Host origin of microbiota drives functional recovery andClostridioides difficileclearance in mice

Abstract

Colonization resistance provided by the gut microbiota is essential for resisting both initial Clostridioides difficile infection (CDI) and potential recurrent infection (rCDI). Although fecal microbiota transplantation (FMT) has been successful in treating rCDI by restoring microbial composition and function, mechanisms underlying efficacy of standardized stool-derived products remain poorly understood. Using a combination of 16S rRNA gene-based and metagenomic sequencing alongside metabolomics, we investigated microbiome recovery following FMT from human and murine donor sources in a mouse model of rCDI. We found that a human-derived microbiota was less effective in clearing C. difficile compared to a mouse-derived microbiota, despite successful microbial engraftment and recovery of bacterial functional potential. Metabolomic analysis revealed deficits in secondary metabolites, suggesting a functional remodeling between human microbes in their new host environment. Collectively, our data revealed additional environmental, ecological, or host factors involved in FMT-based recovery from rCDI.