The micro-organisms living in the gut play an important role in the body's defenses against infection.
Of all the forms of transplantation that currently exist, it is safe to say that a transplant of fecal matter - also known as stool - is one of the strangest that a patient can have. But at the same time, it could also be one of the most important, representing a solution to the problem of antimicrobial resistance that affects many areas of medicine.
Fecal microbiota transplants (FMT) are a form of therapy known as bacteriotherapy, whereby harmless bacteria are utilized to displace harmful organisms. In addition to treating infections, bacteriotherapy should avoid disturbing the natural bacteria that exist within the body, unlike some antibacterial agents.
One story that has been prominently featured in various health news outlets is the case of a woman who became obese after fecal transplantation from an overweight donor. For many people, this story would be the first time they might hear about this form of treatment.
How exactly does the procedure work? Where did it come from? And why is it being used and promoted by doctors ahead of other forms of treatment? In this Spotlight, we investigate and attempt to answer these questions.
The origins of FMT
The first example of FMT can be traced all the way back to China in the 4th century, where literature of the time makes reference to the use of stool transplantation in the treatment of food poisoning and diarrhea.
Later, in the 16th century, an influential herbalist called Li Shizhen is known to have treated abdominal diseases using remedies referred to as "yellow soup" and "golden syrup" that contained fresh, dried or fermented stool.
In 16th century veterinary medicine, a treatment that is still used today known as transfaunation was carried out among ruminating animals. The process involved the transfer of micro-organisms from the stomach of healthy donor animals to those of sick animals.
During World War II, German soldiers confirmed that a Bedouin remedy for bacterial dysentery - the consumption of fresh camel dung - was effective.
The utilization of stool in the treatment of disease is rooted deeply within the history of medicine, and it has been portrayed as effective from the 4th century to the 20th. Medical practice has moved on considerably since these times, however, and the process in which stool is utilized has been refined since the days of Li Shizhen.
How does FMT work?
These days, the FMT procedure is relatively direct. It begins with the selection of a healthy donor, who donates a sample of their stool to be used. The stool sample is then mixed with a solution and strained to remove particulate matter before it is transplanted into the patient.
A number of ways in which the sample can then be placed inside the patient exist. Doctors can use enemas, endoscopy, colonoscopy and sigmoidoscopy. No one method has been found to be better than others, and so often the needs of the patient will determine which approach is used.
Micro-organisms found in the gut have been identified as playing an important role in keeping us healthy. Dr. Henning Gerke, a specialist in gastroenterology and hepatology at the University of Iowa, explains:
"These organisms - bacteria, fungi, protozoa - start colonizing the bowel in infancy. They appear to be important in training our immune systems and keeping pathogens (organisms that cause disease) in check."
The purpose of FMT is, therefore, to create a diversity of micro-organisms within the bowel of the patient, to fight off disease and prevent future afflictions.
Dr. Gerke writes that the idea of exposure to bacteria and parasites being beneficial to health reflects the "hygiene hypothesis," whereby lack of exposure to micro-organisms in early childhood can make individuals more susceptible to disease.
"We know, for instance, that certain autoimmune diseases are less common in countries with lower hygiene standards than those in the industrialized world," explains Dr. Gerke.
The problem with C. diff
Currently, FMT is most commonly utilized to treat patients with C. diff infection, a bacterial infection that occurs due to a shortage of healthy bacteria in the body and attacks the lining of the intestine. Symptoms caused by C. diff infection include diarrhea and abdominal pain.
The infection frequently occurs when an individual takes antibiotics to treat another condition. Although antibiotics can be an effective way of treating bacterial infections, they can also have an adverse effect on the gut microbiota
"Antibiotics are lifesavers, but anytime we give them to a patient to eradicate one pathogen, there's collateral damage, in that along with the bad bacteria we wipe off some good organisms that help keep the complex workings of our gut in perfect balance," says Dr. Maria Oliva-Hemker, director of pediatric gastroenterology at Johns Hopkins Children's Center in Baltimore, MD.
C. diff infection has often been treated with antibiotics in the past; a practice that Dr. Gerke describes as "fighting fire with fire." And ultimately, as Dr. Suchitra Hourigan explains, this ignores what caused the illness in the first place:
"When we administer an antibiotic to treat the C. diff infection, we destroy some of the bad bacteria, but that does not address the other half of the problem - the loss of good bacteria that might have led to the infection to begin with, so we never truly restore the balance in the gut and often the diarrhea returns with a vengeance in a matter of weeks."
Losing good bacteria is not the only problem with continued antibiotic use, however. When antibiotics fail to kill off a strain of bacteria completely, the bacteria can develop a resistance to the medication. As a result, future strains can develop that are heavily resistant to previously effective treatments.
According to the authors of a paper published in Clinical Gastroenterology and Hepatology, C. diff infections are increasing in incidence, severity and mortality. In addition, existing treatment options are limited and many appear to be losing efficacy.
FMT could offer an effective solution to these problems, and according to research cited by the authors, the process is safe, inexpensive and effective with success rates of over 90%. The Mayo Clinic even describe a randomized controlled trial that had to be stopped early due to overwhelmingly positive results.
Current regulation of the procedure
A number of stumbling blocks exist that currently prevent widespread adoption of the procedure, one of which being how the procedure is currently legislated in the US.
Numerous websites contain guides for performing FMT in the home, using readily available household items.
The Food and Drug Administration (FDA) have yet to fully approve FMT. Instead, it exercises enforcement discretion, allowing the use of the procedure for patients who are not responding to standard therapies, provided that informed consent is given and that the use of FMT is regarded as investigational.
Fecal transplants are also classified as drugs within the FDA legislation. Experts believe that this approach to FMT may be problematic.
"It's going to give a monopoly to whatever company gets the drug approved," Mark Smith told The New York Times last year. "We think it should be regulated, but unlike most products the FDA oversees, there's a real risk of the black market. If you restrict access, there's going to be lots of people doing it underground."
In 2012, Mark Smith and colleagues opened the first human stool bank in the US - OpenBiome - in order to make FMT safer, cheaper and more widely available to clinicians and patients. They provide hospitals with frozen stool samples that are ready to be used in FMT.
"People are dying, and it's crazy because we know what the solution is," Smith said. "People are doing fecal transplants in their basements and may not be doing any of the right screening or sterile preparation. We need an intermediate solution until there are commercial products on the market."
The Fecal Transplant Foundation state that there is only a small number of physicians in the US that provide FMT for the large number of patients that would benefit from the procedure. Additionally, many patients do not have a healthy donor who would be able to assist them.
The unknown and the future
At present, there are still a number of unknown factors that need to be explored and understood. Scientists do not yet know how donated bacteria specifically alter the patient's gut microbiota, and out of the trillion bacteria contained in stool, it is unknown which ones are beneficial, which are dangerous and which have no influence.
Future research will determine whether FMT can be used to treat other conditions affecting the gut microbiota.
Clinicians also need to know how to guarantee they can use FMT safely. As the previously mentioned case of the patient becoming obese after FMT attests, there is an element of uncertainty that still surrounds the procedure, even if that particular case involved just a single patient.
Dr. Gerke points out that methods of treatment with stool transplantation are not currently standardized. "More work needs to be done to determine what constitutes the ideal stool donor, optimal method of stool preparation and best route of administration," he states.
The Fecal Transplant Foundation maintain that there has never been a single, serious side effect reported from FMT, in all documentation from 4th century China to the present day. Randomized controlled trials are being conducted at present, with a view to putting an end to this uncertainty.
As well as treating C. diff infection, it may be that FMT could be used to treat other conditions related to the micro-organisms of the gut. Inflammatory bowel disease, irritable bowel syndrome, obesity and type 2 diabetes could be potential targets for future research programs.
Some of the concerns about variables with stool samples could be eradicated with the development of synthetic samples to replace human fecal matter. Already, researchers are developing synthetic stool from bacterial cultures and putting human stool in gel capsules for easy consumption.
"In less than a decade, we'll have lab-cooked poop that we can administer to restore balance in the guts of people with a wide array of conditions caused by the imbalance between good and bad germs," predicts Dr. Oliva-Hemker.
While on the surface it may seem like a messy business, FMT represents both the past and the future of medicine. With antimicrobial resistance a growing problem, this will be an important area of research in the coming years.