The gut microbiota plays a critical role in pathogen defense. Studies using antibiotic-treated mice reveal mechanisms that increase susceptibility to Clostridioides difficile infection (CDI), but risk factors associated with CDI in humans extend beyond antibiotic use. Here, we studied the dysbiotic gut microbiota of a subset of patients with diarrhea and modeled the gut microbiota of these patients by fecal transplantation into germ-free mice. When challenged with C. difficile, the germ-free mice transplanted with fecal samples from patients with dysbiotic microbial communities showed increased gut amino acid concentrations and greater susceptibility to CDI. A C. difficile mutant that was unable to use proline as an energy source was unable to robustly infect germ-free mice transplanted with a dysbiotic or healthy human gut microbiota. Prophylactic dietary intervention using a low-proline or low-protein diet in germ-free mice colonized by a dysbiotic human gut microbiota resulted in decreased expansion of wild-type C. difficile after challenge, suggesting that amino acid availability might be important for CDI. Furthermore, a prophylactic fecal microbiota transplant in mice with dysbiosis reduced proline availability and protected the mice from CDI. Last, we identified clinical risk factors that could potentially predict gut microbial dysbiosis and thus greater susceptibility to CDI in a retrospective cohort of patients with diarrhea. Identifying at-risk individuals and reducing their susceptibility to CDI through gut microbiota-targeted therapies could be a new approach to preventing C. difficile infection in susceptible patients.
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