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Scientists Uncover Hidden Bacteria's Role in Persistent UTIs

UK scientists have offered a fresh insight into why urinary tract infections (UTIs) frequently persist after treatment by discovering that many bacterial strains can hide in the bladder wall.

The researchers used a human tissue model to explore the interaction between host and pathogen for six common species that cause UTIs.

UTIs are common, with recurrence rates of around 25%–30% within 6 months, despite antibiotic therapy. 

Diagnosis rests primarily on the midstream urine culture method. However, researchers from University College London said analysis of infected cells shed by patients could not reveal what was happening in deeper urothelial layers. Also, there were ethical issues involved in taking urothelial biopsies from infected patients.

Therefore, they proposed the use of advanced human-cell models to help fill the gaps regarding knowledge and understanding of UTIs.

Scientists Developed a 'Mini Bladder'

For the study, published in the journal Science Advances, the researchers developed three-dimensional cell models capable of mimicking the biological environment and function of human bladder tissue — so-called 'mini bladders' — in order to observe the interactions between host and pathogen in conditions as close as possible to those found in the human body. 

These mini bladders, grown in plastic dishes bathed in human urine and about the size of a five-pence coin, had seven to eight layers that resembled the structure of the human bladder. They also included life-like human features, such as a mucous-like barrier to separate the bladder wall from the urine, and the ability to emit immune distress signals when attacked.

To explore the interaction between host and pathogen, the mini bladders were exposed to Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Proteus mirabilis, Streptococcus agalactiae, and Klebsiella pneumoniae.

A "Battleground of Diversity"

"We put a variety of UTI bacteria species and strains through their paces and discovered a battleground of diversity," said senior author Professor Jennifer Rohn from the Division of Medicine at UCL. "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," she explained.

The authors found that several uropathogens invaded intracellularly, but also commensal E coli, which they said suggested that invasion was a "shared survival strategy, not solely a virulence hallmark". The E coli adhesin FimH was required for intracellular bacterial community formation, but not for invasion, they stated. 

Other shared lifestyles included filamentation (Gram-negatives), chaining (Gram-positives), and hijacking of exfoliating cells, while biofilm-like aggregates formed mainly with Pseudomonas and Proteus, the researchers found.

"Urothelial cells expelled invasive bacteria, while highly cytotoxic/invasive uropathogens, but not commensals, disrupted host barrier function and strongly induced exfoliation and cytokine production," highlighted the authors.

"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," Professor Rohn said. She pointed out that if this happened with a friendly bug, it wasn'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."

The study also found that human cells were very good at distinguishing friendly from not-so-friendly bacteria, regardless of whether they could invade the bladder wall or not. All the 'bad' bugs tested triggered the production of cytokines, and the shedding of the top layer of the bladder wall, whereas the 'good' bacteria could colonise the bladder wall without triggering an immune response.

"Overall, this work highlights diverse species-/strain-specific infection strategies and corresponding host responses in a human urothelial microenvironment, providing insights at the microtissue, cell, and molecular level," the researchers concluded.

Current Diagnosis Methods "Inadequate"

The study also "confirms what many women who've struggled with persistent UTIs already know, which is that the current methods of diagnosing and treating these infections are inadequate," said Professor Rohn.

"Urine dipstick tests are too likely to miss infections hiding in the bladder wall," she cautioned. "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 3-day course of antibiotics unlikely to eradicate it."

Study first author Dr Carlos Flores, also from UCL's Division of Medicine, said: "Based on our 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."

The study findings also indicated that effective treatments for persistent UTIs might require the ability to penetrate human tissues in order to reach bacterial populations dwelling in the bladder wall. 

Carolyn Andrew, director of the Chronic Urinary Tract Infection Campaign, described the research as a "vitally important step forwards" and said it provided "unequivocal evidence" of the need to improve testing and diagnosis of chronic, persistent UTIs.

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