Study: Overgrowth of Bladder Nerve Cells Could Cause Recurring UTI Symptoms

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Investigators at Duke University and the University of North Carolina determine what causes recurrent UTIs, even after antibiotics cleared the bacterial infection.

An overgrowth of nerve cells in the bladder could be the cause of recurring urinary tract infections (UTIs), according to the authors of a study published in Science Immunology.1,2 Study investigators at Duke University and the University of North Carolina aimed to determine what causes recurrent UTIs, even after antibiotics clear the bacterial infection, according to a press release from Duke Health.1

Word uti concept, urinary tract infection inscription on cubes in doctor hands | Image Credit: valiantsin - stock.adobe.com

Image Credit: valiantsin - stock.adobe.com

“Urinary tract infections account for almost 25% of infections in women,” Soman Abraham, PhD, professor in the departments of Pathology, Molecular Genetics and Microbiology, Integrative Immunobiology, and Cell Biology at Duke University School of Medicine, said in the press release. “Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics. Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy.”1

3 Key Takeaways

  1. Investigators found that overgrowth of nerve cells in the bladder could be the culprit, even after antibiotics have cleared the initial bacterial infection.
  2. The researchers used a combination of human tissue samples and mouse models to investigate the link between nerve cell overgrowth and recurrent UTIs.
  3. The immune response that is triggered comes from mast cells, which release nerve growth factors that can drive overgrowth and increase sensitivity of nerves.

In the study, investigators collected bladder biopsies from those with recurrent UTIs who had pain despite no culturable bacteria in their urine and compared it to those without UTIs, according to the press release.1 Human samples were used to corroborate the data from the mouse models, according to the study authors.2

Further, the investigators used mouse models with recurrent UTIs to determine relevant proteins and cell types that were connected to the pathology of the infection. Investigators also used multiple pairs of targeting mechanisms to confirm observations, using “receptor antagonists and neutralizing antibodies for NGF, CCR2−/− mice and Ly6C blocking antibodies for monocytes, and KitW-sh/W-sh and MCPT5-iDTR mice for mast cells,” the study authors explain.2

“Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs,” said Byron Hayes, previously a postdoctoral fellow in Department of Pathology at Duke, said in the press release. “These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells.”1

Investigators found that biopsies showed that recurrent UTIs enhanced neuropeptide substance P (SP) staining in the lamina propria and elevated urinary SP, which could indicate the sensory nerves for those with recurrent UTIs are in an activated state, according to the study authors.2 Additionally, the study authors confirmed that the results of the mouse models supported this, as it showed that mice who had 3 consecutive UTIs had significant enhancements of neurite length and branch points in the lamina propria approximately 14 days after the third infection.2

According to the press release, the immune response that is triggered comes from mast cells, which release nerve growth factors that can drive overgrowth and increase the sensitivity of nerves. This can cause pain after recurrent UTIs.1 According to the study authors, this can also lead to urinary frequency, which were linked to mast cells.2

“This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women,” Abraham said in the press release. “Understanding the cross-talk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat [UTIs].”1

Investigators found that, in mice, “mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically.”1,2

References
  1. An Overgrowth of Nerve Cells Appears to Cause Lingering Symptoms After Recurrent UTIs. News release. Duke Health. March 1, 2024. Accessed March 4, 2024. https://corporate.dukehealth.org/news/overgrowth-nerve-cells-appears-cause-lingering-symptoms-after-recurrent-utis-0
  2. Hayes BW, Choi HW, Rathore APS, et al. Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity. Sci Immunol. 2024;9(93):eadi5578. doi:10.1126/sciimmunol.adi5578
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