Traditional plant urologicals curb early uropathogenic E. coli infection and strengthen host innate defense

Herbal medicinal products (HMP) are commonly used across Europe to treat urinary tract infections caused by uropathogenic Escherichia coli (UPEC), yet their mechanisms of action often remain unknown. We investigated the potential modes of action of several complex, government‑approved herbal preparations in clinical use. Four aqueous HMP extracts, fully profiled by LC‑MS, did not inhibit UPEC growth but altered early host‑UPEC interactions. A stress‑reporter assay revealed specific induction of surface stress in E. coli K-12 strain MG1655 via the BaeS‑BaeR two‑component system, while osmotic, pH, oxidative, SOS, and other stress pathways remained unchanged. This surface‑stress response impaired type 1 fimbriae expression and function, markedly decreasing adhesion of UPEC strain CFT073 to human T24 bladder cells and also lowering intracellular bacterial counts. The extracts did not negatively affect bacterial biofilm formation. To prove these in vitro effects in a more complex model, the HMP extracts were orally fed to Galleria mellonella larvae to investigate their impact on innate immunity and cellular host response. Oral feeding to uninfected larvae increased innate‑immunity gene (moricin, hemolin) expression in the midgut and in circulating hemocytes and markedly increased survival after UPEC infection. The HMP also caused an upregulation of the expression of innate‑immunity genes (IL‑6, IL‑8, and CXCL‑3) in uninfected human bladder epithelial cells, indicating an enhanced anti‑infective host response. These findings show that HMP can both lower uroepithelial susceptibility to UPEC, by impairing bacterial adhesion and invasion, and enhance host innate defenses. Consequently, such multi‑component herbal mixtures represent a promising alternative or complement to antibiotic therapy for UPEC infections through a dual‑target mechanism. KEY POINTS: • Traditional herbal medicinal products (HMP) against urinary tract infections protect host cells from uropathogenic E. coli attack. • Some HMP reduce UPEC adhesion to and invasion into bladder epithelial cells. • Some HMP are immunostimulatory and reduce host cell susceptibility to infection.