Epithelial Reprogramming by OM-89 Enhances Antibiotic Clearance of Uropathogenic <i>E. coli</i> in a Bladder Organoid Model

Recurrent urinary tract infections (UTIs) are a major clinical burden, often driven by the ability of uropathogenic Escherichia coli (UPEC) to persist intracellularly within bladder epithelial cells, protected from antibiotics and host immune responses. While vaccine and antibiotic alternatives are being explored, strategies that enhance epithelial cell-intrinsic defense mechanisms remain sparse. Here, we show that OM-89 (Uro-Vaxom®), an E. coli lysate, reprograms epithelial antimicrobial responses to enhance intracellular bacterial clearance. Using murine bladder organoids and epithelial cell monolayers, we demonstrate that OM-89 enhances lysosomal acidification and cathepsin activity, promoting trafficking of UPEC into degradative compartments. Unexpectedly, OM-89 also increases epithelial uptake of antibiotics, increasing their intracellular potency and reducing UPEC regrowth after treatment. This dual effect on epithelial immunity and antibiotic accessibility was conserved across multiple UPEC strains and antibiotic classes. Our findings position bladder epithelial cells as active players in the host defense and highlight OM-89 as a tool to amplify their antimicrobial potential, offering a promising adjunctive strategy against intracellular bacterial persistence.