Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for
''Clostridioides difficile'' infection (CDI).
For recurrent CDI, FMT is more effective than
vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...
alone, and may improve the outcome after the first index infection.
Side effects may include a risk of
infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
s, therefore the donor should be
screen
Screen or Screens may refer to:
Arts
* Screen printing (also called ''silkscreening''), a method of printing
* Big screen, a nickname associated with the motion picture industry
* Split screen (filmmaking), a film composition paradigm in which mul ...
ed. FMT involves restoration of the
colonic microflora by introducing healthy bacterial flora through infusion of stool via
colonoscopy,
enema
An enema, also known as a clyster, is an injection of fluid into the lower bowel by way of the rectum.Cullingworth, ''A Manual of Nursing, Medical and Surgical'':155 The word enema can also refer to the liquid injected, as well as to a device ...
,
orogastric tube
Nasogastric intubation is a medical process involving the insertion of a plastic tube (nasogastric tube or NG tube) through the nose, down the oesophagus, and down into the stomach. Orogastric intubation is a similar process involving the inserti ...
, or by mouth in the form of a
capsule containing feces from a healthy donor, which in some cases is
freeze-dried
Freeze drying, also known as lyophilization or cryodesiccation, is a low temperature dehydration process that involves freezing the product and lowering pressure, removing the ice by sublimation. This is in contrast to dehydration by most conve ...
.
With CDI becoming more common, FMT is gaining increasing prominence, with some experts calling for it to become the first-line therapy for CDI.
FMT has been used experimentally to treat other
gastrointestinal disease
Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the gastrointestinal tract, namely the oesophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the liver, ...
s, including
colitis
Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases.
In a medical context, the label ''colitis'' (without qualification ...
,
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
,
irritable bowel syndrome
Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...
, and
neurological
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
conditions, such as
multiple sclerosis and
Parkinson's
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
In the United States, human feces has been regulated as an experimental drug since 2013. In the
United Kingdom
The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...
, FMT regulation is under the remit of the
Medicines and Healthcare products Regulatory Agency.
Medical uses
''Clostridioides difficile'' infection
![Clostridium difficile 01](https://upload.wikimedia.org/wikipedia/commons/0/0f/Clostridium_difficile_01.jpg)
Fecal microbiota transplant is approximately 85–90% effective in people with CDI for whom antibiotics have not worked or in whom the disease recurs following antibiotics.
Most people with CDI recover with one FMT treatment.
A 2009 study found that fecal microbiota transplant was an effective and simple procedure that was more cost-effective than continued antibiotic administration and reduced the incidence of
antibiotic resistance.
Once considered to be a "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
have been moving toward acceptance of FMT as a
standard therapy for relapsing CDI and also Medicare coverage in the United States.
It has been recommended that
endoscopic
An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...
FMT be elevated to
first-line treatment
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
for people with deterioration and severe relapsing ''C. difficile'' infection.
Fecal microbiota, live (Rebyota) was approved for medical use in the United States in November 2022.
Other conditions
Ulcerative colitis
In May 1988, Australian professor Thomas Borody treated the first
ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
patient using FMT, which led to longstanding symptom resolution.
Following on from that, Justin D. Bennet published the first case report documenting reversal of Bennet's own colitis using FMT. 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.
Cancer
Clinical trials are underway to evaluate if FMT from anti-PD-1 immunotherapy donors can promote a therapeutic response in immunotherapy-refractory patients.
Bipolar Disorder
An anecdotal case of a patient with treatment-resistant Bipolar 1 Disorder resolving her symptoms with FMT was published by psychiatrist Russell Hinton in 2020
Adverse effects
Adverse effects were poorly understood as of 2016.
[ They have included bacterial blood infections, fever, SIRS-like syndrome, exacerbation of inflammatory bowel disease in people who also had that condition, and mild GI distress which generally resolve themselves soon after the procedure, including flatulence, diarrhea, irregular bowel movements, abdominal distension/bloating, abdominal pain/tenderness, constipation, cramping, and nausea.] There are also concerns that it may spread COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
.
A person died in the United States in 2019 after receiving an FMT that contained drug-resistant bacteria and another person who received the same transplant was also infected.[ The FDA issued a warning against potentially life-threatening consequences of transplanting material from improperly screened donors.]
Technique
There are evidence-based consensus guidelines for the optimal administration of FMT. Such documents outline the FMT procedure, including preparation of material, donor selection and screening, and FMT administration.
The gut microbiota comprises all microorganisms that reside along the gastrointestinal tract, including commensal, symbiotic and pathogenic organisms. FMT is the transfer of fecal material containing bacteria and natural antibacterials from a healthy individual into a diseased recipient.
Donor selection
Preparing for the procedure requires careful selection and screening of the potential donor. Close relatives are often chosen on account of ease of screening; however, in the case of treatment of active ''C. diff.'', family members and intimate contacts may be more prone to be carriers themselves. This screening involves medical history questionnaires, screening for various chronic medical diseases (e.g. irritable bowel diseases, Crohn's disease, gastrointestinal cancer, etc.), and laboratory testing for pathogenic gastrointestinal infections (e.g. CMV, ''C. diff.'', salmonella, Giardia, GI parasites, etc.).
Specimen preparation
No laboratory standards have been agreed upon, so recommendations vary for size of sample to be prepared, ranging from of fecal material for effective treatment. Fresh stool is used to increase viability of bacteria within the stool and samples are prepared within 6–8 hours. The sample is then diluted with 2.5–5 times the volume of the sample with either normal saline, sterile water, or 4% milk. Some locations mix the sample and the solvent with a mortar and pestle, and others use a blender. There is concern with blender use on account of the introduction of air which may decrease efficacy as well as aerosolization of the feces contaminating the preparation area. The suspension is then strained through a filter and transferred to an administration container. If the suspension is to be used later, it can be frozen after being diluted with 10% glycerol
Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
, and used without loss of efficacy compared to the fresh sample. The fecal transplant material is then prepared and administered in a clinical environment to ensure that precautions are taken.
Administration
After being made into suspensions, the fecal material can be given through nasogastric and nasoduodenal tubes, or through a colonoscope
Colonoscopy () or coloscopy () is the endoscopic examination of the large bowel and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It can provide a visual diagnosis (''e. ...
or as a retention enema
An enema, also known as a clyster, is an injection of fluid into the lower bowel by way of the rectum.Cullingworth, ''A Manual of Nursing, Medical and Surgical'':155 The word enema can also refer to the liquid injected, as well as to a device ...
.
Mechanism of action
One hypothesis behind fecal microbiota transplant rests on the concept of bacterial interference, i.e., using harmless bacteria to displace pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
ic organisms, such as by competitive niche exclusion. In the case of CDI, the ''C. difficile'' pathogen is identifiable. Recently, in a pilot study of five patients, sterile fecal filtrate was demonstrated to be of comparable efficacy to conventional FMT in the treatment of recurrent CDI. The conclusion from this study was that soluble filtrate components (such as bacteriophages, metabolites, and/or bacterial components, such as enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s) may be the key mediators of FMT's efficacy, rather than intact bacteria. It has now been demonstrated that the short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms. Derived from intestinal microbial fermentation of indigestible foods, SCFAs are the main energy source of colonocytes, making them crucial to gastrointestinal healt ...
valerate
Valeric acid or pentanoic acid is a straight-chain alkyl carboxylic acid with the chemical formula . Like other low-molecular-weight carboxylic acids, it has an unpleasant odor. It is found in the perennial flowering plant ''Valeriana officina ...
is restored in human fecal samples from CDI patients and a bioreactor model of recurrent CDI by FMT, but not by antibiotic cessation alone; as such, this may be a key mediator of FMT's efficacy. Other studies have identified rapid-onset but well-maintained changes in the gut bacteriophage profile after successful FMT (with colonisation of the recipient with donor bacteriophages), and this is therefore another key area of interest.
In contrast, in the case of other conditions such as ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
, no single culprit has yet been identified. However, analysis of gut microbiome and metabolome changes after FMT as treatment for ulcerative colitis has identified some possible candidates of interest.
History
The first use of donor feces as a therapeutic agent for food poisoning and diarrhea was recorded in the Handbook of Emergency Medicine by a Chinese man, Hong Ge, in the 4th century. Twelve hundred years later Ming dynasty physician Li Shizhen
Li Shizhen (July 3, 1518 – 1593), courtesy name Dongbi, was a Chinese acupuncturist, herbalist, naturalist, pharmacologist, physician, and writer of the Ming dynasty. He is the author of a 27-year work, found in the ''Compendium o ...
used "yellow soup" (aka "golden syrup") which contained fresh, dry or fermented stool to treat abdominal diseases. "Yellow soup" was made of fecal matter and water, which was drunk by the person.
The consumption of "fresh, warm camel feces" has also been recommended by Bedouins as a remedy for bacterial dysentery
Dysentery (UK pronunciation: , US: ), historically known as the bloody flux, is a type of gastroenteritis that results in bloody diarrhea. Other symptoms may include fever, abdominal pain, and a feeling of incomplete defecation. Complications ...
; its efficacy probably attributable to the antimicrobial subtilisin produced by'' Bacillus subtilis
''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillus ...
'' was anecdotally confirmed by German soldiers of the Afrika Korps
The Afrika Korps or German Africa Corps (, }; DAK) was the German expeditionary force in Africa during the North African Campaign of World War II. First sent as a holding force to shore up the Italian defense of its African colonies, the ...
during World War II
World War II or the Second World War, often abbreviated as WWII or WW2, was a world war that lasted from 1939 to 1945. It involved the vast majority of the world's countries—including all of the great powers—forming two opposing ...
. However, this story is likely a myth, independent research was not able to verify any of these claims.
The first use of FMT in western medicine was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who treated four critically ill people with fulminant pseudomembranous colitis (before ''C. difficile'' was the known cause) using fecal enemas, which resulted in a rapid return to health. For over two decades, FMT has been provided as a treatment option at the Centre for Digestive Diseases in Five Dock
Five Dock is a suburb in the Inner West of Sydney, in the state of New South Wales, Australia. Five Dock is located 10 kilometres west of the Sydney central business district, in the local government area of the City of Canada Bay.
Location
F ...
, by Thomas Borody, the modern-day proponent of FMT. In May 1988 their group treated the first ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
patient using FMT, which resulted in complete resolution of all signs and symptoms long term. In 1989 they treated a total of 55 patients with constipation, diarrhea, abdominal pain, ulcerative colitis, and Crohn's disease with FMT. After FMT, 20 patients were considered "cured" and a further 9 patients had a reduction in symptoms. Stool transplants are considered about 90 percent effective in those with severe cases of ''Clostridium difficile'' colonization, in whom antibiotics have not worked.[
The first ]randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
in ''Clostridium difficile'' infection was published in January 2013. The study was stopped early due to the effectiveness of FMT, with 81% of patients achieving cure after a single infusion and over 90% achieving a cure after a second infusion.
Since that time various institutions have offered FMT as a therapeutic option for a variety of conditions.
Society and culture
Regulation
Interest in FMT grew in 2012 and 2013, as measured by the number of clinical trials and scientific publications.
In the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
, the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
announced in February 2013 that it would hold a public meeting entitled "Fecal Microbiota for Transplantation" which was held on May 2–3, 2013. In May 2013 the FDA also announced that it had been regulating human fecal material as a drug. The American Gastroenterological Association
The American Gastroenterological Association (AGA) is a medical association of gastroenterologists. Approximately 16,000 scientists and physicians are members of the organization.
Overview
The American Gastroenterological Association is a pr ...
(AGA), the American College of Gastroenterology
The American College of Gastroenterology (ACG) is a Bethesda, Maryland–based medical association of gastroenterologists.
The association was founded in 1932 and holds annual meetings and regional postgraduate continuing education courses, es ...
(ACG), the American Society for Gastrointestinal Endoscopy
The American Society for Gastrointestinal Endoscopy (ASGE) is a professional organization of physicians dedicated to improving endoscopy. The ASGE is made up largely of gastroenterologists from the United States. Included in its membership are en ...
(ASGE), and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sought clarification, and the FDA Center for Biologics Evaluation and Research
The Center for Biologics Evaluation and Research (CBER) is one of six main centers for the U.S. Food and Drug Administration (FDA), which is a part of the U.S. Department of Health and Human Services. The current Director of CBER is Peter Marks, ...
(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. 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.
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 (, July 18, 2013).
In March 2014, the FDA issued a proposed update (called "draft guidance") that, when finalized, is intended to supersede the July 2013 enforcement policy for FMT to treat ''C. difficile'' infections unresponsive to standard therapies. It proposed an interim discretionary enforcement period, if 1) informed consent is used, mentioning investigational aspect and risks, 2) stool donor is known to either the person with the condition or physician, and 3) stool donor and stool are screened and tested under the direction of the physician (, February 26, 2014). Some doctors and people who want to use FMT have been worried that the proposal, if finalized, would shutter the handful of stool banks which have sprung up, using anonymous donors and ship to providers hundreds of miles away.
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.
The FDA has issued three safety alerts regarding the transmission of pathogens. The first safety alert, issued in June 2019, described the transmission of a multidrug resistant organism from a donor stool that resulted in the death of one person. The second safety alert, issued in March 2020, was regarding FMT produced from improperly tested donor stools from a stool bank which resulted in several people hospitalizations and two deaths. A safety alert in late March, 2020, was due to concerns of transmission of COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
in donor stool.
Stool banks
In 2012, a team of researchers from the Massachusetts Institute of Technology
The Massachusetts Institute of Technology (MIT) is a private land-grant research university in Cambridge, Massachusetts. Established in 1861, MIT has played a key role in the development of modern technology and science, and is one of the ...
founded OpenBiome, the first public stool bank in the United States
Across Europe, numerous stool banks have emerged to serve the increasing demand. While consensus rapports exists, standard operation procedures still differ. Institutions in the Netherlands have published their protocols for managing FMT, and in Denmark institutions manages FMT according to the European Tissue and Cell directive.
Research
Cultured intestinal bacteria are being studied as an alternative to fecal microbiota transplant. One example is the rectal bacteriotherapy (RBT), developed by Tvede and Helms, containing 12 individually cultured strains of anaerobic and aerobic bacteria originating from healthy human faeces. Research has also been done to identify the most relevant microbes within fecal transplants, which could then be isolated and manufactured via industrial fermentation
Industrial fermentation is the intentional use of fermentation in manufacturing products useful to humans. In addition to the mass production of fermented foods and drinks, industrial fermentation has widespread applications in chemical industry. ...
; such standardized products would be more scalable, would reduce the risk of infections from unwanted microbes, and would improve the scientific study of the approach, since the same substance would be administered each time.
Veterinary use
Elephant
Elephants are the largest existing land animals. Three living species are currently recognised: the African bush elephant, the African forest elephant, and the Asian elephant. They are the only surviving members of the family Elephantidae ...
s, hippos
A hippo or hippopotamus is either of two species of large African mammal which live mainly in and near water:
* Hippopotamus
* Pygmy hippopotamus
Hippo or Hippos may also refer to:
Toponymy
* The ancient city of Hippo Regius (modern Annaba, Al ...
, koala
The koala or, inaccurately, koala bear (''Phascolarctos cinereus''), is an arboreal herbivorous marsupial native to Australia. It is the only extant representative of the family Phascolarctidae and its closest living relatives are the w ...
s, and pandas
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a controversial hypothetical diagnosis for a subset of children with rapid onset of obsessive-compulsive disorder (OCD) or tic disorders. Sy ...
are born with sterile intestines, and to digest vegetation need bacteria which they obtain by eating their mothers' feces, a practice termed coprophagia. Other animals eat dung.
In veterinary medicine
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
fecal microbiota transplant has been known as "transfaunation" and is used to treat ruminating animals, like cows and sheep, by feeding rumen
The rumen, also known as a paunch, is the largest stomach compartment in ruminants and the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. The rumen's microbial favoring environment al ...
contents of a healthy animal to another individual of the same species in order to colonize its gastrointestinal tract with normal bacteria.
Terminology
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''.
In pop culture
A Season 23 episode of South Park titled “Turd Burglars” heavily features fecal transplants.
See also
* Jo Zayner, a biohacker who attempted a full fecal microbiota transplant on themselves in 2016.
References
Further reading
*
{{authority control
Experimental medical treatments
Feces