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Microbes Behind Successful Fecal Microbiota Transplantations May Become Basis for New Treatments

NEW YORK – A research team that included investigators at the Icahn School of Medicine at Mount Sinai and Janssen Research and Development has described the bacterial components of fecal microbiota transplantation. The hope is that these bugs may ultimately become part of feces-free treatments for persistent Clostridium difficile infection.

"We have identified a select group of bacteria in a real-life human study that can serve as an ideal starting point for a synthetic FMT product — without the 'fecal' component," co-author Ari Grinspan, an associate professor of medicine who is affiliated with the Icahn School of Medicine at Mount Sinai's Precision Immunology Institute and the Icahn Institute for Data Science and Genomic Technology, said in a statement.

For their study, published in Nature Microbiology on Monday, Grinspan and his colleagues sequenced the genomes of bacterial isolates from more than 1,000 different strains found in fecal samples from nine healthy FMT donors and more than a dozen patients who received FMT to treat repeated C. difficile infections.

When the team applied its Strainer statistical framework to metagenomic sequence data representing the same FMT donors and recipients or to samples collected sequentially from another 13 individuals who got FMT in the clinic, it saw that the vast majority of original bugs disappeared from recipients' gut microbial communities, while the strains acquired through FMT stuck around for up to five years after the transplant.

"We found that 80 [percent] of recipient gut bacterial strains pre-FMT were eliminated by FMT and that post-FMT the strains present persisted up to five years later, together with environmentally acquired strains," the authors reported. "Quantification of donor bacterial strain engraftment in recipients independently explained … the clinical outcomes (relapse or success) after initial and repeat FMT."

The findings also pointed to sets of donated microbes that reliably take hold in the guts of FMT recipients, the investigators reported, offering clues to microbes that may be therapeutically relevant without the use of full fecal transplants.

"An important result from our study is the identification of a select mixture of live bacterial strains that stably engraft for five years in patients who are symptom-free post-FMT," the authors explained. "These strains are an ideal starting point for a synthetic [live biotherapeutic product]-free of multi-drug-resistant organisms that might serve as an FMT alternative for recurrent [C. difficile infection]."

Although FMT has proven successful for treating C. difficile infections, particularly those that arise repeatedly in the same individual, the team noted that the US Food and Drug Administration has put out advisories stemming from FMT procedures with severe adverse events.

Because some of these concerns have cropped up around using whole stool samples containing indeterminate microbial collections, the authors reasoned that some of these challenges might be overcome by more fully mapping beneficial bugs in donor samples used in successful FMTs.

"Knowing which bacterial strains are transferred to the recipient gut microbiota is critical to our understanding of why some patients respond to FMT and others do not," senior author Jeremiah Faith, a researcher at the Icahn School of Medicine at Mount Sinai, said in a statement.

For their study, the investigators started by sequencing the genomes of 2,987 bacteria, spanning 207 bacterial species and some 1,008 strains, that were isolated from 22 FMT donors or recipients. By setting these genomes alongside 85 metagenomic sequences from donors and recipients sampled over time for up to five years post-transplant, they got a look at strain dynamics in guts of FMT recipients before treatment and for up to five years afterward.

Along with subsequent validation experiments in FMT recipients and in mouse models transplanted with specific bacterial strain sets, the team turned to the Strainer tool to come up with a metric dubbed the "proportional engraftment of donor strains," or PEDS, which appeared to coincide with FMT outcomes in 10 more FMT recipients over several years.

There, engraftment reached around 83 percent, on average, before settling slightly lower: 71 percent of bacterial strains from FMT donors appeared to stick around in the long term in recipients who did not experience C. difficile relapse, as did fewer than 25 percent of strains present in recipients prior to FMT. In contrast, PEDS dipped dramatically in two FMT recipients who went on to experience early C. difficile relapse, the authors noted.

"These results suggest that FMT represents a semi-permanent alteration of the host microbiome — a remarkably durable therapeutic from a single administration, whose stability resembles that of healthy controls," they wrote, noting that "PEDS is a predictive measure of FMT success and recurrent [C. difficile infection] relapse."

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