Quantification of discrete gut bacterial strains following fecal transplantation for recurrent Clostridioides difficile infection demonstrates long-term stable engraftment in non-relapsing recipients

Fecal Microbiota Transplantation (FMT), while successful for the treatment of recurrent Clostridioides difficile (rCDI) infection, lacks a quantitative identification of the discrete bacterial strains that transmit and stably engraft in recipients, and their association with clinical outcomes. Using >1,000 unique bacterial strains isolated and sequenced from a combination of 22 FMT donors and recipients, we develop a statistical approach Strainer to detect and track sequenced bacterial strains from low depth metagenomic sequencing data. On application to 14 FMT interventions, we detect stable and high engraftment of ∼71% of gut microbiota strains in recipients at even 5-years post-transplant, a remarkably durable therapeutic from a single administration. We found differential transmission and engraftment efficacy across bacterial taxonomic groups over short and long-time scales. Although ∼80% of the original pre-FMT recipient strains were eliminated by the FMT, those strains that remain persist even 5 years later, along with newer strains acquired from the environment. The precise quantification of donor bacterial strains in recipients independently explained the clinical outcomes of early and late relapse. Our framework identifies the consistently engrafting discrete bacterial strains for use in Live Biotherapeutic Products (LBP) as a safer, scalable alternative to FMT and enables systematic evaluation of different FMT and LBP study designs. ### Competing Interest Statement Jeremiah Faith is on the scientific advisory board of Vedanta Biosciences Dirk Gevers is an employee of Janssen Research & Development * AUC : Area Under the Curve Blu : Blautia Rum : Ruminococcus Bif : Bifidobacterium Bac : Bacteriodes Esc : Escherichia Ali : Alistipes Par : Parabacteriodes Bar : Barnesiella Clo : Clostridium Eub : Eubacterium Pho : Phocea Cop : Coprococcus Egg : Eggerthella Ery : Erysipelatoclostridium Dor : Dorea Ros : Roseburia Odo : Odoribacter Par : Parabacteriodes Str : Streptococcus