Clostridioides difficile (formerly Clostridium difficile)-associated diarrhea is currently the most frequently occurring nosocomial diarrhea worldwide. During its infection cycle this pathogen needs to survive in phage-rich gut communities. Recent data strongly suggest that regulatory RNAs control gene expression in C. difficile and many of these RNAs appear to modulate C. difficile-phage interactions. Of the 200 regulatory RNAs identified by deep sequencing and targeted approaches, many function as antitoxins within type I toxin-antitoxin modules and CRISPR RNAs for anti-phage defenses. In this review, we discuss recent insights into the role of RNAs in modulating interactions between C. difficile and phages in light of intriguing data in other prokaryotes.
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