The Latest Poop on Fecal Microbiota Transplantation
Updated: Dec 4, 2019
“Poop is one of the most wholesome, beautiful and natural experiences that money can buy.”
- Steve Martin
If you are one of the many thousands of patients who were cured of Clostridioides difficile infection (CDI) by fecal microbiota transplantation (FMT), you are likely in full agreement with Steve Martin. CDI is the most serious form of gastroenteritis in the U.S., where it causes excessive suffering of an estimated half-million people and kills about 15,000 per year. And according to the website of OpenBiome, a nonprofit stool bank that provides stool-derived preparations for FMT by clinicians in more than 1,000 healthcare institutions, the cost of fecal microbiota preparations is $1595 per treatment—a small price to pay for anyone afflicted with CDI. Before focusing on what’s new in the field of FMT a little background information is needed, especially if you’re surprised, if not astonished, to hear that human fecal material is now routinely used to treat patients.
First, what is FMT? By definition, FMT, also known as stool transplant, is the process of transplantation of fecal bacteria from a healthy donor into a recipient. The primary goal of the procedure is to restore the bacterial population colonizing the colon of a patient with a healthy bacterial flora (microbiota) from the stool donor. This therapeutic approach isn’t new. In fact, it was used 1700 years ago by Ge Hong, an ancient Chinese physician who treated patients suffering from severe diarrhea with what was called “yellow soup.”
The first use of FMT in western medicine was published in 1958 by Ben Eiseman and colleagues, a team of surgeons from Colorado, who successfully treated four critically ill people with fulminant pseudomembranous colitis (before C. difficile was the known cause) using fecal enemas. Contemporaneously, with the emergence of a nationwide CDI epidemic in the late 1970s, FMT witnessed an incredible and sustained renaissance. And when a highly toxic strain of C. difficile arrived about two decades later, the need to assess FMT as a treatment became more urgent.
How does FMT work? In a healthy gut, C. difficile is out-competed by many different bacterial species, virtually all of which are either harmless or play a role in human health. Antibiotic treatment, however, disrupts this ecosystem by killing the protective bacteria. C. difficile forms spores that are resistant to antibiotics. When it is no longer outcompeted, C. difficile establishes itself in the gut and produces toxins that damage the colon leaving patients suffering from severe diarrhea, abdominal pain, and fever. But, with an infusion of other bacteria from a healthy donor's stool, the C. difficile is again out-competed.
For the first two decades of the CDI epidemic, it was exclusively a problem in hospitalized patients where many patients are elderly and treated with antibiotics—two big risk factors. In the past several years, however, CDI has moved into the community. The common denominator for CDI in both settings is the use of antibiotics which eliminate protective bacteria.
Somewhat counterintuitively, an antibiotic, such as vancomycin or fidaxomicin, is the first-line treatment of CDI. These antibiotics are effective in more than 75% of patients. But recurrences are not uncommon, albeit somewhat less with the more expensive drug fidaxomicin.
FMT has been extensively investigated in clinical trials in the U.S. and other countries in the treatment of recurrent infections (rCDI). A variety of routes of administration have been used including nasogastric administration, rectal enema, colonic administration, and oral preparations of frozen fecal microbial capsules. Mean cure rates of FMT for rCDI are between 91% to 96%, which equals or surpasses the success with various antibiotic regimens.
One of the recent advances in FMT was reported by Gianluca Ianiro, et al in the November 4, 2019, issue of the Annals of Internal Medicine. A dreaded complication of CDI is the development of bloodstream infection by other bacterial species—an infection that is often fatal. In this prospective study of 290 inpatients with CDI in an Italian academic medical center, the incidence of bloodstream infection was significantly lower in those treated with FMT when compared to patients receiving antibiotic treatment. Also, FMT was associated with better overall survival and reduced days of hospitalization.
Is FMT safe? Currently, in the US, fecal microbiota is considered by the Federal Drug Administration (FDA) “an investigational new drug.” Based on the evidence so far of its efficacy and safety, FMT is not FDA-approved for any medical condition. Over the last few years, however, the FDA has allowed clinicians to treat patients with CDI as clinical development of therapy progressed through the approval process.
On November 4, 2019, the FDA convened a public hearing to obtain input on the state of the science regarding FMT for treatment of CDI not responsive to standard antibiotic treatment. While some research companies and clinical researchers argue that the current safeguards are overly cumbersome and delay progress, others aren’t convinced that FMT meets safety standards.
Another new development in the field of FMT that will certainly weigh in on the FDA’s decision about regulation is a report in the October 30, 2019, New England Journal of Medicine. In this report, two patients are described who received FMTs at Massachusetts General Hospital to treat CDI. Both patients developed a bloodstream infection that was caused by an antibiotic-resistant Escherichia coli that produced an extended spectrum beta lactamase (ESBL) that destroys many types of antibiotics. The strain of E. coli that infected both patients, one of whom died, was traced to the same donor stool. While donor stools are routinely screened for a variety of potential pathogens, these case reports add antibiotic-resistant bacteria to the list.
The composition of donor stools is an important consideration not only for safety reasons but also because the nature of the microbiota shapes the response to FMT. As there are more than 2,000 bacterial species within the healthy gut microbiome, not surprisingly the ones that serve as the best competitors of C. difficile are yet to be determined.
Currently, researchers are exploring FMT's potential role in treating other gastrointestinal diseases, such as irritable bowel syndrome, ulcerative colitis, and Crohn's Disease, as well as a host of medical conditions in which an imbalance of the gut microbiome (a condition termed dysbiosis) is implicated. Pointing to the potential importance of the composition of the donor stool is a 2015 randomized controlled trial in ulcerative colitis using five stool donors. The researchers found that 78% of patients achieving remission received stool from a single donor. Such variability of patient responses to FMT recently has provided a framework for researchers in rational stool donor selection for FMT clinical trials.
As the field of FMT progresses, we can anticipate additional successes as well as curveballs. For example, a group of Dutch researchers recently identified Blastocystis in the feces of eight FMT-treated patients with rCDI that originated in fecal suspensions obtained from 10 different donors. This parasite is rarely if ever pathogenic, and it didn’t produce symptoms or affect the outcomes of the FMTs. Nonetheless, this report serves as a reminder of the importance of rigorous assessments of the safety of FMT before jumping fully onboard this rapidly moving bandwagon.