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Fecal microbiota transplant

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Fecal microbiota transplant
Escherichia coli at 10,000× magnification
Other namesfecal bacteriotherapy, fecal transfusion, fecal transplant, stool transplant

Fecal microbiota transplant (FMT), also known as a stool transplant,[1] is the process of transplantation of fecal bacteria from a healthy individual into a recipient. FMT involves restoration of the colonic microflora by introducing healthy bacterial flora through infusion of stool, e.g. by colonoscopy, enema, orogastric tube or by mouth in the form of a capsule containing freeze-dried material, obtained from a healthy donor. The effectiveness of FMT has been established in clinical trials for the treatment of Clostridium difficile infection (CDI),[2][3] whose effects can range from diarrhea to pseudomembranous colitis.

Due to an epidemic of CDI in North America and Europe, FMT has gained increasing prominence, with some experts calling for it to become first-line therapy for CDI.[4] In 2013 a randomized, controlled trial of FMT from healthy donors showed it to be highly effective in treating recurrent C. difficile in adults, and more effective than vancomycin alone.[2] FMT has been used experimentally to treat other gastrointestinal diseases, including colitis, constipation, irritable bowel syndrome, and neurological conditions such as multiple sclerosis and Parkinson's.[5][6] In the United States, the Food and Drug Administration (FDA) has regulated human feces as an experimental drug since 2013.

Definition

Fecal microbiota transplantation or FMT is the transfer of fecal material containing bacteria and natural antibacterials from a healthy individual into a diseased recipient.[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restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have now been replaced by the new term fecal microbiota transplantation.[7]

Medical uses

Clostridium difficile infection

Clostridium difficile 01
Further information: Clostridium difficile infection

Fecal microbiota transplant is approximately 85 percent to 90 percent effective in those for whom antibiotics have not worked or in whom the disease recurs following antibiotics.[8][9] Most people with CDI recover with one FMT treatment.[7][10][4]

A 2009 study found that fecal microbiota transplant was an effective and simple procedure that was more cost-effective than continued antibiotic administration and reduced the incidence of antibiotic resistance.[11]

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, position statements by specialists in infectious diseases and other societies[7] have been moving toward acceptance of FMT as standard therapy for relapsing CDI and also Medicare coverage in the United States.[12]

It has been recommended that endoscopic FMT be elevated to first-line treatment for people with clinical deterioration and severe relapsing C. difficile infection.[4]

Ulcerative colitis and other gastrointestinal conditions

In May of 1988, Australian Professor Thomas Borody treated the first ulcerative colitis patient using fecal microbiota transplantation, which led to longstanding symptom resolution.[13] Following on from that, Bennet published the first case report documenting reversal of Bennet's own colitis using FMT.[14] While C. difficile is easily eradicated with a single FMT infusion, 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.[15]

Adverse effects

Adverse effects were poorly understood as of 2016.[16] They have included bacterial blood infections, fever, exacerbation of inflammatory bowel disease in people who also had that condition, and mild GI distress which generally resolved soon after the procedure including flatulence, diarrhea, irregular bowel movements, abdominal distension/bloating, abdominal pain/tenderness, constipation, cramping, and nausea.[16]

Technique

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.[7]

Donor selection

Preparing for the procedure requires careful selection and screening of the potential donor. Although a close relative is often the easiest donor to obtain and have tested, they may be a disadvantage as they may be an asymptomatic carrier of C. difficile.[7] This screening involves medical history questionnaires, screening for various chronic medical diseases (i.e. Irritable bowel diseases, Crohn’s disease, Gastrointestinal cancer, etc.),[17][18][19][20] and laboratory testing for pathogenic gastrointestinal infections (i.e. CMV, C. diff, Salmonella, Giardia, GI parasites, etc.).[7][18][19]

Specimen preparation

No laboratory standards have been agreed upon,[19] so recommendations vary for size of sample to be prepared, ranging from 30 to 100 grams (1.1 to 3.5 ounces) of fecal material for effective treatment.[18][20][9][21] Fresh stool is used to increase viability of bacteria within the stool[19][20] and samples are prepared within 6–8 hours.[19][18][20] The sample is then diluted with 2.5-5 times the volume of the sample with either normal saline,[19][18] sterile water,[19][18] or 4% milk.[7] Some locations mix the sample and the solvent with a mortar and pestle,[20] and others use a blender.[19][18][20] There is concern with blender use on account of the introduction of air which may decrease efficacy[5] as well as aerosolization of the feces contaminating the preparation area.[18][20] The suspension is then strained through a filter and transferred to administration container.[19][18][20] If the suspension is to be used later, it can be frozen after being diluted with 10% glycerol,[19][18][20] and used without loss of efficacy compared to the fresh sample.[18][21] The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.[5]

Administration

After being made into suspensions, the fecal material can be given up-to-down through nasogastric and nasoduodenal tubes, or back-up through a colonoscope or as a retention enema.[7]

Mechanism of action

The hypothesis behind fecal microbiota transplant 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.[22] However, in the case of other conditions such as ulcerative colitis, no single culprit has yet been identified.[23]

History

The concept of treating fecal diseases with fecal matter originated in China millennia ago. Fourth century Chinese medical literature mentions it to treat food poisoning and severe diarrhea. 1200 years later Li Shizhen used "yellow soup" (aka "golden syrup") which contained fresh, dry or fermented stool to treat abdominal diseases.[24] "Yellow soup" was made of fecal matter and water, which was drunk by the person.[25]

The consumption of "fresh, warm camel feces" has also been recommended by Bedouins as a remedy for bacterial dysentery; its efficacy probably attributable to the antimicrobial subtilisin produced by Bacillus subtilis was anecdotally confirmed by German soldiers of the Afrika Korps during World War II".[26]

The first use of FMT in western medicine was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill people with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas, which resulted in a rapid return to health.[27] For over two decades, FMT has been provided as a treatment option at the Centre for Digestive Diseases in Five Dock, by Professor Thomas Borody, the modern day proponent of FMT. In May of 1988 their group treated the first ulcerative colitis patient using FMT, which resulted in complete resolution of all signs and symptoms long-term.[13] In 1989 they treated a total of 55 patients with constipation, diarrhea, abdominal pain, ulcerative colitis, and Crohn’s disease with FMT. After FMT, 20 patients were considered 'cured' and a further 9 patients had a reduction in symptoms.[28] Stool transplants are considered about 90 percent effective in those with severe cases of Clostridium difficile colonization, in whom antibiotics have not worked.[8]

The first randomized controlled trial in clostridium difficile infection was published in January 2013.[2] The study was stopped early due to the effectiveness of FMT, with 81% of patients achieving cure after a single infusion and over 90% achieving a cure after a second infusion.

Since that time various institutions have offered FMT as a therapeutic option for a variety of conditions.[15]

Society and culture

Regulation

Interest in FMT surged in 2012 and 2013, as measured by the number of clinical trials and scientific publications.[29]

In the United States, the FDA announced in February 2013 that it would hold a public meeting entitled "Fecal Microbiota for Transplantation" which was held on May 2–3, 2013.[30][31] In May 2013 the FDA also announced that it had been regulating human fecal material as a drug.[32] 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, and the FDA Center for Biologics Evaluation and Research (CBER) stated that FMT falls within the definition of a biological product as defined in the Public Health Service Act and the definition of a drug within the meaning of the Federal Food, Drug, and Cosmetic Act.[33] It argued since FMT is used to prevent, treat, or cure a disease or condition, and intended to affect the structure or any function of the body, "a product for such use" would require an Investigational New Drug (IND) application.[33]

In July 2013, the FDA issued an enforcement policy ("guidance") regarding the IND requirement for using FMT to treat C. difficile infection unresponsive to standard therapies (78 FR 42965, July 18, 2013).[34]

In March 2014, the FDA issued a proposed update (called "draft guidance") that, when finalized, is intended to supersede the July 2013 enforcement policy for FMT to treat C. difficile infections unresponsive to standard therapies. It proposed an interim discretionary enforcement period, if 1) informed consent is used, mentioning investigational aspect and risks, 2) stool donor is known to either the person with the condition or physician, and 3) if stool donor and stool are screened and tested under the direction of the physician (79 FR 10814, February 26, 2014).[35] Some doctors and people who want to use FMT have been worried that the proposal, if finalized, would shutter the handful of stool banks which have sprung up, using anonymous donors and ship to providers hundreds of miles away.[29][36][37]

As of 2015 FMT for recurrent C. difficile infections can be done without mandatory donor and stool screening, whereas FMT for other indications cannot be performed without an IND.[32]

Stool banks

In 2012, a team of researchers from the Massachusetts Institute of Technology founded OpenBiome, the first public stool bank in the United States[38]

Across Europe, numerous stool banks have emerged to serve the increasing demand. While consensus rapports exists,[39] standard operation procedures still differs. Institutions in the Netherlands have published their protocols for managing FMT,[40] and in Denmark institutions manages FMT according to the European Tissue and Cell directive.[41]

In 2016, a team of entrepreneurs launched the Asia Microbiota Bank in Hong Kong, which is the first commercial stool bank in Asia[42]. The Bank also supports the Hong Kong Digestive Centre, which supplies fecal microbiota transplantation both via enema and oral capsule.

Research

Cultured intestinal bacteria are being studied as an alternative to fecal microbiota transplant.[43] Research has also been done to identify the most relevant microbes within fecal transplants, which could then be isolated and manufactured via industrial fermentation; such standardized products would be more scalable, would reduce the risk of infections from unwanted microbes, and would improve the scientific study of the approach, since the same substance would be administered each time.[44]

Veterinary use

Elephants, hippos, koalas, and pandas are born with sterile intestines, and to digest vegetation need bacteria which they obtain by eating their mothers' feces, a practice termed coprophagia. Other animals eat dung.[45]

In veterinary medicine fecal microbiota transplant has been known as "transfaunation" and is used to treat ruminating animals, like cows and sheep, by feeding rumen contents of a healthy animal to another individual of the same species in order to colonize its gastrointestinal tract with normal bacteria.[46]

References

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  31. ^ 78 FR 12763, February 25, 2013
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  33. ^ a b AGA Confirms IND is Required for Fecal Microbiota Transplantation, American Gastroenterological Association, May 6, 2013, archived from the original on May 10, 2013
  34. ^ "Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies". Food and Drug Administration. July 2013.
  35. ^ "Draft Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies". Food and Drug Administration. March 2014.
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  39. ^ Cammarota G, Ianiro G, Tilg H, Rajilić-Stojanović M, Kump P, Satokari R, Sokol H, Arkkila P, Pintus C, Hart A, Segal J, Aloi M, Masucci L, Molinaro A, Scaldaferri F, Gasbarrini G, Lopez-Sanroman A, Link A, de Groot P, de Vos WM, Högenauer C, Malfertheiner P, Mattila E, Milosavljević T, Nieuwdorp M, Sanguinetti M, Simren M, Gasbarrini A (April 2017). "European consensus conference on faecal microbiota transplantation in clinical practice". Gut. 66 (4): 569–580. doi:10.1136/gutjnl-2016-313017. PMID 28087657.
  40. ^ Terveer EM, van Beurden YH, Goorhuis A, Seegers JF, Bauer MP, van Nood E, Dijkgraaf MG, Mulder CJ, Vandenbroucke-Grauls CM, Verspaget HW, Keller JJ, Kuijper EJ (December 2017). "How to: Establish and run a stool bank". Clinical Microbiology and Infection. 23 (12): 924–930. doi:10.1016/j.cmi.2017.05.015. PMID 28529025.
  41. ^ Jørgensen SM, Hansen MM, Erikstrup C, Dahlerup JF, Hvas CL (November 2017). "Faecal microbiota transplantation: establishment of a clinical application framework". European Journal of Gastroenterology & Hepatology. 29 (11): e36–e45. doi:10.1097/MEG.0000000000000958. PMID 28863010.
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Further reading

  • Bibbò S, Ianiro G, Gasbarrini A, Cammarota G (December 2017). "Fecal microbiota transplantation: past, present and future perspectives". Minerva Gastroenterologica E Dietologica. 63 (4): 420–430. doi:10.23736/S1121-421X.17.02374-1. PMID 28927251.
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