Bacteriophage-Clostridioides difficile interactions: From the impact of phages on bacterial virulence to new therapeutic strategies.

Clostridioides difficile infections (CDI) are a major cause of nosocomial post-antibiotic diarrhoea. The pathogen's virulence is based on its production of toxins that alter the intestinal barrier, leading to inflammation that upsets the balance of the microbiota. Its ability to sporulate favours dissemination in hospital environments, and its resilience to antibiotics leads to recurrent infections. Bacteriophages are natural predators, specific to a single bacterium, or even a single strain. They offer promising therapeutic prospects and are already being used in osteoarticular and pulmonary infections. Interactions between phages and bacteria are numerous and bacterial gene expression, thus influencing pathogenicity. The aim of this thesis is to detail the numerous therapeutic applications of phages and to explore the opportunities offered by the latest bioengineering technologies to develop phages adapted to the infectious context of CDI and specifically targeting pathogenic C. difficile strains within the microbiota. Each player in the infectious site, as well as coevolutionary dynamics, will need to be considered to guarantee the long-term effectiveness of phage therapy. Implementing this innovative approach requires interdisciplinary coordination combining microbiology, bioengineering and clinical science to respect practical constraints while integrating fundamental knowledge. This operational flexibility will be crucial in producing effective and sustainable phage therapy.