A team led by investigators at the Broad Institute have started untangling the bacterial strains that influence successful fecal microbiota transplantation (FMT) engraftment in individuals treated for recurrent Clostridium difficile infection.
As they reported in Cell Host & Microbe today, researchers from the Broad Institute, Massachusetts Institute of Technology, Massachusetts General Hospital, and elsewhere used deep metagenomic sequencing to profile FMT in four FMT donors and 19 recipients with C. difficile infections, retracing the gut microbiome features that coincided with successful fecal transplant engraftment.
The initial gut microbial communities in both the donors and the recipients seemed to influence this process, the team noted, particularly bacterial abundance and strain phylogeny. The final gut microbe composition differed between donors and post-FMT recipients, though, with specific strains that originated in the host either taking hold or falling by the wayside in recipients in an “all-or-nothing” manner.
“This paper provides a context for understanding how to make these live biological therapeutics as an alternative to transferring raw fecal matter,” co-senior author Eric Alm, co-director of MIT’s Center for Microbiome Informatics and Therapeutics, said in a statement.
“We describe a model focused on three elements, including bacterial engraftment, growth, and mechanism of action, that need to be considered when developing these live therapies targeting the gut microorganisms, or microbiome,” added Alm, who is also affiliated with the Broad Institute and Finch Therapeutics.
Along with its use for treating recurrent C. difficile infection, the team noted that FMT has been proposed in other conditions such as inflammatory bowel disease and metabolic syndrome. Even so, there is a ways to go in understanding the factors influencing bacterial engraftment and effectiveness in the recipient gut — information needed to move the approach from a shotgun approach using fecal donor material to microbe-based treatments based on purified collections of specific bacteria.
“Although the success of FMT requires donor bacteria to engraft in the patient’s gut, the forces governing engraftment in humans are unknown,” the authors wrote.
To follow this process, the researchers used the Illumina GAIIx instrument to do deep metagenomic sequencing on seven stool samples from four healthy donors and 67 samples collected over time from 19 individuals treated for C. difficile infection with FMT.
With the help of statistical modeling and a new computational method dubbed Strain Finder, the team looked at the bacterial species that successfully engrafted in FMT recipients and followed strain genotypes over time. It also mapped the metagenomes to Human Microbiome Project reference genomes to take a look at bacterial taxa abundance.
Prior to treatment, for example, FMT recipients had lower-than-usual gut microbiome diversity. And while gut microbial community patterns shifted in recipients after FMT, the resulting gut microbiomes continued to differ from the original donor microbiomes, the researchers reported.
Even so, their analytical methods made it possible predict post-FMR metagenomic operational taxa unit abundance and incidence.
With nearly 1,100 bacterial strains in the 79 samples considered, the team traced transmission of certain strains from FMT donors to recipients, noting that bacterial strains tended to engraft in an “all-or-nothing” manner, “whereby no strains or complete sets of strains colonize the patients.”
“We find that engraftment can be predicted largely from the abundance and phylogeny of bacteria in the donor and the pre-FMT patient,” Alm and co-authors wrote. “Furthermore, donor strains within a species engraft in an all-or-nothing manner and previously undetected strains frequently colonize patients receiving FMT.”
Such patterns were supported by the researchers’ follow-up analyses on 16S ribosomal RNA sequence data for stool samples from 10 more FMT donors and 18 recipients, as well as an analysis of metagenomic sequence data for samples from five individuals treated with FMT for metabolic syndrome.
“Together,” they authors said, “these findings suggest that the principles of engraftment we discovered for recurrent C. difficile infection may generalize to other disease indications, including metabolic syndrome.”
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