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Faecal microbiota transplant
Faecal microbiota transplant (FMT) is the transplant or infusion of faecal suspension from a healthy individual into the GI tract of another affected individual. In essence, it is a direct and radical way of recolonising the gut of an individual with an established healthy microbiome.
Our GI tract contains over a trillion bacterial cells, outnumbering our human cells at a ratio of 10:1.4
History of FMT
The theory of recolonising the gut is not a new one. In the animal kingdom, the instinctive behaviour of coprophagy, the ingestion of faeces, is common practice and is believed to diversify animal gut microbiomes and protect against pathogenic bacteria.5,6,7
Documentation of faecal material being used as a therapeutic agent dates back to the 4th Century in Chinese medicine where dried, fermented and fresh samples were used to treat various illnesses.8 And in Europe during the 1600s, a book was written by German physician Christian Paullini, outlining the virtues of faecal material as a therapeutic agent.
The first record of a faecal transplant in modern medicine was carried out in 1958 by Eiseman et al, a group of surgeons who were faced with patients with fulminant pseudomembranous colitis and faecal infusion enemas were given to four patients, with total resolution of symptoms. Eiseman et al postulated further clinical applications for this procedure9 but this was halted due to the advent of the discovery and approval of vancomycin.10
To date, over 550 faecal transplants have been recorded in the literature worldwide.1
Clostridium difficile is a spore-forming anaerobe that is the leading cause of nosocomial or iatrogenic diarrhoea in the industrialised world.11 C. difficile is a native to our distal colon and is carried by approximately 3 per cent of the population. However, its overgrowth is held in check by commensal gut bacteria — when the gut flora have been eliminated or disrupted by antibiotic use, C. difficile flourishes.
Antibiotics such as fluoroquinolones, broad-spectrum cephalosporins and clindamycin are the most common offending agents but CDI can occur with any antibiotic. It is an extremely virulent bacterium due to its sporulation efficiency and genetic diversity. Transmission of C. difficile infection (CDI) is via the faecal-oral route and spores can survive on surfaces for months. While the incidence of CDI has been decreasing in the past number of years in hospitals, there is an increasing trend of community-acquired CDI and the emergence of CDI in previously-considered low-risk groups such as children, peripartum women and persons with no previous antibiotic exposure.15
The cost, both human and financial, of CDI is huge. The mortality of CDI is reported at 22 per cent overall and it is directly responsible for death in 2 per cent of cases and a contributor to death in 7 per cent of cases.12
The financial cost on our already-stretched healthcare system is enormous. CDI lengthens hospital stay by a median of seven days and the average cost of a patient per episode of an acquired CDI ranges from €4,067 to €9,276.13 In the US, CDI is estimated to cost $3 billion (€2.65 billion) per annum.14
Irish data surrounding CDI shows an Irish weighted mean incidence of 7.3 cases per 10,000 patient days; this figure is higher than the European average.14
The recurrence rate for CDI is approximately 20 per cent after initial treatment and patients who experience one recurrence have a 40 per cent risk of another recurrence.16,17,18
How does FMT work against C. difficile?
The aim of FMT is to induce a stable and diverse community of gut micro-organisms, the goal of which is to replace the disrupted microbiome that occurs in CDI.
A number of hypotheses exist to explain the methods by which the gut microbiome counteracts CDI.
Firstly, the classic mechanism of ecology is that no two species can occupy the same niche in an ecosystem at the same time.19 This microbiome can aggregate and result in a synergistic biofilm that produces bacteriocins.
These antimicrobial peptides inhibit the growth of certain species of bacteria, and so are a narrow-spectrum antimicrobial in their own right. One such bacteriocin produced by Bacillus thuringiensis against C. difficile is called thuricin CD and is currently undergoing clinical trials. Interestingly, thuricin CD selectively kills C. difficile while leaving dominant bacterial populations intact.20
The microbiome can alter the life-cycle of C. difficile indirectly by using the host. Many colonic bacteria can alter the life-cycle of C. difficile by the metabolism of bile acids. Primary bile acids lead to an environment that is favourable to C. difficile population but when colonic bacteria deconjugate bile acids to secondary bile acids, the gut environment becomes inhospitable to CDI and so is protective.21 The commensal bacteria in our guts can also trigger and modulate immune reactions to pathogenic bacteria and much research has been done on the toll-like receptor (TLR) signalling in the gut.22
Regardless of the mechanism of action of FMT, the data speaks for itself. The primary cure rate of FMT when used in recurrent C. difficile is over 90 per cent and the secondary cure rate is 98 per cent.23,24,25 In a recent open-label RCT comparing FMT against antibiotic therapy alone, FMT showed far superior outcomes and as a result, the study had to be terminated prematurely. In this study, recurrence rates of 62 per cent were seen post vancomycin therapy and only 6 per cent recurrence seen post FMT.26
Challenges of FMT
There are many challenges that face the utilisation and progress of FMT. The first challenge is the natural aversion that we, as humans, have against the ingestion or infusion of faeces. Both the preparation and administration of the faecal transplant is a struggle for patients and staff alike.
This natural aversion lends itself to further challenges with donor recruitment, especially in cases where a family member or partner donor cannot be used or is not available. This then leads to an over-reliance on family members volunteering their stool, however a biobank of donor microbiomes is now available in the US and may overcome these issues.
A more modern challenge of FMT is the increasing information that is accessible to patients regarding FMT for the treatment of recurrent C. difficile but also many other GI disease processes. Many websites and forums are dedicated to the utilisation of FMT at home and advise on DIY kits that can be used to infuse faeces without prior screening or medical consultation. As a result, desperate patients will seek this treatment and physicians will need to be prepared to answer their queries.
In a qualitative study of patients with ulcerative colitis,27 the majority of patients welcomed this treatment and also expressed their eagerness that this treatment become readily available.
One of the greatest challenges is the unknown risk associated with FMT. When transferring bodily fluids, there is always a risk that an unknown infection could be transmitted and have a hugely detrimental effect on the patient’s health. We are also unaware of the long-term sequelae of FMT. Recent research in the field has found that disrupted microbiomes are associated with many human diseases,28 for example type 2 diabetes, obesity, metabolic syndrome and IBD. While it is unknown whether these disruptions are causal or consequential, an FMT in a very young patient could potentially expose them to a new disease process.
FMT in the future
The future on FMT depends heavily on the advent of stardardisation of protocols, including route of administration. In our case, we chose naso-jejunal tube due to the fragility of the patient, however administration via colonoscopy and enemas are also options to consider.
The route of administration dictates the number of FMTs needed to achieve cure, and so further confounds results. A step to further clarify the role of FMT in C. difficile infection would be guidelines on who should receive FMT and where FMT fits into the treatment paradigm of this infection.
A step towards this standardisation was published in JAMA in 2014,29 whereby FMT was administered as frozen slurry, encapsulated and administered orally over two days. The results of this study showed similar outcomes to infusion FMT but its relevance for the future of FMT is promising. This study could lead to the establishment of a stool bank, whereby all donor faeces are frozen and so can be encapsulated and shipped to centres where they are needed. Not only does this make FMT more accessible to patients, but it is also a non-invasive technique for altering the microbiome.
Stool-based therapeutics are currently being researched30 and trialled in many centres around the world and the challenges we face today are likely to be rapidly addressed. Similarly, a better understanding of the mechanism underlying successful FMT will lead to the development of novel therapeutic molecules, subverting any need for actual faecal transplant in the future. However for the time being, FMT remains a viable and useful clinical option for severe, recurrent C. difficile-related illness.
In the past 60 years, since the discovery and ubiquitous use of antibiotics, both in medicine and in the food industry, our gut microbiomes have been changing and adapting to the constant offensive of these therapies. As a result, many human diseases have been found to show a dysbiosis in gut microbiomes and could be a clue to the pathogenesis of many GI and non-GI illnesses. The scope for research in this field with FMT and these established pathologies is an exciting prospect and could yield many discoveries yet to come.
NL, an 81-year-old lady, was brought in by ambulance and admitted to Tallaght Hospital in July 2014 following the second episode of four days of watery diarrhoea associated with abdominal cramps, foul-smelling faeces and faecal incontinence. Past medical history was significant for multiple comorbidities such as type 2 diabetes, CKD stage III, COPD and diverticular disease.
She had previously been admitted in July 2014 for C. difficile-positive diarrhoea and most notably had a nine-week admission in April 2014 for pneumococcal sepsis, culminating in two ICU admissions.
The patient was haemodynamically stable and so her care was centered on fluid resuscitation, electrolyte correction and infection control measures. Investigations yielded leukocytosis, an acute kidney injury with creatinine at 190μmol/l and disruption to electrolytes. Stool samples were C. difficile toxin-positive and treatment with oral vancomycin was commenced.
The patient continued to have diarrhoea and vancomycin pulsed and tapering regimens were used, to no effect. Four weeks after admission, the diarrhoea continued and the antibiotic fidaxomicin was used, again with no effect.
At this juncture, the patient weighed 35kg (having lost 10kg over seven weeks) and had suffered multiple falls at night due to nocturnal diarrhoeal symptoms. Her clinical condition was declining and without further antibiotic regimens to use, we began the process of a work-up for faecal microbiota transplant (FMT).
We looked to our colleagues internationally and studied multiple protocols, including recent NICE recommendations,1 for both the ward and the laboratory.2,3 We devised a local protocol using an MDT approach including microbiology, nursing staff and infection control.
Informed consent from both the recipient and the donor was sought and completed prior to FMT.
The donor was a member of the patient’s family who did not live with the patient. Donor screening involved questions regarding general health (medications, recent antibiotic use and autoimmune disorders ruled out), serum testing for hepatitis B and C, HIV, syphilis, and TB and three consecutive stool samples for culture and sensitivities, ova and parasite screening and C. difficile toxin.
A date was set for the FMT to take place and the patient was commenced on a one-week course of vancomycin 500mg BD, the last dose of which was to stop 24 hours prior to the procedure. The day prior to the procedure, an NJ tube was inserted by a specialist nurse and bowel preparation was given to remove the existing microbial populations in order to replace them.
The donor submitted the faeces to the laboratory on the day of the transplant and the stool was processed within six hours of defecation. Approximately 200g of fresh stool was mixed with 0.9 per cent saline and sieved through gauze to remove particulate matter. The slurry was then placed in 100ml syringes to be administered by hand; 150ml was administered on the ward, at a rate of 1.5ml/minute and so the transplant itself took one hour and 40 minutes and the NJ tube was flushed, once finished, and removed two hours post-FMT.
Within 48 hours of the infusion, our patient went from opening her bowels seven-to-10 times per day to once daily.
One week post-FMT, our patient was discharged from our care to a convalescent facility.
One month post transplant, our patient was reviewed in the Gastroenterology Outpatients Department. She had gained 4kg since her discharge and reported regular, once-daily bowel motions, with no recurrence of her diarrhoeal symptoms.
- NICE Guidelines — Faecal microbiota transplant for recurrent Clostridium difficile. NICE interventional procedure guidance. [IPG485] Published date: March 2014.
- Pathak R, Enuh HA, Patel A, Wickremesinghe P. Treatment of relapsing Clostridium difficile infection using faecal microbiota transplantation. Clin Exp Gastroenterol 2013;7:1-6.
- Smits, Loek P, et al. Therapeutic potential of faecal microbiota transplantation.’ Gastroenterology 145.5 (2013): 946-953.
- Bäckhed, Fredrik, et al. Host-bacterial mutualism in the human intestine. Science 307.5717 (2005): 1915-1920.
- Ley RE, Lozupone CA, Hamady M, et al. Worlds within worlds: Evolution of the vertebrate gut microbiota. Nat Rev Microbiol 2008;6:776–788.
- Hopkins DW, Chudek JA, Bignell DE, et al. Application of 13C NMR to investigate the transformations and biodegradation of organic materials by wood- and soil-feeding termites and a coprophagous litter-dwelling dipteran larva. Biodegradation 1998;9:423–431.
- Guy PR. Coprophagy in the African elephant (Loxadonta africana Blumenbach). Afr J Ecol 1977;15:174.
- Zhang F, Luo W, Shi Y, et al. Should we standardize the 1,700-year-old faecal microbiota transplantation? Am J Gastroenterol 2012;107:1755; author reply 6.
- Eiseman B, Silen W, Bascom GS, et al. Faecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854–859.
- Anderson RCGR, Higgins HM Jr, Pettinga CD. Symposium: How a drug is born. Cincinnati J Med 1961;42:49-60.
- Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): Data review and recommendations for diagnosing Clostridium difficile infection (CDI). Clin Miocrobiol Infect. 2009;15(12):1053-66.
- Bauer MP, Notermans DW, van Benthem BH, Brazier JS, Wilcox MH, Rupnik M, et al. Clostridium difficile infection in Europe: A hospital-based survey. Lancet 2011;377(9759):63-73.
- Vonberg RP, Reichardt C, Behnke M, Schwab F, Zindler S, Gastmeier P. Costs of nosocomial Clostridium difficile-associated diarrhoea. J Hosp Infect. 2008;70(1):15-20.
- Surveillance, diagnosis and management of Clostridium difficile infection in Ireland. National Clinical Guideline No 3. June 2014.
- Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: New developments in epidemiology and pathogenesis. Nat Rev Miocrobiol. 2009;7(7):526-36.
- Kelly CR, de Leon L, Jasutkar N. Faecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: Methodology and results. J Clin Gastroenterol. 2012;46:145–149.
- McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: Treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769–1775.
- McFarland LV, Surawicz CM, Rubin M, Fekety R, Elmer GW, Greenberg RN. Recurrent Clostridium difficile disease: Epidemiology and clinical characteristics. Infect Control Hosp Epidemiol. 1999;20: 43–50.
- Merrigan MM, Sambol SP, Johnson S, et al. New approach to the management of Clostridium difficile infection: Colonisation with non-toxigenic C. difficile during daily ampicillin or ceftriaxone administration. Int J Antimicrob Agents 2009;33 (Suppl 1):S46–S50.
- Rea MC, Dobson A, O’Sullivan O, et al. Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon. Proc Natl Acad Sci USA 2011;108(Suppl 1): 4,639-4,644.
- Giel JL, Sorg JA, Sonenshein AL, Zhu J. Metabolism of bile salts in mice influences spore germination in Clostridium difficile. PLoS One 2010;5:e8740.
- Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, et al. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004; 118:229–241.
- Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic faecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:1079–1087.
- Musgrave CR, Bookstaver PB, Sutton SS, Miller AD. Use of alternative or adjuvant pharmacologic treatment strategies in the prevention and treatment of Clostridium difficile infection. Int J Infect Dis. 2011;15: e438–e448.
- Rohlke F, Stollman N. Faecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol. 2012;5: 403–420.
- Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368:407–415.
- Kahn, S., Gorawara-Bhat, R and Rubin, D.T. Faecal bacteriotherapy for ulcerative colitis: Patients are ready, are we? Inflamm Bowel Dis. http:// dx.doi.org/10.1002/ibd.21775.
- Lee, Woo Jung, et al. Fecal microbiota transplantation: A review of emerging indications beyond relapsing Clostridium difficile toxin colitis. Gastroenterology & Hepatology 11.1 (2015): 25.
- Youngster, Ilan, et al. Oral, capsulised, frozen faecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA 312.17 (2014): 1772-1778.
- Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: RePOOPulating’ the gut. Microbiome 2013;1:1–12.