A microphysiological human mini-bladder reveals urine-urothelium interplay in tissue resilience and UPEC recurrence in urinary tract infections

TL;DR

A mini-bladder model shows how urine composition affects bladder health and contributes to recurring UTIs.

Contribution

The mini-bladder model reveals urine-urothelium interactions and UPEC recurrence dynamics in UTIs.

Findings

High-solute urine weakens bladder tissue and increases UTI susceptibility.

Fosfomycin monotherapy leads to CWD UPEC formation in urine and urothelial layers.

Tissue-associated CWD UPEC contributes to UTI recurrence and antibiotic tolerance.

Abstract

Urine is a dynamic and highly variable biofluid. Urine-urothelium interactions are a critical yet underexplored factor in bladder homoeostasis and urinary tract infections (UTIs). Here, we report on a human ‘mini-bladder’ model that exposes a stratified urothelium to urine of defined composition, and incorporates micturition. Prolonged exposure to high-solute concentration urine weakens tight junctions, dysregulates immune responses, and reduces bladder tissue resilience. This increases susceptibility to colonisation of the bladder by uropathogenic Escherichia coli (UPEC) which reduces efficacy of antibiotic therapy. In high-solute concentration urine, Fosfomycin monotherapy – prescribed for uncomplicated UTIs, induces the formation of cell wall-deficient (CWD) UPEC in the urine (as observed in patients with recurrent UTIs) but also within deeper urothelial layers. Tissue-associated CWD UPEC directly contributes to recurrence. Our findings expand the conceptual role for CWD UPEC in UTIs, and demonstrate the power of the mini-bladder platform to capture urine-urothelial microenvironment dynamics that actively shape UTI pathogenesis and antibiotic tolerance.

In this work, authors develop a “mini-bladder” model with a perfusable lumen that reveals how urine and its solute composition impact tissue resilience and enables cell-wall-deficient uropathogenic Escherichia coli to persist in tissues and drive recurrence in urinary tract infections.

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