Mucin-rich environment shapes Pseudomonas aeruginosa cytotoxicity and phage-mediated epithelial protection

Chronic respiratory diseases (CRDs) are characterized by excessive mucin accumulation that alters host-pathogen interactions within airway epithelia. Although bacteriophage therapy is increasingly considered as an alternative to antibiotics, it remains unclear how mucin-rich environments influence bacterial virulence and phage efficacy. Here, we show that exogenous mucin reshapes outcomes during Pseudomonas aeruginosa in epithelial cells. Mucin exposure induces transcriptional changes, increases epithelial susceptibility to bacterial cytotoxicity, and reduces bacterial adhesion and internalization. Surprisingly, mucin simultaneously enhances phage-mediated protection, preserving epithelial viability without impairing phage amplification. Moreover, prolonged bacterial exposure to mucin increases the cytotoxicity activity of cell-free secretomes, while altering the phenotypic and genotypic characteristics of phage-resistant bacteria. Together, these findings reveal that mucin-rich environments exert opposing effects on infection dynamics by increasing host vulnerability while enhancing phage-mediated control of bacterial infection. Our results highlight the mucosal environment as a key determinant of phage therapy outcomes and bacterial adaptation.