PROJECT SUMMARY The treatment of recurrent Clostridioides difficile infection (rCDI) by fecal microbiota transplantation (FMT) is the defining success amongst therapeutics aimed to manipulate the microbiome with cure rates typically exceeding 80% of recipients. This success has facilitated numerous clinical trials yielding important insights that have advanced clinical care including the quantification of the durable stability of frozen fecal slurries that enabled stool biobanks, the studies of fecal slurry administration that compared efficacies across administration routes of oral, colonoscopic, and nasogastric, and the application of FMT in other conditions including ulcerative colitis where it appears to have modest efficacy. However, the use of complex fecal slurries as a therapy is a challenge due to our inability to completely determine the safety of a product that varies with each FMT donor, including some that have transmitted opportunistic pathogens that led to serious adverse events. The scaling of FMT is also a challenge, as the drug material is sourced from individual human donations that are finite in supply and labor intensive to process into the final product. We propose to administer live biotherapeutic products (LBP) as an alternative to FMT. We have isolated the strains for this LBP from known-successful FMT donors allowing us to compare (Aim 1) the clinical response and (Aim 2) the microbial engraftment of the FMT with that of the LBP. The LBP was specifically designed to contain prevalent human gut microbes that have engrafted in a majority of recipients and that are not associated with severe adverse events in prior FMT studies. The results from this pilot and feasibility clinical trial (60 subjects, N=30 FMT and N=30 LBP) will provide important safety data, clinical insights, and basic science results to advance the potential of LBPs as novel therapeutics.