Faecal microbiota transplant
Faecal microbiota transplant (FMT), also known as a stool transplant and faecal bacteriotherapy, refers to the process of transferring beneficial faecal bacteria taken from a healthy donor to a patient. The aim of such treatment is to restore the diverse community of beneficial microorganisms in the gut of patients who have failed to respond to standard therapies like antibiotics and to reduce the severity of certain gut disorders.
This diagram shows some of the beneficial and harmful bacteria that live in the human intestine. The aim of faecal microbiota transplantation (FMT) is to harness beneficial bacteria contained in the stools taken from healthy donors to treat patients with diseases caused by disturbances to their gut microflora.
The therapeutic potential of FMT has gained a great deal of medical attention in recent years. Its potential as a treatment was first recognised in the case of Clostridium difficile infection (CDI). The infection is caused by a type of a Gram-positive, anaerobic, spore-forming bacterium that lives in the gut. In most cases this bacterium, often abbreviated to C. diff or C. difficile, is harmless and kept in check by the millions of other bacteria that live in the intestine because they out compete C. diff for nutrients. C. diff can become harmful, however, when it significantly multiplies and starts to produce toxins that affect the lining of the bowel. This can happen, for example, when the ecosystem of gut bacteria is disturbed by antibiotic treatment.
Severe CDI can cause severe diarrhoea, dehydration, inflammation of the colon and sepsis. CDI is responsible for most hospital-acquired diarrhoea, especially among the elderly and people with weakened immune systems. Though most cases of infection can be treated with antibiotics, like metronidazole and vancomycin, one in three people will get the infection again and recurring infections can be difficult to treat. This reflects the fact that C. diff are increasingly antibiotic-resistant. Just how troubling CDI has become can be seen from one American epidemic which in 2011 caused nearly 7,000 infections and 300 deaths per day. A large proportion of the infections were due to antibiotic resistant C. diff strains (Borody et al.).
Recent studies, including randomised clinical trials, have shown FMT to be highly effective in combating recurrent and intractable CDI. One review of thirty-seven studies showed FMT to be effective in 88 to 92 per cent of cases (Quraishi et al.). Inspired by the success of FMT in treating CDI, researchers are now exploring whether the treatment might also be used to treat other antibiotic-resistant bacterial infections which are becoming more prevalent.
Efforts are also currently underway to establish whether FMT could be used to treat metabolic syndrome. Metabolic syndrome is a term given to a cluster of different metabolic abnormalities, like type 2 diabetes, obesity, high blood pressure, high blood sugar and abnormal cholesterol levels. When combined in a patient, these symptoms heighten their risk of coronary heart disease, stroke and other disorders affecting blood vessels. In addition to metabolic syndrome, FMT is also thought to have therapeutic potential for other seemingly unrelated conditions, such as autism, Alzheimer’s and Parkinson’s disease (Wang et al.).
Interest in FMT is reflective of a more general investigation into the role that bacteria play in the underlying physiology of many medical conditions. Understanding these interactions could pave the way to combating such diseases. Just how much importance is attached to such research can be gauged from the US$170 million dedicated to funding the Human Microbiome Project (HMP), which was set up in 2007. The Project aimed to improve our understanding of the microbial flora involved in human health and disease. Part of its remit was to establish a stool collection and processing manual, which put in place significant guidelines for future FMT studies (dbGaP). The HMP uncovered a significant link between the gut microbiome and various diseases. This helped to rekindle considerable interest in FMT within the scientific community and spurred on a huge venture-capital investment in microbiome companies. According to the Wall Street Journal such funding increased by 458.5 percent to $114.5 million between 2011 and 2015 in contrast to the overall venture investment, which only increased by 103 percent (Gormley).
The first instance of FMT was recorded in fourth century China by Ge Hong, a traditional Chinese medicine doctor. Hong described giving a human faecal suspension by mouth to treat patients with severe food poisoning and diarrhoea. Published in the first Chinese handbook of emergency medicine, this treatment was handed down through the generations. By the sixteenth century faeces-derived preparations had become a common treatment in China for various gastrointestinal problems including constipation, diarrhoea and abdominal pain, as well as for treating symptoms like fever and pain. These were recorded by the Chinese doctor Li Shizhen (1518–1593). The treatment typically used fermented faecal solutions, fresh faecal suspensions, dry faeces and infant faeces. Such preparations were commonly called ‘yellow soup’ to make them less repulsive to patients (Zhang et al. 2012).
In Europe the first recorded use of FMT took place in veterinary medicine. The procedure was carried out by Fabricius Acquapendente (1537-1619), an Italian anatomist and surgeon, who transferred gastrointestinal content from a healthy animal to a sick one. This process, subsequently called ‘transfaunation’, became a widespread treatment for animals. Yet, many years passed before FMT was considered a suitable treatment for humans. The use of human excrement from healthy individuals to cure internal or external disease was first suggested in a textbook published by the German physician Christian Paullini (1643-1712) in 1686. This was just five years after Antonie van Leeuwenhoek (1632-1723), a Dutch microbiologist, made the seminal discovery of microbes in his stools (de Groot et al.).
The concept that gut microbes might have a beneficial role in human health was taken a stage further two centuries later through the work of Élie Metchnikoff (1845-1916), a Ukrainian bacteriologist and zoologist based at the Pasteur Institute in Paris. He observed that the regular consumption of lactic acid bacteria in fermented dairy products, such as yoghurt, contributed to the long life expectancy of Bulgarian farmers despite them living in poor living conditions. He himself noticed an improvement to his digestion and immunity after experimenting with eating fermented foods himself. Metchnikoff concluded that this was down to the new diet helping to change the balance of microbes in his gut. Specifically, it appeared to increase the number of lactic acid bacteria, which were known to protect against toxins that accelerate the aging of cells. Publishing his findings in 1907, Mechinikoff hypothesised that it might be possible to enhance health and delay aging by eating fermented milk products like yoghurt to introduce beneficial microbes to replace harmful ones (Anukam, Reid).
Just one year before Metchnikoff announced his results, Henry Tissier, a French paediatrician at the Pasteur Institute, independently suggested that babies with diarrhoea might be beneficially treated with a type of bacteria called Bifidobacterium bifidum. This was based on his discovery that children with diarrhoea tended to have a lower abundance of such bacteria in their stools than those without such symptoms. Tissier believed that the administration of Bifidobacteria bifidum could help displace the pathogenic bacteria causing the diarrhoea (Gogineni et al.).
The notion that some gut bacteria could help restore health was not confined to researchers at the Pasteur Institute. Another person thinking along the same lines was Alfred Nissle (1874-1965), a German bacteriologist, who from 1912 was based at the Hygiene Institute of the Albert-Ludwigs-University of Freiburg. This emerged out of his observation that some Escherichia coli (E. coli) strains from stool samples, taken from healthy medical students at Freiburg University, appeared to inhibit the growth of Salmonella and other enteropathogens on petri dishes. The possibility that E. coli could be used as a weapon against disease was further brought home to Nissle in 1917 when he isolated a specific strain of E. coli in the stools of a German soldier in a military hospital in Freiburg that appeared to have protected him against Shigella, a pathogen that had caused severe diarrhoea among his comrades. The strain proved highly destructive of Shigella in his laboratory tests (Sonneborn).
The importance of gut bacteria was once again brought home in 1941 when the Nazi medical corps began looking for ways to alleviate an outbreak of dysentery among troops fighting in North Africa. Early on, the Nazi doctors noticed that local nomads seemed to fare much better against outbreaks of dysentery because of their tradition of eating fresh warm camel dung whenever they experienced slight diarrhoea. Analysis of the camel stools revealed it to contain Bacillus subtilis, a type of bacterial organism that can kill other bacteria, including those that cause dysentery. Not wishing to give camel dung directly to the troops, the German medical corps found a way of cultivating the bacteria in large vats which were then administered either in a broth or in powder form to prevent dysentery (DeSalle, Perkins).
Despite the early clinical applications of FMT, such treatment largely faded out of view with the arrival of antibiotics in the late 1940s, which was heralded as a cure for bacterial infections. It did not take long, however, before medical practitioners began to realise the new therapy was not a total panacea. Firstly, the bacteria developed resistance to the drugs. Secondly, prolonged use of such treatment increased a patient’s susceptibility to diarrhoea and secondary infections like CDI. Such complications are linked to the disruption antibiotics cause to normal gut microflora. This is because antibiotics destroy beneficial bacteria alongside harmful ones.
One of the first attempts to use FMT to counter the side effects of antibiotics was undertaken in 1957 at an American hospital in Newport, Rhode Island. The treatment was tried out with surgical patients. As was common for the period, such patients were routinely given large doses of antibiotics to sterilise their bowel flora before an operation and for many days afterwards to prevent infection. Many of the patients, however, got diarrhoea, flatulence and indigestion from the antibiotics. So prevalent was the problem that one of the hospital’s doctors decided to see if FMT could help. Each patient was asked to supply a specimen of their stools on admission for surgery, which was processed into gelatin capsules. The patients were told to take two capsules twice a day following surgery. Understandably, the nature of the trial, which was conducted unofficially, did not sit well with the chief hospital administrator who immediately brought it to an end. While no data was published from the trial the anecdotal evidence suggested better outcomes for the treatment group (Falkow).
Just a year after the Newport trial, a group of surgeons based at the University of Colorado, led by Ben Eiseman (1917-2012), successfully treated four patients suffering from pseudomembranous colitis, an inflammation of the large intestine due to an overgrowth of antibiotic-resistant C. diff. This was already surfacing as a major problem in the 1950s and was frequently fatal. The patients who took part in the trial had failed to respond to other treatments. They made full recoveries after being given faecal enemas from a healthy donor. Sixteen more cases were later treated following the same protocol, with an astonishing 94 percent success rate (Eiseman et al.). Despite the success of this trial, FMT was only adopted on a wide scale in the 2000s as a result of the rise of CDI epidemics. FMT is now a standard treatment for antibiotic-resistant CDI. The therapy can be administered through oral capsules, enemas or duodenal infusions (de Groot et al.; Gianotti, Moss; Gargiullo et al.).
In addition to being adopted to eradicate C. diff, FMT is beginning to be used to combat other multidrug resistant organisms (MDROs). Its potential for such treatment was first discovered in 2012, when a 66-year-old patient with recurrent CDI who was also infected with MDROs, including Acinetobacter baumannii and Pseudomonas aeruginosa, was given FMT. The treatment not only managed to reduce the patient’s CDI but also the other MDROS. Scientists hypothesised that the FMT eliminated the MDROs by restoring the patient’s normal gut flora, in particular the presence of Barnesiella spp., a common species in a healthy gut (Crum-Cianflone et al; Bilinski et al. 2016 and 2017).
Currently the Food and Drug Administration (FDA) classifies FMT as an ‘investigational new drug (IND)’. Established in 2013 this regulation sought to ensure the safety of FMT. Many physicians were discouraged from pursuing such treatment because of the extensive paperwork involved in submitting an IND application before administering any FMT, and the fact that the FDA could take 30 days to give its approval for the treatment. Fortunately, the FDA relaxed its regulations a year later, allowing the procedure to be carried out without an IND application (Kelly et al. 2014). In the UK, FMT is approved for treating CDI and the National Institute for Health and Care Excellence (NICE) has issued full guidance to the NHS in England, Wales, Scotland and Northern Ireland on FMT for recurrent C. difficile infection.
Overall the application of FMT involves the use of a stool taken from a carefully screened healthy individual. This can be either sourced from someone the patient knows, usually a healthy relative, or from an anonymous donor. The most cost-effective approach is to use stools from an anonymous donor who will already have been screened for various diseases. The same donor can donate multiple times to save the cost of health screening. There is no significant difference, however, in clinical outcomes between anonymous and patient-selected donors (Kassam et al.).
Once received, the stool sample is initially put through a process of homogenisation, filtration and centrifugation to concentrate the bacteria density. One gram of stools is estimated to contain 1010-12 bacterial cells. A single dose usually uses 50g of faecal matter. The stools can be administered immediately after being processed or frozen at -80°C for later use. Both approaches have a similar cure rate but frozen stool is preferred due to cost effectiveness (Hamilton et al.).
All patients must discontinue any antibiotic therapy for one to three days before any FMT is administered. Various routes are used to administer the treatment. The different delivery methods are generally grouped into two categories: via the upper gastrointestinal (GI) tract or the lower GI tract. Delivery via the upper GI tract utilises either an oral capsule or a narrow flexible tube passed through the nose into the stomach or the intestine. While the nasogastric tube ensures a more direct delivery to the target site, oral capsules have been shown to be equally effective (Kao et al.). The University of Birmingham is currently piloting one of the largest trials in the world to assess two possible FMT delivery routes for the treatment of ulcerative colitis (UC). Launched in 2018, the 'STOP-Colitis' trial is being conducted across Birmingham, Glasgow and London to determine the optimum delivery route and the efficacy of FMT for the treatment of UC.
FMT has so far proven most beneficial in treating CDI, but it was recently also shown to be effective in a number of other diseases. Studies have shown that FMT from lean donors, for example, can improve insulin sensitivity in patients whose cells do not respond properly to the hormone insulin which is responsible for maintaining normal blood sugar levels. Unfortunately, the effects of FMT only lasted up to 6 weeks following its administration (Vrieze et al.).
Restoring the normal gut microbiota via FMT has also shown efficacy in decolonising MDROs simultaneously. Between 2015 and 2016 FMT was administered by Polish researchers to a group of 20 patients with blood disorders infected with one to four strains of MDROs, including Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, methicillin-resistant S.aureus and vancomycin-resistant E.faecalis. The treatment proved highly efficient at eradicating antibiotic resistant bacteria. Repeated administration of FMT managed to completely decolonise such bacteria in 75 per cent of the patients treated (Bilinski et al. 2017). FMT could thus provide an important tool to the fight against rising antibiotic resistance.
Another area where the treatment holds promise is in the alleviation of obesity. This has emerged out of an experiment carried out with germ-free transgenic mice in 2005 and 2007 which demonstrated that gut microbiota can affect the rate of metabolism. In particular, the study showed obesity to be correlated with a low abundance of Bacteroidetes and high abundance of Firmicutes (Ley et al.; Backed et al.). Similar observations were also made in humans. FMT aims to manipulate the balance of bacterial species in the gut to help regulate the balance of energy within obese individuals. A randomised trial was launched in 2017 to test this idea. Twenty-two obese people without any obesity-related conditions were recruited into an initial trial that lasted 12 weeks. Half of the participants were given FMT capsules from a lean donor. While none of those given the treatment experienced any weight loss, the microbial makeup of their stools began to resemble that of a lean donor. Whether the right bacteria are being changed remains to be seen, but the initial trial provides a glimpse of the potential of FMT in tackling obesity (Allgeretti et al).
FMT could also help in the treatment of irritable bowel syndrome (IBS). The exact cause of IBS is still unknown but it is attributed to the composition of bacteria in the large intestine. Symptoms of IBS include cramping, abdominal pain, diarrhoea and constipation. Various trials have been done with IBS patients with FMT using different routes of administration. Overall FMT recipients generally report less IBS-related symptoms and a higher quality of life (Schmulson, Bashashati). The FMT approach was also evaluated to be more cost-effective than conventional therapy. The cost reduction is mostly derived from savings on medical expenses (Zhang et al. 2017).
FMT is still a very novel treatment so its potential side effects are not yet fully understood. One of the challenges is that stools contain a complex mixture of living bacteria and other organisms. A guideline of exclusion criteria, including obesity and history of various viral infections such as HIV and HBV, was implemented early on to prevent any side effects arising from the nature of the donor’s stools.
Even so, there is always the danger that screening tests might fail to detect a pathogen. An oversight in the screening process can be fatal, as seen in the case of a 73-year-old patient’s death in June 2019 after he received a stool transplant containing an antibiotic-resistant strain of E. coli. This strain of E. coli produces extended-spectrum beta-lactamase, an enzyme that breaks down and confers resistance against certain groups of antibiotics. The FDA reported that the stool was not screened for the presence of drug-resistant bacteria before the procedure (DeFelipp et al.). Following this incident, FDA established specific MDRO testing to ensure FMT safety.
Another concern is that too little is known about the long-term effects of altering one’s microbiota. This is an especially difficult challenge because of the highly dynamic composition of live microbiota in the gut. Despite increasing knowledge about bacterial diversity in the gut, very little is known for example about the viral and fungal composition in the gut. Just how complex this issue is was flagged up in trial to assess its use for CDI. One female patient experienced a sudden increase in her weight after receiving FMT to treat her recurrent antibiotic-resistant CDI. A stool sample was taken from her daughter who was of a healthy weight at the time of the treatment. However, the daughter subsequently became obese. It did not take long before the same phenomenon was observed in the mother whose CDI was successfully treated with the FMT. Disturbingly, the patient’s BMI increased despite having had a medically supervised diet (Alang, Kelly).
Although FMT is widely accepted for the treatment of CDI, it remains an 'investigation new drug’ for the treatment of any disease other than CDI. This entails a laborious IND application which discourages many physicians and severely limits its the diseases for which it has been investigated. In March 2016, FDA announced its intention to revise its regulations, but these have yet to be finalised (Kelly, Tebas).
There is also a need for more evidence of FMT’s efficacy on non-CDI diseases. For example, FMT has been proposed as a viable treatment for IBD but as of 2018, there has been only five randomised controlled trials published, each using different selection criteria and routes of administration (Schumulson, Bashashati). Larger sample size randomised controlled trials with standardised procedures are still needed to objectively assess FMT as a therapeutic approach.
This piece was written in February 2020 by Lara Marks and Jakrin Bamrungthai
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Faecal microbiota transplant: timeline of key events
|0340||First record of the application of faecal microbiota transplant (FMT)|
|1570 - 1619||First application of FMT in animals||Aquapendente|
|1578||FMT described for the treatment of abdominal diseases|
|1681||Discovery of microbes in stools||Van Leeuwenhoek|
|1907||Birth of probiotics||Metchnikoff|
|1917||Discovery of a beneficial strain of Escherichia coli||Nissle|
|1941||FMT developed to treat German troops||Zhang|
|December 1945||Nobel Prize jointly awarded to Alexander Fleming, Ernst B Chain and Howard W Florey for the discovery of penicillin and its curative effect||Fleming, Chain, Florey||St. Mary's Hospital, London|
|1957||FMT tried out unofficially in surgical patients suffering diarrhoea and other complications from antibiotics|
|November 1958||FMT successfuly treated four patients with C.diff. resistant to antibiotics||Eiseman||Denver VA Medical Center, Colorado|
|21 Jan 1989||First report of FMT used to treat ulcerative colitis||Bennett, Brinkman|
|2005 - 2007||FMT-associated weight gain was evaluated in a series of different experiments||Ruth||Washington University|
|2007 - 2016||Human Microbiome Project (HMP) carried out|
|2008 - 2012||METAgenomics of the Human Intestinal Tract (MetaHIT) project carried out|
|5 Feb 2013||Results published for first randomised controlled FMT trial for recurrent CDI||van Nood||Academic Medical Center, University of Amsterdam,|
|6 Jun 2013||Correlation found between gut microbiota and type II diabetes||Karlsson||Chalmers University of Technology|
|July 2013||The US FDA classified FMT as an 'investigational new drug (IND)'|
|March 2014||UK National Institute for Health and Care Excellence (NICE) issued guidelines for the use of FMT for recurrent CDI|
|March 2014||FDA issued draft guidelines for the use of FMT for treating recurrent CDI|
|November 2014||FMT used to treat a multi-drug resistant E.coli||Singh||Academic Medical Center - University of Amsterdam|
|December 2014||The EU Commission concluded that the purposes of FMT are not ‘intended for human applications’ within the meaning of EU Tissues and Cells Directive|
|January 2015 - Jan 2016||Polish clinicians used FMT in patients with blood disorders to combat colonisation of MDROs||Crum-Cianflone||Cripps Mercy Hospital, San Diego|
|February 2015||Report of a woman suddenly gaining weight after receiving FMT using a stool sample from her daughter||Alang, Kelly||Newport hospital, Rhode Island|
|March 2016||FDA announced its intention to revise its FMT oversight|
|March 2016||Trial demonstrated enema-based FMT to be safe and effective||Orenstein|
|10 Jul 2017||Results published from first randomised controlled FMT trial for obesity||Thompson||Brigham and Women's Hospital|
|4 Oct 2017||Chinese study showed FMT to be more cost-effective than conventional treatment for inflammatory bowel disease||Zhang||Hospital of Nanjing Medical University|
|March 2018 - Apr 2019||STOP-Colitis Pilot Trial||University of Birmingham|
|13 Jun 2019||FDA issued a warning after a patient died from FMT treatment|
First record of the application of faecal microbiota transplant (FMT)
1570 - 1619
First application of FMT in animals
FMT described for the treatment of abdominal diseases
Discovery of microbes in stools
Birth of probiotics
Discovery of a beneficial strain of Escherichia coli
FMT developed to treat German troops
Nobel Prize jointly awarded to Alexander Fleming, Ernst B Chain and Howard W Florey for the discovery of penicillin and its curative effect
FMT tried out unofficially in surgical patients suffering diarrhoea and other complications from antibiotics
FMT successfuly treated four patients with C.diff. resistant to antibiotics
21 Jan 1989
First report of FMT used to treat ulcerative colitis
2005 - 2007
FMT-associated weight gain was evaluated in a series of different experiments
2007 - 2016
Human Microbiome Project (HMP) carried out
2008 - 2012
METAgenomics of the Human Intestinal Tract (MetaHIT) project carried out
5 Feb 2013
Results published for first randomised controlled FMT trial for recurrent CDI
6 Jun 2013
Correlation found between gut microbiota and type II diabetes
The US FDA classified FMT as an 'investigational new drug (IND)'
UK National Institute for Health and Care Excellence (NICE) issued guidelines for the use of FMT for recurrent CDI
FDA issued draft guidelines for the use of FMT for treating recurrent CDI
FMT used to treat a multi-drug resistant E.coli
The EU Commission concluded that the purposes of FMT are not ‘intended for human applications’ within the meaning of EU Tissues and Cells Directive
Jan 2015 - Jan 2016
Polish clinicians used FMT in patients with blood disorders to combat colonisation of MDROs
Report of a woman suddenly gaining weight after receiving FMT using a stool sample from her daughter
FDA announced its intention to revise its FMT oversight
Trial demonstrated enema-based FMT to be safe and effective
10 Jul 2017
Results published from first randomised controlled FMT trial for obesity
4 Oct 2017
Chinese study showed FMT to be more cost-effective than conventional treatment for inflammatory bowel disease
Mar 2018 - Apr 2019
STOP-Colitis Pilot Trial
13 Jun 2019
FDA issued a warning after a patient died from FMT treatment