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] It has been proven to be a highly 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 are currently 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restoration of the entire fecal microbiota, not just a single agent or combination of agents, these terms have now been replaced by the new term 'Fecal Microbiota Transplantation'.[2] FMT involves restoration of the colonic flora by introducing healthy bacterial flora through infusion of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 can also be used to treat other conditions, including colitis,[10] constipation,[10] irritable bowel syndrome,[10] and some neurological conditions.[11][12]

Procedure

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][13][14] However 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] The procedure can be carried out via enema,[16] through the colonoscope,[17] or through a nasogastric or nasoduodenal tube.[18] 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.[19] 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 over 370 published reports there has been no reported infection transmission.[20] 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]

A modified form of fecal bacteriotherapy (Autologous Restoration of Gastrointestinal Flora - ARGF) was being developed as of 2009.[21] 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.[22] The preparation has been shown to be as effective at restoring missing and deficient bacterial constituents as crude homogenised FMT.[23]

History

The concept of treating fecal diseases with fecal matter originated in China millennium ago. Yellow soup; was made of fecal matter and water; which was drunk by the patient.[24]

The first description of FMT was published in 1958 by 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.[16] Stool transplants, are about 90% effective in those with severe cases of Clostridium difficile colonization; in whom antibiotics have not worked.[25][25]

Since that time various institutions have offered the treatment 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 options for over 20 years. In May 1988 the CDD treated the first idiopathic colitis patient with FMT which resulted in a durable clinical and histological cure.[26] Since that time, a number of publications have reported the successful treatment of UC with FMT,[27][28][29][30][31] 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,[32] neurological conditions,[11] obesity, metabolic syndrome and diabetes,[20] Multiple Sclerosis,[33] and Parkinson's disease[12] is now being explored.

In animals

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

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.[34][35][36] The introduction of normal flora results in durable implantation of these components.[37] 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.[38] 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.[16]

Benefits

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.[39] 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".[40]

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.[14] 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.[41]

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][42]

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 that 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.[20]

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. ↑ 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. ↑ 8.0 8.1 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: 130116140046009. doi:10.1056/NEJMoa1205037. PMID 23323867. 
  9. ↑ Grady, Denise (16 January 2013). "When Pills Fail, This, er, Option Provides a Cure". New York Times. Retrieved 2013-01-16. 
  10. ↑ 10.0 10.1 10.2 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. 
  11. ↑ 11.0 11.1 Borody TJ, Leis S, Campbell J, et al. (2011). "Fecal Microbiota Transplantation (FMT) in multiple sclerosis (MS)". Am J Gastroenterol 106: S352. 
  12. ↑ 12.0 12.1 12.2 Ananthaswamy, Anil (19 January 2011). "Faecal transplant eases symptoms of Parkinson's". New Scientist. Retrieved 2013-01-22. 
  13. ↑ 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. 
  14. ↑ 14.0 14.1 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. 
  15. ↑ Borody TJ, Campbell J. Fecal microbiota transplantation: current status and future directions. Exp Rev Gastroenterol Hepatol 2011; 5(6): 653-655
  16. ↑ 16.0 16.1 16.2 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. 
  17. ↑ 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. 
  18. ↑ 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. 
  19. ↑ Borody TJ, Leis S, Pang G et al. Fecal Bacteriotherapy in the treatment of recurrent Clostridium difficile infection. UpToDate
  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. ↑ Martin WJ (2009). "Encapsulated Medicines for Iatrogenic Diseases". British Patent Application: GB0916335.3. 
  22. ↑ 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
  23. ↑ 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
  24. ↑ "Therapeutic Poop: Hope for Cure of Childhood Diarrhea Comes Straight from the Gut". July 29, 2013. 
  25. ↑ 25.0 25.1 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. PMID 23869970. 
  26. ↑ Borody TJ, Campbell J. Fecal microbiota transplantation: current status and future directions. Expert Rev Gastroenterol Hepatol 2011; 5(6): 653-655
  27. ↑ Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet 1989; 1: 164
  28. ↑ 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
  29. ↑ 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
  30. ↑ 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. 
  31. ↑ Borody TJ, Paramsothy S, Agrawal G. Fecal Microbiota Transplantation: Indications, Methods, Evidence and Future Directions. Curr Gastroenterol Rep 2013; 15: 337
  32. ↑ 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. 
  33. ↑ Borody TJ, Leis S, Campbell J, Torres M, Nowak A. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS). Am J Gastroenterol 2011; 106: S352
  34. ↑ 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. 
  35. ↑ 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. 
  36. ↑ Tvede M, Rask-Madsen J (1989). "Bacteriohterapy for chronic relapsing clostridium difficile diarrhoea in six patients". Lancet 333 (8648): 1156–1160. doi:10.1016/S0140-6736(89)92749-9. 
  37. ↑ 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. 
  38. ↑ 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. 
  39. ↑ 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. 
  40. ↑ Floch MH (2010). "Fecal Bacteriotherapy, Fecal Transplant and the Microbiome". J Clin Gastroenterol 44 (8): 529–530. doi:10.1097/MCG.0b013e3181e1d6e2. PMID 20601895. 
  41. ↑ 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. 
  42. ↑ 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: 130116140046009. doi:10.1056/NEJMe1214816. PMID 23323865. 

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