Fecal bacteriotherapy

Escherichia coli at 10,000× magnification

A 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 enema, orogastric tube or orally in the form of a capsule containing freeze-dried material, obtained from a healthy donor. A limited number of studies have shown it to be an effective treatment for patients suffering from Clostridium difficile infection (CDI), which 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. 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. 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. In the United States, the Food and Drug Administration (FDA) has regulated human faeces 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.[2] 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restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have now been replaced by the new term fecal microbiota transplantation.[2]

Medical uses

Clostridium difficile infection

Clostridium difficile infection (CDI) 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 commonly used broad acting antibiotics that are prescribed empirically.[4] As of 2009 an estimated 3 million new acute Clostridium difficile infections were diagnosed in the US 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] This epidemic of CDI in North America and Europe, has made FMT increasingly attractive, with some experts calling for it to become first-line therapy for CDI.[7]

The original cause of CDI is damage of the normal human flora and removal of protective Bacteroidetes and Firmicutes species. FMT restores the colonic microbiota to its natural state by replacing missing Bacteroidetes and Firmicutes species, eradicates C. difficile including its spores, and resolves 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.[8] Anecdotal reports had shown FMT to be an effective treatment for patients with recurrent CDI.[3] Most patients with CDI recover clinically and their CDI is eradicated after just one treatment.[2][9][10]

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

In 2013, a randomized, controlled trial of FMT published in the New England Medical Journal in January 2013 reported a 94% cure rate of pseudomembranous colitis caused by Clostridium difficile in adults,compared to just 31% with Vancomycin alone. 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.[12][13][14]

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[2] have been moving toward acceptance of FMT as standard therapy for relapsing CDI and also Medicare coverage in the United States.[15]

It has now been recommended that endoscopic FMT be elevated to first-line treatment for patients with clinical deterioration and severe relapsing C. difficile infection.[10] 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.

Ulcerative colitis and other gastrointestinal conditions

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'.[16]

FMT has been used to treat other conditions, including colitis,[17] constipation,[17] and irritable bowel syndrome.[17]

Autoimmune and neurologic conditions

The therapeutic potential of FMT in non-gastroenterologic conditions, including autoimmune disorders,[18] neurological conditions,[19] obesity, metabolic syndrome and diabetes,[20] multiple sclerosis,[19] and Parkinson's disease[21] are now being explored. As of May 2008, studies had shown that FMT can have a positive effect on devastating neurological diseases such as Parkinson's disease.[21] 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 a technique intended to be used in Borody's future case studies involving Parkinson's disease.[20]

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.[2]

Donor selection

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.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] In more than 370 published reports there has been no reported infection transmission.[20]

Specimen preparation

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.[22] The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.[23]

Administration

Numerous techniques have been published, and choice depends on suitability and ease. The procedure involves single or multiple infusions of bacterial fecal flora originating from a healthy donor by enema,[24] through a colonoscope,[25] or through a nasogastric or nasoduodenal tube.[26] There does not appear to be any significant methodological difference in efficacy between the various routes. A recent study [27] anyway has shown that fecal transplant through colonoscopy has a better outcome than transplant performed with a nasogastric or nasoduodenal tube, with a success rate of 90% of patients treated with transplant by colonoscopy vs 81% [28] of patients treated with transplant by NG tube.

Autologous restoration of gastrointestinal flora

A modified form of fecal bacteriotherapy (autologous restoration of gastrointestinal flora—ARGF) was being developed as of 2009.[29] An autologous fecal sample, provided by the patient before anticipated medical treatment with antibiotics, is stored in a refrigerator. Should the patient subsequently develop C. difficile infection 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 C. difficile colonisation. In comparison, the introduction of donor flora facilitates colonisation with a more robust, C. difficile-resistant flora.

Standardised filtrate

Researchers have also produced a standardised filtrate composed of viable fecal bacteria in a colourless, odourless form.[30] The preparation has been shown to be as effective at restoring missing and deficient bacterial constituents as crude homogenised FMT.[31]

Public stool bank in the United States

In 2012, a team of researchers from the Massachusetts Institute of Technology founded OpenBiome, the first public stool bank in the United States[32] OpenBiome provides clinicians with frozen, ready-to-administer stool samples for use in treating C. difficile, and supports clinical research into the use of faecal transfer for other indications.

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.[33]'Yellow soup' was made of fecal matter and water, which was drunk by the patient.[34]

The consumption of "fresh, warm camel feces has 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".[35]

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.[24] Stool transplants, are about 90% effective in those with severe cases of Clostridium difficile colonization, in whom antibiotics have not worked.[36][36]

Since that time various institutions have offered FMT as a therapeutic option for a variety of conditions. At the Centre for Digestive Diseases in Sydney, Australia, FMT has been offered as a treatment option 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.[37] Since that time, a number of publications have reported the successful treatment of UC with FMT,[38][39][40][41][42] with clinical trials now underway in this indication.

In animals

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. Many other vegetarian mammals eat dung "because it's so hard to extract nourishment from their nutrient-poor diet".[43]

In veterinary medicine fecal bacteriotherapy has been known as 'transfaunation' and is used to treat ruminating animals, like cows and sheep, by feeding rumen of a healthy animal to another individual of the same species in order to colonize its gastrointestinal tract with normal bacteria.[44]

The Italian Renaissance anatomist Hieronymus Fabricius was familiar of transfaunation.

Theoretical basis

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.[45][46][47] The introduction of normal flora results in durable implantation of these components.[48]

Another postulated 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 originates from soil bacteria, and Bacillus thuringiensis which has been proven to produce bacteriocins specific for C. difficile.[49] The potential combination of replacing missing components and 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.

Regulation

Interest in FMT as measured by the number of clinical trials and scientific publications surged in 2012 and 2013.[50] The first rigorous, head-to-head study (randomized controlled trial) published in January 2013 showed FMT was superior to antibiotics for patients with recurring C. difficile.[12]

The FDA announced in February 2013 it would hold a public meeting entitled "Fecal Microbiota for Transplantation" which was held on 2–3 May 2013.[51][52] In May 2013 the FDA also announced that it had been regulating human faeces as a drug.[53] 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.[54] 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.[54]

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, 18 July 2013).[55]

In February 2014, a gastroenterologist, a biological engineering professor from Massachusetts Institute of Technology (MIT) and an MIT microbiology PhD candidate, with the latter two being co-founders of the stool bank OpenBiome, recommended that for medical use, human stool should be considered a tissue not a drug, and argued that although the strict requirements protect patients it also limits access to care and that if stool was treated as a tissue product or given its own classification like blood it would keep patients safe, ensure broad access and facilitate research.[53]

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 patient or physician and 3) if stool donor and stool are screened and tested under the direction of the physician (79 FR 10814, 26 February 2014).[56] Some doctors and patients 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.[50][57][58]

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.[53]

See also

References

  1. ↑ Rowan, Karen (20 October 2012). "'Poop Transplants' May Combat Bacterial Infections". LiveScience.com. Retrieved 2012-10-20.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Bakken, Johan S.; Borody, Thomas; Brandt, Lawrence J.; Brill, Joel V.; Demarco, Daniel C.; Franzos, Marc Alaric; Kelly, Colleen; Khoruts, Alexander; Louie, Thomas; Martinelli, Lawrence P.; Moore, Thomas A.; Russell, George; Surawicz, Christina (1 December 2011). "Treating Clostridium difficile Infection With Fecal Microbiota Transplantation". Clinical Gastroenterology and Hepatology 9 (12): 1044–1049. doi:10.1016/j.cgh.2011.08.014. PMC 3223289. PMID 21871249.
  3. ↑ 3.0 3.1 Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011; 9(2): 88-96
  4. ↑ Gould CV, McDonald LC. (2008). "Bench-to-bedside review: Clostridium difficile colitis". Crit Care 12 (1): 203. doi:10.1186/cc6207. PMC 2374604. PMID 18279531.
  5. ↑ Sailhamer EA, Carson K, Chang Y, Zacharias N, Spaniolas K, Tabbara M, Alam HB, DeMoya MA, Velmahos GC. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality. Arch Surg 2009; 144: 433-439
  6. ↑ Jarvis WR, Schlosser J, Jarvis AA, Chin RY. National point prevalence of Clostridium difficile in US health care facility inpatients. Am J Infect Control 2009; 37: 263-270
  7. ↑ Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: "first-line" treatment for severe Clostridium difficile infection? J Clin Gastroenterol 2011; 45: 655-657
  8. ↑ Best EL, Fawley WN, Parnell P et al. (2010). "The potential for airborne dispersal of clostridium difficile from symptomatic patients". Clin Infect Dis 50 (11): 1450–1457. doi:10.1086/652648. PMID 20415567.
  9. ↑ Kelly CR, De Leon L, Jasutkar N (2012). "Fecal Microbiota Transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results". J Clin Gastroenterol 46 (2): 145–149. doi:10.1097/MCG.0b013e318234570b. PMID 22157239.
  10. ↑ 10.0 10.1 Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: "first-line" treatment for severe Clostridium difficile infection? (Sep 2011). "Endoscopic Fecal Microbiota Transplantation". J Clin Gastroenterol 45 (8): 655–657. doi:10.1097/MCG.0b013e3182257d4f. PMID 21716124.
  11. ↑ Bakken JS (Dec 2009). "Fecal bacteriotherapy for recurrent Clostridium difficile infection". Anaerobe 15 (6): 285–289. doi:10.1016/j.anaerobe.2009.09.007. PMID 19778623.
  12. ↑ 12.0 12.1 van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ (16 Jan 2013). "Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile". N Engl J Med 368 (5): 130116140046009. doi:10.1056/NEJMoa1205037. PMID 23323867.
  13. ↑ Kelly CP. Fecal Microbiota Transplantation - An Old Therapy Comes of Age (16 Jan 2013). "Fecal Microbiota Transplantation — an Old Therapy Comes of Age". N Engl J Med 368 (5): 130116140046009. doi:10.1056/NEJMe1214816. PMID 23323865.
  14. ↑ Grady, Denise (16 January 2013). "When Pills Fail, This, er, Option Provides a Cure". New York Times. Retrieved 2013-01-16.
  15. ↑ Floch MH (2010). "Fecal Bacteriotherapy, Fecal Transplant and the Microbiome". J Clin Gastroenterol 44 (8): 529–530. doi:10.1097/MCG.0b013e3181e1d6e2. PMID 20601895.
  16. ↑ Borody TJ, Campbell J. Fecal microbiota transplantation: current status and future directions. Exp Rev Gastroenterol Hepatol 2011; 5(6): 653-655
  17. ↑ 17.0 17.1 17.2 Borody, TJ; George, L; Andrews, P; Brandl, S; Noonan, S; Cole, P; Hyland, L; Morgan, A; Maysey, J; Moore-Jones, D (15 May 1989). "Bowel-flora alteration: a potential cure for inflammatory bowel disease and irritable bowel syndrome?". The Medical journal of Australia 150 (10): 604. PMID 2783214.
  18. ↑ Borody TJ, Campbell J, Torres M et al. (2011). "Reversal of idiopathic thrombocytopenic purpura (ITP) with Fecal Microbiota Transplantation (FMT)". Am J Gastroenterol 106: S352.
  19. ↑ 19.0 19.1 Borody TJ, Leis S, Campbell J et al. (2011). "Fecal Microbiota Transplantation (FMT) in multiple sclerosis (MS)". Am J Gastroenterol 106: S352.
  20. ↑ 20.0 20.1 20.2 Borody TJ, Khoruts A (20 Dec 2011). "Fecal microbiota transplantation and emerging applications". Nature Reviews Gastroenterology & Hepatology 9 (2): 88–96. doi:10.1038/nrgastro.2011.244. PMID 22183182.
  21. ↑ 21.0 21.1 Ananthaswamy, Anil (19 January 2011). "Faecal transplant eases symptoms of Parkinson's". New Scientist. Retrieved 2013-01-22.
  22. ↑ Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M (November 2013). "Therapeutic potential of fecal microbiota transplantation". Gastroenterology 145 (5): 946–53. doi:10.1053/j.gastro.2013.08.058. PMID 24018052.
  23. ↑ Borody TJ, Leis S, Pang G et al. Fecal Bacteriotherapy in the treatment of recurrent Clostridium difficile infection. UpToDate
  24. ↑ 24.0 24.1 Eiseman B, Silen W, Bascom GS et al. (1958). "Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis". Surgery 44 (5): 854–859. PMID 13592638.
  25. ↑ Lund-Tonnesen S, Berstad A, Schreiner A et al. (1998). "Clostridium-difficile-associated diarrhea treated with homologous feces". Tidsskr nor Laegeforen 118 (7): 1027–1030. PMID 9531822.
  26. ↑ Persky SE, Brandt LJ (2000). "Treatment of recurrent Clostridium-difficile-associated diarrhea by administration of donated stool directly through a colonoscope". Am J Gastroenterol 95 (11): 3283–3285. doi:10.1111/j.1572-0241.2000.03302.x. PMID 11095355.
  27. ↑ Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection, Aliment Pharmacol Ther. 2015 Mar 1. doi: 10.1111/apt.13144
  28. ↑ Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. doi: 10.1056/NEJMoa1205037.
  29. ↑ Martin WJ (2009). "Encapsulated Medicines for Iatrogenic Diseases". British Patent Application: GB0916335.3.
  30. ↑ Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardised frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:761-767
  31. ↑ Hamilton MJ, Weingarden AR, Unno T, Khoruts A Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013; 4: 1-11
  32. ↑ Smith, Peter Andrey (17 Feb 2014). "A New Kind of Transplant Bank". The New York Times. Retrieved 2014-07-10.
  33. ↑ Henning Gerke (December 2014). "Whats the lowdown on 'fecal transplantation'?". Health at Iowa. U of Iowa. Retrieved 14 January 2015.
  34. ↑ "Therapeutic Poop: Hope for Cure of Childhood Diarrhea Comes Straight from the Gut". The Johns Hopkins Childrens Center. The Johns Hopkins University. July 29, 2013.
  35. ↑ Lewin, Ralph A. (2001). "More on merde". Perspectives in Biology and Medicine 44 (4): 594–607. doi:10.1353/pbm.2001.0067. PMID 11600805.
  36. ↑ 36.0 36.1 Burke, KE; Lamont, JT (August 2013). "Fecal Transplantation for Recurrent Clostridium difficile Infection in Older Adults: A Review.". Journal of the American Geriatrics Society 61 (8): 1394–8. doi:10.1111/jgs.12378. PMID 23869970.
  37. ↑ Borody TJ, Campbell J. Fecal microbiota transplantation: current status and future directions. Expert Rev Gastroenterol Hepatol 2011; 5(6): 653-655
  38. ↑ Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet 1989; 1: 164
  39. ↑ Borody T, Warren E, Leis S, Surace R, Ashman O. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003; 37(1):42-47
  40. ↑ Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakis S. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol 2004; 38(6): 475-83
  41. ↑ Borody TJ, Torres M, Campbell J et al. (2011). "Reversal of inflammatory bowel disease (IBD) with recurrent fecal microbiota transplants (FMT)". Am J Gastroenterol 106: S352.
  42. ↑ Borody TJ, Paramsothy S, Agrawal G. Fecal Microbiota Transplantation: Indications, Methods, Evidence and Future Directions. Curr Gastroenterol Rep 2013; 15: 337
  43. ↑ "BBC Nature — Dung eater videos, news and facts". Bbc.co.uk. n.d. Retrieved 2011-11-27.
  44. ↑ DePeters EJ; George LW (26 September 2014). "Rumen transfaunation.". Immunology Letters 162 (2 Part A): 69–76. doi:10.1016/j.imlet.2014.05.009.
  45. ↑ Chang JY, Antopoulos DA, Kalra A et al. (2008). "Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea". J Infect Dis 197 (3): 438. doi:10.1086/525047.
  46. ↑ Khoruts A, Dicksved J, Jansson JK et al. (2010). "Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea". J Clin Gastroenterol 44 (5): 354–360. doi:10.1097/MCG.0b013e3181c87e02. PMID 20048681.
  47. ↑ Tvede M, Rask-Madsen J (1989). "Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients". Lancet 333 (8648): 1156–1160. doi:10.1016/S0140-6736(89)92749-9.
  48. ↑ Grehan MJ, Borody TJ, Leis SM et al. (2010). "Durable alteration of the colonic microbiota by the administration of donor fecal flora". J Clin Gastroenterol 44 (8): 551–561. doi:10.1097/MCG.0b013e3181e5d06b. PMID 20716985.
  49. ↑ Rea MC, Dobson A, O'Sullivan O, Crispie F, Fouhy F, Cotter PD, Shanahan F, Kiely B, Hill C, Ross RP (15 Mar 2011). "Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon". Proc Natl Acad Sci U S A 108 (Suppl 1): 4639–4644. doi:10.1073/pnas.1001224107. PMC 3063588. PMID 20616009.
  50. ↑ 50.0 50.1 "FDA struggles to regulate fecal transplants". CBS News. Associated Press. 26 June 2014.
  51. ↑ "Public Workshop: Fecal Microbiota for Transplantation". Food and Drug Administration. 10 March 2014.
  52. ↑ 78 FR 12763, 25 February 2013
  53. ↑ 53.0 53.1 53.2 Smith, Mark B.; Kelly, Colleen; Alm, Eric J. (19 February 2014). "Policy: How to regulate faecal transplants". Nature.
  54. ↑ 54.0 54.1 AGA Confirms IND is Required for Fecal Microbiota Transplantation, American Gastroenterological Association, 6 May 2013
  55. ↑ "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.
  56. ↑ "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.
  57. ↑ Gabrielle Emanuel (7 March 2014). "MIT Lab Hosts Nation's First Stool Bank, But Will It Survive?". WBUR-FM.
  58. ↑ "Fecal transplantation poses dilemma for FDA". Nature Biotechnology 32 (5): 401–402. 8 May 2014. doi:10.1038/nbt0514-401.

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