Accelerating microbiota recovery to protect against Clostridioides difficile

Project summary Opportunistic Clostridioides difficile (previously Clostridium difficile) infection is a significant public health threat, primarily affecting hospitalized patients and leading to severe, life-threatening diarrhea. The CDC classifies C. difficile infection as an urgent health threat due to its high incidence, morbidity, and mortality rates. The infection typically follows antibiotic therapy (i.e., treatment with 3rd generation cephalosporins, fluoroquinolones, and clindamycin), which disrupts colonization resistance mediated by the normal colonic microbiota, allowing C. difficile to colonize the gastrointestinal tract and begin producing toxins to trigger antibiotic-associated colitis. Our long-term research goal is to understand how colonization resistance can be strengthened to prevent C. difficile infection. Our central hypothesis is that restoring epithelial hypoxia after antibiotic treatment can accelerate microbiota recovery to restore colonization resistance against C. difficile. We will test our hypothesis using the following specific aims: (i) determine whether treatment with a second-generation probiotic, Anaerostipes caccae, can accelerate microbiota recovery after antibiotic treatment to restore colonization resistance against C. difficile, and (ii) determine whether pharmacological activation of epithelial peroxisome proliferator–activated receptor gamma signaling can accelerate microbiota recovery to restore colonization resistance against C. difficile. The proposed experiments provide innovation by establishing a proof of concept for a completely new and original starting point for preventing C. difficile infection. This outcome will be significant by providing mechanistic insights into colonization resistance against an important opportunistic pathogen, which will be of wide appeal among researchers interested in antimicrobial-resistant infections, microbiota research, and intestinal biology.