Fecal bacteriotherapy

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Fecal bacteria at 10,000× magnification

Fecal microbiota transplantation (FMT) also known as a stool transplant[1] is the process of transplantation of fecal bacteria from a healthy individual into a recipient.[2] A limited number of studies have shown it to be an effective treatment for patients suffering from Clostridium difficile infection (CDI), which produces effects ranging from diarrhea to pseudomembranous colitis.[3] Beginning in 2000, hypervirulent strains of C. difficile have emerged, which seem to be linked to antibiotics that are commonly used in empiric treatments.[4] In the U.S alone, an estimated 3 million new acute Clostridium difficile infections currently are diagnosed annually.[5] Of these, a subgroup will go on to develop fulminant CDI which results in approximately 300 deaths per day or almost 110,000 deaths per year.[6] Due to the epidemic in North America and Europe, FMT has gained increasing prominence, with some experts calling for it to become first-line therapy for CDI.[7]

Previous terms for the procedure include fecal bacteriotherapy, fecal transfusion, fecal transplant, stool transplant, fecal enema, and human probiotic infusion (HPI). Because the procedure involves the complete restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have now been replaced by the new term 'Fecal Microbiota Transplantation'.[2] FMT involves restoration of the colonic flora by introducing healthy bacterial flora through infusion of stool, e.g. by enema, obtained from a healthy human donor.

Infusion of feces from healthy donors was demonstrated in a randomized, controlled trial to be highly effective in treating recurrent C. difficile, and more effective than vancomycin alone.[8][9] It also may be used to treat other conditions, including colitis,[10] constipation,[10] irritable bowel syndrome,[10] and some neurological conditions.[11][12] In the United States, the Food and Drug Administration (FDA) regulates human faeces as an experimental drug.[13][14][15]

Technique[edit]

Preparing for the procedure requires careful selection and screening of the donor and excluding those who test positive for certain diseases as well as any donor carrying any pathogenic gastrointestinal infectious agent. Approximately 200-300 grams of fecal material is recommended per treatment for optimum results. Fresh stools have been recommended to be used within six hours, however frozen stool samples can also be used without loss of efficacy. There is evidence that the relapse rate is 2 fold greater when water is used as opposed to saline as the dilution agent. There is also some evidence that using infusions of greater than 500 ml produces a higher success rate compared to infusions using less than 200 ml of prepared solution. Research is needed to determine whether certain mixing methods such as using an electric blender reduce the efficacy of treatment via oxygenating the solution and killing obligate anaerobes.[16] The procedure involves single to multiple infusions (e.g. by enema) of bacterial fecal flora originating from a healthy donor. Most patients with CDI recover clinically and their CDI is eradicated after just one treatment.[2][17][18] While C. difficile is easily eradicated with a single FMT infusion, however, this generally appears to not be the case with ulcerative colitis. Published experience of ulcerative colitis treatment with FMT largely shows that multiple and recurrent infusions are required to achieve prolonged remission or 'cure'.[19] The procedure can be carried out via enema,[20] through the colonoscope,[21] or through a nasogastric or nasoduodenal tube.[22] Although a close relative is often the easiest donor to obtain and have tested, there is no reason to expect this to affect the success of the procedure as genetic similarities or differences do not appear to play a role;[2] indeed, in some situations a close relative may be an asymptomatic carrier of C.difficile, a disadvantage. Donors must be tested for a wide array of bacterial and parasitic infections.[2] The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.[23] The fecal microbiota infusions can be administered via various routes depending on suitability and ease, although enema infusion is perhaps the simplest. There does not appear to be any significant methodological difference in efficacy between the various routes. Repeat stool testing should be performed on patients to confirm eradication of CDI. In more than 370 published reports there has been no reported infection transmission.[24] A team of international gastroenterologists and infectious disease specialists have published formal standard practice guidelines for performing FMT which outline in detail the FMT procedure, including preparation of material, donor selection and screening, and FMT administration.[2] In 2012, a team of researchers at MIT founded OpenBiome, the first public stool bank in the U.S.[25] OpenBiome provides clinicians with frozen, ready-to-administer stool samples for use in treating C. difficile, and supports clinical research into the use of FMT for other indications.

A modified form of fecal bacteriotherapy (Autologous Restoration of Gastrointestinal Flora - ARGF) was being developed as of 2009.[26] Medical treatment with antibiotics often is the cause of C. difficile in a patient. An autologous fecal sample, provided by the patient before medical treatment, is stored in a refrigerator. Should the patient subsequently develop C. difficile, the sample is extracted with saline and filtered. The filtrate is freeze-dried and the resulting solid enclosed in enteric-coated capsules. Administration of the capsules is hypothesised to restore the patient's original colonic flora and combat C. difficile. However using one's own original colonic flora which made them susceptible to the CDI infection in the first place obviously holds a foreseeable disadvantage. As such, it is likely that following treatment the patient will still remain susceptible to CDI colonisation. In comparison, the introduction of donor flora facilitates colonisation with a more robust, CDI-resistant flora.

Researchers have also produced a standardised filtrate composed virtually entirely of viable fecal bacteria in a colourless, odourless form.[27] The preparation has been shown to be as effective at restoring missing and deficient bacterial constituents as crude homogenised FMT.[28]

History[edit]

The concept of treating fecal diseases with fecal matter originated in China millennia ago. 'Yellow soup' was made of fecal matter and water, which was drunk by the patient.[29]

The first description of FMT was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill patients with fulminant pseudomembranous colitis (before C.difficile was the known cause) using fecal enemas, which resulted in a rapid return to health.[20] Stool transplants, are about 90% effective in those with severe cases of Clostridium difficile colonization, in whom antibiotics have not worked.[30][30]

Since that time various institutions have offered the treatment as a therapeutic option for a variety of conditions. At the Centre for Digestive Diseases[31] in Sydney Australia, FMT has been offered as a treatment options for more than 20 years. In May 1988 the CDD treated the first idiopathic colitis patient with FMT which resulted in a durable clinical and histological cure.[32] Since that time, a number of publications have reported the successful treatment of UC with FMT,[33][34][35][36][37] with clinical trials now underway in this indication.

As the use of FMT continues to expand, the therapeutic potential of FMT in other conditions, including autoimmune disorders,[38] neurological conditions,[11] obesity, metabolic syndrome and diabetes,[24] Multiple Sclerosis,[39] and Parkinson's disease[12] is now being explored.

In animals[edit]

Elephants, hippos, koalas, and pandas are born with sterile intestines, and to digest vegetation need bacteria obtained from eating their mothers' feces: see Coprophagia#Vertebrates.

Theoretical basis[edit]

The hypothesis behind fecal bacteriotherapy rests on the concept of bacterial interference, i.e. using harmless bacteria to displace pathogenic organisms. In the case of CDI, the C.difficile pathogen is identifiable. However in the case of other conditions such as ulcerative colitis, no single 'culprit' has yet been identified. In patients with relapsing CDI, the mechanism of action may be the restoration of missing components of the flora including Bacteroidetes and Firmicutes.[40][41][42] The introduction of normal flora results in durable implantation of these components.[43] Another theoretical mechanism entails the production of antimicrobial agents (Bacteriocins) by the introduced colonic flora to eradicate C. difficile. This may be a similar mechanism to that of Vancomycin which originated from soil bacteria, and bacillus thuringiensis which has been proven to produce bacteriocins specific for C. difficile.[44] The potential combination of replacement of missing components and production of antimicrobial products manufactured by the incoming flora are likely to be the mechanisms curing CDI. In the case of ulcerative colitis, it is likely that a shared infectious mechanism is at play, where the offending infective agent/s are still unknown. Given the response to FMT, it is scientifically plausible that an infection persists but cannot be identified as was the case with pseudomembranous colitis when it was first treated in 1958.[20]

Benefits[edit]

Benefits of FMT include the restoration of the colonic microbiota to its natural state by replacing missing Bacteroidetes and Firmicutes species, eradication of C. difficile, and resolution of clinical symptoms such as diarrhea, cramping, and urgency. Antibiotic resistance in CDI is an uncommon event- rather CDI relapses due to the presence of C. difficile spores.[45] Not only is FMT effective at eradicating the infection, and replacing microbiota deficiencies as described in CDI, but it also eradicates its spores to prevent recurrence.

Although once considered to be "last resort therapy" by some medical professionals due to its unusual nature and 'invasiveness' compared with antibiotics; perceived potential risk of infection transmission; and lack of Medicare coverage for donor stool, the recent position statement by specialists in infectious diseases and other societies[2] is moving away from FMT as a last-resort treatment and toward acceptance of FMT as standard therapy for relapsing CDI and also Medicare coverage in the United States. Dr Martin Floch, the Editor-In-Chief of the Journal of Clinical Gastroenterology, announced in a recent editorial that "FMT using donor stool has arrived as a successful therapy".[46]

Given that antibiotics are the original cause of CDI through their damage of the normal human flora and removal of protective Bacteroidetes and Firmicutes species further antibiotic therapy should be avoided. It has now been recommended that endoscopic Fecal Microbiota Transplantation be elevated to first-line treatment for patients with clinical deterioration and severe relapsing C. difficile infection.[18] The earlier the infusion is initiated, the less likely the patient's condition will deteriorate, thereby preventing the higher mortality rate associated with severely affected patients. Fecal Microbiota Transplantation is being increasingly used in clinical practice and, since complications of FMT are rare, its use is likely to increase.

A 2009 study found that fecal bacteriotherapy has the advantages of being an effective and simple procedure that is more cost-effective than continued antibiotic administration and reduces the incidence of antibiotic resistance.[47]

A randomised study published in the New England Medical Journal in January 2013 reported a 94% cure rate of pseudomembranous colitis caused by Clostridium difficile, by administering fecal microbiota transplant compared to just 31% with Vancomycin. The study was stopped prematurely as it was considered unethical not to offer the FMT to all participants of the study due to the outstanding results.[8][48]

As of May 2008, studies have also shown that FMT can have a positive effect on devastating neurological diseases such as Parkinson's disease.[12] While Dr. Thomas Borody was experimenting with patients who were afflicted by both CDI and Parkinson's disease, he realized that after fecal therapy the symptoms of Parkinson's in his patients began to decrease; some to the point that the Parkinson's could not be detected by other neurologists. The hypothesis for future studies is that the fluctuation in the body's microbiome done by FMT can also be recreated by adding anti-Clostridium difficile antibodies to the patient's body and this technique shall be used in Dr. Borody's future case studies involving Parkinson's disease.[24]

Regulation[edit]

In May 2013, the US Food and Drug Administration (FDA) issued a public announcement that it had been regulating human faeces as an experimental drug.[13][14] The FDA announced a public workshop in the Federal Register on 25 February 2013 (78 F.R. 12763) entitled "Fecal Microbiota for Transplantation" which was held on 2-3 May 2013.[49] After the American Gastroenterological Association (AGA), the American College of Gastroenterology (ACG), the American Society for Gastrointestinal Endoscopy (ASGE), and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sought clarification about regulatory issues, the FDA Center for Biologics Evaluation and Research (CBER) stated that since FMT is used to prevent, treat, or cure a disease or condition, it would fall within the definition of a biological product as defined in the Public Health Service Act (42 U.S.C. § 262(i)) and the definition of a drug within the meaning of the Federal Food, Drug, and Cosmetic Act (FDCA; 21 U.S.C. § 321(g)), as well as the definition of a drug under the FDCA if its intended to affect the structure or any function of the body, and since the FDA has not approved FMT for therapeutic uses, a product for such use would require an Investigational New Drug application (IND; regulations at 21 C.F.R. 312).[15] The FDA issued guidance for industry entitled "Enforcement Policy Regarding IND Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies" in July 2013 (78 F.R. 42965, 18 July 2013),[50] and draft guidance for industry in March 2014 (79 F.R. 10814, 26 February 2014).[51]

The March 2014 FDA draft guidance says doctors should only use stool from a donor who is "known" to either the patient or their physician, and some doctors and patients are worried that the proposal, if finalized, would shutter the handful of stool banks, which use anonymous donors and ship to providers hundreds of miles away.[14][52][53]

See also[edit]

References[edit]

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