Epithelial physiology and immune status as decision points in the initiation of toxin-induced Clostridioides difficile colitis
Jun.-Prof. Dr. Franziska Faber & Jun.-Prof. Dr. Alexander Westermann
A healthy microbiota presents the most formidable barrier against enteric infections. This protective function, called colonisation resistance (CR), comprises various mechanisms that can be either direct/microbiota-mediated or indirect/host-mediated. Antibiotic-induced disruption of the microbiota leads to a breakdown of CR and increased susceptibility to enteric infections. Clostridioides difficile (Cd) is a spore-forming human pathogen that exploits antibiotic-associated dysbiosis to cause detrimental colitis through the production of enterotoxins. Antibiotic-induced changes of the microbiota and its metabolome favor intestinal spore germination and vegetative growth by Cd, and failure of microbiota recovery is associated with disease recurrence. While mechanisms of post-antibiotic Cd colonisation are increasingly well understood, the impact of post-antibiotic changes in epithelial responses to Cd toxins remains an open question. Here, we aim to dissect post-antibiotic epithelial responses to Cd toxins, and how they are modulated by the microbiota, using Bacteroides thetaiotaomicron (Bt) as a representative mucus-associated gut commensal. By combining classic microbiological techniques, biochemical and imaging assays with transcriptomics, metabolomics, and drug-based host perturbation experiments, we will unravel how Bt modulates epithelial immune responses to Cd toxins at multiple levels. This strategy will identify novel molecular decision points to develop urgently needed, host-centric intervention strategies against C. difficile infections (CDI).