Micro-Bladder Model Demonstrates How Phage Therapy Could Help to Reduce Recurrent UTIs

Researchers headed by a team at the Centre for Kidney and Bladder Health, Division of Medicine, University College London, have used a novel human 3D micro-bladder model to demonstrate how phage therapy could help to reduce recurrent urinary tract infections (UTIs), which happen when the bacteria responsible “hide” in the tissue of the bladder.

Focusing on infections caused by uropathogenic Escherichia coli (UPEC) the team found that a cocktail of phages—viruses that infect destroy bacteria—can wipe out bacteria hidden deep within the bladder wall, in what the researchers label “reservoirs,” which normal antibiotics can’t touch. Research lead professor Jennifer Rohn, PhD, UCL Division of Medicine, said, “Recurrent UTIs are incredibly frustrating for patients because the bacteria can survive antibiotics by retreating into protected reservoirs inside the bladder wall. Building a micro-bladder has allowed us to mimic real conditions in the urinary tract and see why antibiotics that look powerful in standard lab tests often fall short.”

Rohn is senior and co-corresponding author of the team’s published paper in Nature Communications, titled “Effect of human urinary microenvironment and fluid flow on antibiotic and phage therapy efficacy against uropathogenic Escherichia coli,” in which they concluded that their findings “… demonstrate that the bladder microenvironment profoundly influences UPEC infection dynamics and therapeutic outcomes, underscoring the need for advanced models to guide treatment strategies in the antibiotic resistance era.”

UTIs are one of the world’s most common infections, with around 400 million cases each year. They can be painful and disruptive, and for many people the infection can return after taking a course of antibiotics. Repeated antibiotic exposure contributes to the rising problem of antimicrobial resistance (AMR). “Urinary tract infection (UTI) remains a major global health burden, with frequent recurrences and rising antimicrobial resistance compromising treatment efficacy,” the authors stated.

Rohn and colleagues sought to understand why this happens by engineering a novel human 3D micro-bladder model that includes flowing urine to mimic the environment found in the human bladder. They used this bladder model to test phage therapy on UTI bacteria.

The team centered their studies on uropathogenic Escherichia coli, a strain of E. coli adapted to infect the urinary tract and the cause of most UTIs. In hospitals, bacteria from a patient’s urine can be tested to see which antibiotics stop them growing, but these tests are usually done in a still, nutrient-rich liquid.

The scientists found that UPEC introduced to the micro-bladder became better at sticking to the bladder surface, and were more likely to invade the bladder lining and set up protected reservoirs of bacteria hidden inside bladder cells where they are harder to reach. The team then tested nitrofurantoin (a commonly used antibiotic for UTIs). In standard lab tests this treatment typically works well, but in the micro-bladder it struggled to fully clear the infection.

The researchers also tested a cocktail of phages, which are viruses that infect and destroy bacteria. On its own, the phage cocktail also found it difficult to clear bacteria in a flowing environment. However, when the scientists combined phages with the antibiotic, the results improved, suggesting that a two-pronged approach could be more effective than either treatment alone.

One significant finding was that unlike the antibiotics, the phage treatment was able to reduce the number of protected bacterial reservoirs inside the bladder wall. Because these reservoirs can act like a breeding ground for future infection, reducing them could be an important step towards preventing UTIs from repeatedly returning. “A bacteriophage cocktail (LCPR1) inhibited intracellular bacterial communities, preserved urothelial viability and induced inflammatory cytokine and chemokine secretion,” the team stated.

First and co-corresponding author Garcia Maset, PhD, said “What’s particularly promising is that phage therapy was able to reach these hidden reservoirs of bacteria, rooting out the cause of the infection. We also discovered that urine flow substantially changes how bacteria behave and respond to treatment, suggesting that many conventional laboratory tests may be missing important aspects of the infection process.”

The study findings also indicated that phages may boost the bladder tissue’s own early defense response. Researchers saw signs of increased immune signaling, including cytokines and chemokines (messenger proteins that help the body coordinate inflammation and bring immune cells to the site of infection).

Co-author Martha Clokie, PhD, director of the Becky Mayer Centre for Phage Research at the University of Leicester, “This study shows why it is so important to test phages under conditions that genuinely reflect the human body. By combining a realistic flowing micro-bladder model with phage and antibiotic treatment, we can begin to understand how best to use phages alongside existing medicines to achieve better outcomes for patients.” The authors added, “Collectively, these experiments revealed the profound influence of microenvironmental context on UPEC infection dynamics and treatment response.”

Phage therapy is not yet a routine treatment for UTIs, and more research will be needed to confirm how well it works, how best to deliver it, and which patients are most likely to benefit. However, this study offers a promising route towards longer-lasting relief for people living with repeat UTIs.

The device design and image-analysis tools used in this study have been made freely available to encourage broader adoption across laboratories, with the hope they could find wider application in research focusing on the impact of flow-mediated mechanostimulation on biological systems.

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