From colonization to infection: Genomic evolution of Clostridioides difficile pathogenesis.

Clostridioides difficile is a spore-forming, toxin-producing anaerobe that is a leading cause of healthcare-associated infections. Its success as a pathogen reflects a complex interplay between bacterial evolution, virulence regulation, ecological adaptation, environmental selection, and host susceptibility. Comparative genomics has revealed deep C. difficile lineage diversification, driven by mobile genetic elements and selective pressures from antibiotics and host environments. These events affect strain-specific virulence by shaping the organization and regulation of the pathogenicity toxin loci, metabolic adaptations for nutrient utilization, and enhanced spore resilience. This review integrates evolutionary and genomic perspectives to illustrate how adaptive diversification has sculpted C. difficile pathogenesis and epidemic success.