Health Letter, March 2023
By Nina Zeldes, MSc, Ph.D.
Fecal matter transplants (FMTs) have been used in clinical trials to treat a variety of health conditions for years. However, the first product that contains live microorganisms produced from stool (fecal matter) from healthy donors was only approved by the Food and Drug Administration (FDA) in November 2022. This product is indicated only for adult patients who have a serious recurring infection called recurring Clostridioides difficile infection (CDI) and is meant to help to restore sick patients’ gut microbiome.
What is the human microbiome?
The human body is home to trillions of microorganisms, such as bacteria, viruses and other microbial cells that make up the so-called human microbiome. But because these organisms are so small, they only amount to about 1–3% of a person’s body mass. Most of these microbes live in the intestinal tract, or gut, and also are referred to as the “gut flora” or “gut microbiome”. Although researchers estimate that there are over 1,000 types of gut microbes, a healthy person’s digestive tract tends to have a mix of at least 160 different species.
Generally, these microbes are not harmful to the human body. In fact, many are important for our overall health, because they are helpful to digestion, are involved in producing vitamins that our bodies cannot produce by themselves and are necessary for the immune system to work well. Having many and diverse types of “good” organisms also can help to keep harmful pathogens in check. For example, researchers have found that patients suffering from diseases such as CDI, irritable bowel syndrome, ulcerative colitis or Crohn’s disease tend to have fewer and less diverse helpful microbes than do healthy individuals.
The makeup of an individual’s gut flora changes over their lifetime depending on numerous factors including sex, age, race, lifestyle and diet. There are also several factors that can disturb the amount and balance of helpful microbes, including treatment with antibiotics, as discussed in more detail below.
What are fecal matter transplants?
Because many of the microbes that live in the gut are also found in fecal matter, fecal microbes of a healthy donor can be placed — or transplanted — into the gut of a patient. This transfer is called a fecal matter transplant, sometimes also referred to as fecal microbiota or stool transplants.
However, since harmful microorganisms also can be transferred accidentally through FMTs, the donor and their stool donation must be screened and tested for different disease-causing bacteria and viruses. The stool donations are then diluted, filtered and prepared for transplantation (via capsules that can be swallowed, enema or colonoscopy, or a tube inserted through the nose and into the stomach).
FMTs are generally considered to be relatively safe, with adverse effects largely restricted to mild, short-lived gastrointestinal disturbances, especially when the donor and their stool donation have been thoroughly screened and tested.
Furthermore, researchers are not exactly sure yet how and why FMTs seem to work. It is most likely that the healthy microbes introduced into the patient’s gut help resolve the patient’s unhealthy balance by adding missing strains of gut microbes. At the same time, it is not yet known whether FMTs have other beneficial effects or whether there are possible undesirable long-term consequences of changing a person’s gut flora.
More severe complications also have been reported, including some caused by the transplant’s delivery method (such as perforations of the intestine) but also bacterial or viral infections that can be life-threatening. For example, several patients were hospitalized and two died after they received a FMT as part of a clinical trial because the transplant contained a rare type of Escherichia coli (e. Coli) bacterium for which the donations had not been screened.
FMT for Clostridioides difficile infection
To date, most information on the safety and effectiveness of FMTs is available for the treatment of recurrent infection with the toxin-producing bacterium Clostridioides difficile. CDI can cause abdominal pain, severe diarrhea and colitis (an inflammation of the colon). Every year, there are almost half a million of these infections in the U.S., causing 15,000–30,000 deaths.
Although anyone can get CDI, older patients and those who have received antibiotic treatments are most at risk. In fact, according to the CDC, this infection is seven to 10 times more likely to occur during or after treatment with antibiotics, because in addition to killing bacteria originally targeted by the antibiotic treatment, these antibiotics also can destroy gut flora. This, in turn, can enable harmful bacteria in the gut, such as Clostridioides difficile, to take over. Unfortunately, for about 10–30% of patients the infection recurs after the initial treatment, either once or several times (called recurrent CDI). Each recurrence also makes an additional subsequent recurrence more likely.
CDI and recurring CDI are treated with antibiotics. However, several case studies and clinical trials have shown that transplanted fecal microbiota can be an effective treatment alternative for patients with recurring CDI. In fact, in 2022 the FDA approved the first fecal microbiota product for this condition.
The approval of the fecal microbiota product RBX2660, which is administered by enema and now marketed under the brand name REBYOTA, was based on data from six clinical trials. The product’s safety was demonstrated by a combined analysis of five of these studies and showed that 23% of patients who received the fecal microbiota product experienced treatment-emergent adverse events, compared with 19% in the placebo group. These adverse effects were mainly mild or moderate and included abdominal pain, diarrhea, bloating, gas and nausea. However, twice as many patients taking RBX2660 (14%) than those who received a placebo (7%) experienced serious adverse events. It is also important to note that participants across these studies were mainly female (67%) and White (94%), which reduces what we know about the safety of this treatment for other patient groups.
The data about the effectiveness of this product come only from a subset of these studies, which showed that treatment with RBX2660 was considered a success for significantly more patients (71%) than treatment with a placebo (58%). Although the experts on the committee that advised FDA in this approval decision considered this effect to be only “modest,” they noted that “even a modest treatment effect could be clinically meaningful for patients with recurrent CDI that have not responded to other available treatment options.”
Since RBX2660 is a fecal microbiota product, it contains microbes and other particles and can therefore transmit infectious agents or food allergens. However, the committee members again argued that having a regulated product available is a safer choice for patients, especially because patients can access FMTs in various unregulated ways.
What does this approval mean for patients?
To date, RBX2660 is the only FDA-approved fecal microbiota product available and is only indicated to reduce the recurrence of CDI in adult patients who have previously been treated with antibiotics for CDI. Although there are clinical trials that test FMTs for a range of other conditions, including inflammatory bowel disease, obesity, Crohn’s disease and autism, there is no conclusive evidence yet on the safety or efficacy of this type of treatment for these conditions.
For this reason, any treatment with FMTs for any condition other than recurring CDI is considered investigational by the FDA and should only be used as part of a clinical trial. In addition, doctors need to inform patients about the risks of the procedure and ensure that the stool donor and stool were sufficiently screened and tested, and that the fecal material to be transplanted is properly stored and handled.
Still, some patients who suffer from conditions other than recurrent CDI look to FMT as a last resort, for example because other treatments they have tried for their condition have not worked or they have a very low quality of life. Given the restrictions of receiving FMTs in a health care setting, some may even consider performing this procedure in their own homes without oversight from a health care provider. However, such do-it-yourself fecal transplants are inadvisable and can be very dangerous, especially if the donated stool is not adequately screened.
Patients should only consider this procedure after speaking with their health care provider and by using adequately tested stool donations under medical supervision, for example as part of a clinical trial. Moreover, it is important to remember that until reliable clinical data for conditions other than recurrent CDI become available, the true short- and long-term benefits and risks of this treatment remain unknown.