What is the Active Ingredient in FMT for CDI?
Sterile fecal filtrates—containing bacterial debris, proteins, antimicrobial compounds, metabolic products, and microbial DNA, rather than intact microorganisms—appear to be effective for treatment of recurrent Clostridium difficile infection (CDI), researchers report in the March issue of Gastroenterology.
Fecal microbiota transplantation (FMT) is an effective therapy of recurrent CDI—a single treatment resolves the infection in 85%–90% of patients. In the process of FMT, patients are given transplants of fresh or cryopreserved stool from healthy, well-characterized donors.
FMT is believed to improve intestinal dysbiosis by transferring a stable, viable, diverse, and healthy microbial community from donor to recipient.
Despite its efficacy and good short-term safety profile, FMT is faced with the challenges of standardization and the incalculable long-term risks inherent to the transfer of living microorganisms. Also, although FMT has been shown to be safe and effective in immunocompromised patients, it would be best to reduce the risk of adverse events in patients with limited eligibility for FMT.
During FMT, considerable amounts of stool water containing dead bacteria, their debris, and their metabolites are transferred, in addition to the living microbiota. Stephan J. Ott et al therefore examined whether the ingredients of fecal water alone (bacterial debris, proteins, antimicrobial compounds, metabolic products, or oligonucleotides/DNA) had any effects in patients with CDI.
Stool was collected from 5 donors selected by the patients and fully characterized according to FMT standards. The stool was then sterile filtered to remove small particles and bacteria, and the filtrate was transferred to patients in a single administration via nasojejunal tube.
Fecal samples were collected from patients before and at 1 week and 6 weeks after FFT. Microbiome, virome, and proteome profiles of donors and patients were compared.
The first patient (a 59-year-old woman with 3 episodes of recurrent CDI over a 6-month period, a first episode of CDI after sigmoid resection due to life-threatening recurrent diverticulitis with severe bleeding, and pseudomembranous colitis) was treated with sterile filtrate from stool from her son. The patient was discharged on the next day and was symptom-free after 3 days. C difficile remained undetectable at 4 weeks after the procedure. The patient had no further diarrhea, regained her normal weight, and has remained symptom-free at 2 years and her most recent check in (5 months after the study was completed).
Ott et al found that in all 5 patients, transfer of the fecal filtrate restored normal stool habits and eliminated symptoms of CDI for a minimum period of 6 months. 16S ribosomal RNA gene analysis comparing patients’ fecal microbiota before, 1 week after, and 6 weeks after transfer revealed substantial bacterial community shifts in all patients.
The authors observed diverse bacterial DNA signatures in the filtrates, and proteome analyses identified no obvious protein candidates associated with therapeutic efficacy.
They identified about 300 different proteins in each of the filtrates they analyzed—most proteins were of human origin, but the filtrates also contained 20–60 bacterial and fungal proteins. The major human proteins in the filtrate proteome were human enzymes such as intestinal-type alkaline phosphatase, chymotrypsin-like elastases, and α amylases. Bacterial proteins included metabolic enzymes and redox proteins without obvious microbiome-modifying properties, such as glyceraldehyde-3-phosphate dehydrogenase, phosphoenolpyruvate carboxykinase, glutaredoxin-1, or thioredoxin-1.
Analysis of virus-like particles from a filtrate showed a complex signature of bacteriophages. Bacterial phylogeny and virome profile analyses of fecal samples from recipients indicated longitudinal changes in microbial and viral community structures after transfer of the fecal filtrate.
Ott et al propose that the active component of FMT therapy might not be living bacteria, but bacterial components, antimicrobial compounds of bacterial origin (bacteriocins), or bacteriophages that contribute to a healthy intestinal microenvironment. These could be common to all successful FMT therapies and even rather unspecific regarding the bacterial strain(s) used for therapies. They propose that bacteriophages affect community dynamics of gut microbiota to resolve dysbiosis.
The authors propose that bacterial cell wall components or DNA fragments, which could stimulate host responses via pattern recognition receptors, might also alter the niches required for expansion of beneficial bacteria or successful colonization by new bacteria.
Ott et al conclude that transfer of fecal filtrate is effective for patients with recurrent CDI, resolves diarrhea after infection, and avoids the risks of transferring live microorganisms. Other advantages include the potential for standardization and for development of an inexpensive and convenient formulation (such as capsules filled with freeze-dried filtrate, without the need to conserve living bacteria or spores).
The authors state that transfer of fecal filtrate be evaluated in a controlled study in comparison with standard FMT.