Artificial mini bladders give insight into UTIs

Urinary tract infections are one of the most common infections worldwide, estimated to affect 400 million people.

The burden is expected to grow. About 250,000 UTI-related deaths are associated with antimicrobial resistance (AMR), and 30% of UTIs recur within 6 months despite treatment with antibiotics.

New research in the journal Science Advances suggests that the current “one size fits all” approach to diagnosing and treating UTIs is inadequate. The findings indicate that effective treatments for persistent UTIs may require the ability to penetrate human tissues to reach bacterial populations dwelling inside cells of the bladder wall. 

Scientists from University College London (UCL) in the UK developed 3-dimensional cell models which mimic the biological environment and function of human bladder tissue.

They exposed these “mini bladders” to bacterial species commonly found in the human bladder to observe the interactions between the host and pathogens in conditions as close to the human body as possible.

The mini bladders’ 7-8 layers resemble the structure of the human bladder and can operate in 100% urine. They also include features such as a mucous-like barrier that separates the bladder wall from urine, and the ability to emit immune distress signals when attacked.

“We put a variety of UTI bacteria species and strains through their paces and discovered a battleground of diversity,” says Professor Jennifer Rohn, senior author of the study, from UCL Division of Medicine. “One of the key observations was the importance of persistence. If you want to be a successful pathogen, you have to have strategies that help you to survive treatment and hide from patrolling immune cells, which means you live to fight another day.

“Some species of both ‘good’ and ‘bad’ bugs formed pods within the bladder wall, most likely as a way of surviving in this harsh environment. If this happens with a friendly bug, this isn’t a problem. But if the bug is causing an infection, this poses a serious problem for diagnosis and treatment because the bacteria aren’t necessarily going to be detected in a urine sample or be in a position where oral antibiotics can reach them,” Rohn says.

But human cells are very good at telling the difference between friendly and pathogenic bacteria. All of the infection-causing bacteria triggered the production of immune molecules, called cytokines, and the shedding of the top layer of the bladder wall. But the good bacteria could colonise the bladder wall without triggering an immune response.

Dr Carlos Flores, first author of the study from UCL Division of Medicine says, based on the results, next-generation diagnostics for UTIs could focus on identifying ‘bad’ bugs based on how the body responds, rather than trying to spot the presence of problem bacteria among the background noise of the microbiome. “There are so many species and strains of bacteria in the human bladder that we don’t fully understand, but the body seems to be pretty good at telling friend from foe.”

Rohn concludes that the primary method of diagnosing UTIs, called urine dipstick test, is too likely to miss infections hiding in the bladder wall.

“Especially when a patient’s first response to discomfort is to drinks lots of water, which dilutes the test,” he says.

“Not all bugs can be cultured in the lab, and even if they could be that doesn’t tell us if this strain is the cause of an infection or if its position in the bladder wall would make the standard three-day course of antibiotics unlikely to eradicate it.”

Carolyn Andrew, Director of the Chronic Urinary Tract Infection Campaign (CUTIC) in the UK adds: “This research has been instrumental in providing unequivocal evidence for our national campaign to improve testing and diagnosis of chronic, persistent UTIs.”