The History of Fecal Microbiota Transplantation
Joann Kwah, MD, FACG and Lawrence J. Brandt, MD, MACG, AGAF, FASGE
Fecal microbiota transplantation (FMT) is the transfer of intestinal microbiota from a healthy donor to a recipient who has a certain disease with the intention of treating that disease.1 Today, this concept is based on the knowledge that certain diseases are associated with an altered intestinal microbiome and the observation that restoration of a balanced, healthy intestinal microbiome may result in cure (eg, Clostridioides difficile infection [CDI]) or improvement of disease (eg, inflammatory bowel disease [IBD] or irritable bowel syndrome). The use of feces to treat a variety of ailments goes back more than 1000 years, but only recently has it gained recognition in humans as a potential treatment for gastrointestinal (GI) diseases and, perhaps, for some non-GI diseases as well. This chapter reviews the history and evolution of FMT.
Early Use of Fecal Microbiota Transplantation
The use of FMT dates back to fourth century China, when Ge Hong described the use of human fecal suspension given by mouth for the treatment of food poisoning or severe diarrhea.2 In the 16th century, Li Shizhen described oral administration of fermented fecal solution, fresh fecal suspension, dry feces, or infant feces for the treatment of severe diarrhea, fever, pain, vomiting, and constipation.2 The fermented fecal solution was referred to as yellow soup to make it a more palatable nostrum. In the 17th century, cud (partially digested food from the first stomach of a ruminant) given orally and fecal suspensions given orally or by enema, termed transfaunation, were used in veterinary medicine to treat ruminants off feed with a variety of disorders and horses with chronic diarrhea.3
It was not until 1958, however, that Ben Eiseman, an American surgeon, wrote the first published report of fecal suspension used in Western medicine: a case series of 4 patients precariously ill with pseudomembranous enterocolitis caused by Micrococcus pyogenes and treated with fecal enemas. The stool donors used were surgical residents caring for the patients. The author notes dramatic improvement just hours after its administration.4
Nonetheless, FMT remained a largely forgotten therapy until 1983, when Schwan et al5 reported the first case of FMT given by enema to treat CDI. Up until 1989, retention enemas had been the most common technique for FMT. In 1991, Aas et al6 used a nasogastric tube as the route of administration. In 1998, Lund-Tønnesen administered stool via gastroscopy and colonoscopy.7 In 2000, a case report by Persky and Brandt8 described an older woman with CDI not responding to standard therapy who was symptomatically cured within several hours by one infusion of a saline suspension of her husband’s stool administered colonoscopically by infusion. The material was infused in 10- to 20-mL increments every 10 cm throughout the colon upon withdrawal. This report served to raise awareness of this therapy for recurrent CDI (rCDI).
Fecal Microbiota Transplantation in the 21st Century
Silverman et al9 detailed the self-administration of FMT by enema in 2010 with donors screened by physicians, which resulted in the wider use of FMT. The use of FMT capsules were first reported by Louie et al,10 who administered 24 to 34 capsules to 27 patients with CDI and achieved a 100% cure rate. Additionally, Hamilton et al11 in 2012 reported that frozen FMT was just as effective as fresh FMT, which served to show that stool samples could be processed at a Good Manufacturing Practice (GMP) facility and shipped safely without loss of therapeutic effect over long distances, thus greatly increasing availability of FMT. It has since been noted by others that FMT administered via processed frozen fecal suspensions has efficacy rates similar to those of FMT performed using fresh stool.12 The possibility of widespread distribution from a central facility has been proven by a large US stool bank (OpenBiome, Cambridge, MA), which supports access to FMT. As of October 2019, the stool bank has reported shipping more than 50,000 FMT treatments to physicians in 50 states and 7 countries (Practical Pearl 3-1).13
As the delivery of FMT evolves from fresh fecal suspensions to the use of frozen material processed under GMP best practices, the content of the product is also changing. Historically, Tvede and Rask-Madsen14 demonstrated the effectiveness of a 10-bacterial strain combination to successfully treat 5 patients with rCDI. The authors concluded that the 3 species in this combination contributing to remission belonged to the Bacteroides genus (B. ovatus, B. thetaiotaomicron, and B. vulgatus). Graham et al15 subsequently confirmed the role of Bacteroides species, curing 1 patient with rCDI with the same 3 species of Bacteroides. There is now a sector within the biotechnology industry devoted to microbiome therapeutics, where companies such as Finch Therapeutics Group Inc, Seres Therapeutics Inc, and Rebiotix Inc are developing technologies to restore a healthy composition of microbes. Clinical trials are ongoing with these microbiome therapies for diseases including CDI and IBD (Table 3-1).
Practical Pearl 3-1
Is All Fecal Microbiota Transplantation the Same?
- Over time, the level of manufacturing requirements that constitutes a safe FMT have increased.
- First-generation FMT, described by Eiseman et al4 as a “fecal enema” without any manipulation, filtering, or donor screening, is no longer the current standard.
- In comparison, current-generation FMT products from stool banks have rigorous donor screening and apply significant processing under GMP manufacturing practice; however, patients performing do-it-yourself FMT or individual clinicians attempting FMT may not adhere to the same screening or manufacturing standards.
- Accordingly, there is ongoing conflation of the term FMT in the field, and it is important for clinicians to recognize that donor screening, manufacturing processing, cryoprotectant, formulation, delivery, and dose have an impact on both the safety and efficacy outcomes.
- Given the variability in donor material procurement and processing of FMT, safety and efficacy from one FMT product may not have the same results as another, and clinicians must be mindful to apply best practices in evidence-based medicine.