PersonalizedClostridioides difficileengraftment risk prediction and probiotic therapy assessment in the human gut

Abstract

AbstractClostridioides difficilecolonizes up to 30-40% of community-dwelling adults without causing disease.C. difficileinfections (CDIs) are the leading cause of antibiotic-associated diarrhea in the U.S. and typically develop in individuals following disruption of the gut microbiota due to antibiotic or chemotherapy treatments. Further treatment of CDI with antibiotics is not always effective and can lead to antibiotic resistance and recurrent infections (rCDI). The most effective treatment for rCDI is the reestablishment of an intact microbiota via fecal microbiota transplants (FMTs). However, the success of FMTs has been difficult to generalize because the microbial interactions that prevent engraftment and facilitate the successful clearance ofC. difficileare still only partially understood. Here we show how microbial community-scale metabolic models (MCMMs) accurately predicted known instances ofC. difficilecolonization susceptibility or resistancein vitroandin vivo. MCMMs provide detailed mechanistic insights into the ecological interactions that governC. difficileengraftment, like cross-feeding or competition involving metabolites like succinate, trehalose, and ornithine, which differ from person to person. Indeed, three distinctC. difficilemetabolic niches emerge from our MCMMs, two associated with positive growth rates and one that represents non-growth, which are consistently observed across 15,204 individuals from five independent cohorts. Finally, we show how MCMMs can predict personalized engraftment andC. difficilegrowth suppression for a probiotic cocktail (VE303) designed to replace FMTs for the treatment rCDI. Overall, this powerful modeling approach predicts personalizedC. difficileengraftment risk and can be leveraged to assess probiotic treatment efficacy. MCMMs could be extended to understand the mechanistic underpinnings of personalized engraftment of other opportunistic bacterial pathogens, beneficial probiotic organisms, or more complex microbial consortia.