been treated for CDI in 35 publications with a cumulative cure rate of 95%. The results are summarized in Table 2 . At the authors’ center alone, approximately 100 patients have been treated for CDI, spanning 24 years.

FMT brought into clinical use after the CDI epidemic

Since 2000, there has been a steady increase in CDI rates in numerous health care facilities in the United States, Canada, and Europe, and CDI has reached epidemic proportions in the United States due in part to the emergence of the new hypervirulent toxigenic strains, such as the NAP1/BI/027 strain. This strain has increased toxins A and B production and high-level resistance to fluoroquinolones, secretes an additional binary toxin, and is associated with increased disease severity and worsening outcomes. It has been implicated in outbreaks of CDI worldwide and isolated from 82% of CDI cases during the 2001 to 2003 Quebec outbreaks, where hundreds of patients were infected and several deaths occurred, as well as the devastating outbreak in the Niagara, Ontario, area that caused more than 30 deaths in 2011.

An estimated 3 million new acute CDIs are diagnosed annually in the United States alone. Of these 3 million cases, up to 35%, or approximately 1.05 million patients, fail initial antibiotic treatment and experience a symptomatic relapse. Of this relapsing population, approximately 50% to 65% of patients go on to have multiple relapses (MR-CDI). More worrying is the subset of acute CDI patients who progress to severe CDI due to antibiotic nonresponse, particularly in the presence of the hypervirulent 027 strain and, from there, fulminant CDI (F-CDI), which is frequently fatal.

The rapidly changing epidemiology of CDI in recent years has largely caught the medical community off-guard, and the response has been generally ineffective. Strategies to counter this epidemic included discontinuing the inciting antibiotic and restricting the use of high-risk antibiotics and use of specific antibiotic treatments once the etiology was known. These interventions, however, have failed to arrest the epidemic and, in retrospect, have not taken into account the pathophysiology of relapsing CDI. Despite CDI most commonly occurring after antibiotic exposure, first-line therapies rely heavily on antibiotics, such as vancomycin, metronidazole, and fidaxomicin, which fail to correct the underlying flora deficiencies. Once patients have failed first-line therapies, current CDI therapies lack a solution for the underlying bowel flora deficiencies driving the MR-CDI.

The inability of antibiotic-based measures to hinder the spread of infection suggests that unless drastic and novel therapeutic strategies are used that address the underlying microbiota defects, this epidemic will continue to spread unabated. The predictable consequences include rising morbidity, prolonged illness, greater risk of complications, and higher mortality rates. A crisis has been building in the past 2 decades due in part to the emerging epidemic strain and reducing efficacy of antibiotics, particularly in the face of the epidemic strains. Instead of predicting and preparing for this day by focusing on the cause, however, the medical community has continued to rely on antibiotics, incorporating new models, sophisticated combinations, and novel routes of administrations ; reducing vancomycin protocols ; and developing antitoxin antibodies. An alternative and more effective approach is to address the fundamental microbiota pathology —known since 1989. The industry is scrambling to develop new therapeutic strategies, such as toxin scavengers, immune stimulants, and newer antimicrobials, to counteract this epidemic rather than repairing the underlying microbiota defect. These therapies will unlikely be available for several years, leaving prescribing physicians limited in their choice of curative options while prolonging the duration of the epidemic. It is not hard to fully grasp this scenario, which demands focus and action to avert an ongoing global CDI health care crisis, the latest casualty being Australia with the start of its epidemic.

FMT offers the particularly attractive therapeutic solution of eradicating CDI through the re-establishment of normal intestinal flora composition via the implantation of missing fecal components provided from a healthy donor. Originally a last-ditch therapy for dying patients, the nearly 100% cure rates achieved in MR-CDI and F-CDI have driven institutions worldwide to adopt FMT earlier with an emphasis for FMT to become the first-line treatment option.

GUT mirobiota—the virtual organ

The human gut microbiota is the term used to collectively describe the complex ecosystem of some 10 ¹⁴ bacterial cells housed within the gastrointestinal tract. Extensively more complex than previously believed, the number of microbial cells outnumber the human somatic cells by approximately 1 order of magnitude. Concurrently the microbiome, which is the collective genomes of the gut microbiota, outweighs the human genome by up to 2 orders of magnitude. Recent research has offered new insights into the microbial diversity of the gut microbiota, with the dominant organisms belonging to 7 main bacterial divisions (ie, Firmicutes, Bacteroides, Proteobacteria, Fusobacteria, Verrucomicrobia, Cyanobacteria, and Actinobacteria). Of these, Firmicutes and Bacteroides are the most abundant of the species, comprising approximately 70% of all gut bacteria.

Until recently, the function of the gut microbiota has been underestimated. Commonly believed a waste product of digestion destined for elimination, rarely was it considered an organ of microbial cells contained within humans with critical roles in immunity and energy metabolism—among other roles. With the development of molecular-based metagenomics, metabolomics, and proteomics, various functions of the gastrointestinal microbiota are beginning to be unraveled. Several diverse functions can be ascribed to this microbial organ, summarized in 4 broad categories: (1) pathogen resistance and clearance, (2) immunomodulation, (3) control of epithelial cell proliferation and differentiation, and (4) nutrition and metabolism.

Constantly interfacing with the external environment, arguably one of the most important functions of the gut microbiota, is defense against invading pathogens. This occurs not only through competition for nutrients and adhesion sites, termed colonization resistance , but also through the production of bacteriocins and bacterial-derived immunomodulatory molecules. The intestinal microbiota has been identified as a rich source of protective probiotics, which produce novel antimicrobial and, more specifically, antipathogenic bacteriocins. Thuricin CD is a narrow-spectrum bacteriocin produced by Bacillus thuringiensis found to possess potent activity against C difficile . For the most part—similar to bacterially derived vancomycin —bacteriocins have a narrow spectrum of activity, inhibiting strains closely related to the producer. Some bacteriocins, however, such as nisin, possess a broad spectrum of inhibition, active against a vast array of gram-positive bacteria. In recent years, there has been a particular focus on bacteriocin-producing gut bacteria. Bacteriocin production is believed to provide strains with a competitive advantage within complex microbial environments as a consequence of their associated antimicrobial activity, enabling the establishment and prevalence of producing strains as well as directly inhibiting pathogens within the gut. The production of these antimicrobial peptides and associated intestinal producing strains is one likely mechanism contributing to FMT’s efficacy to beneficially influence the microbial communities of the gastrointestinal tract and facilitate durable implantation.