A perplexing problem for many people with recurrent urinary tract infections (rUTIs) is persistent pelvic pain and incontinence, even after antibiotics have successfully cleared the bacterial infection. A study by Duke Health scientists has now identified at least part of the likely cause of these symptoms as immune cell activity that encourages pain-sensing nerve cells to grow in the bladder.
Pelvic pain and incontinence linger for some patients in recovery from recurrent UTIs (rUTIs) due to immune cell activity that encourages pain-sensing nerves to grow, suggests the new study involving patient samples and mouse models.
The team’s research found increased levels of neuropeptide called substance P in the bladders of patients with rUTI. This peptide directly supports growth of pain-sensing nerves in the genitourinary tract. Subsequent investigations in mouse models found that following infection, monocytes and mast cells kept secreting nerve growth factor (NGF), which aided sprouting of pain-sensing nerves, thereby increasing substance P levels.
The team suggests that their findings could potentially point to a new approach to managing symptoms of recurring UTIs that would more effectively target the problem and reduce unnecessary antibiotic use. “This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women,” said Soman Abraham, PhD, professor in the departments of Pathology, Molecular genetics and microbiology, integrative immunobiology, and cell biology at Duke University School of Medicine. “Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections.”
Abraham is senior author of the team’s published paper in Science Immunology, titled “Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity,” in which the authors noted, “… our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.”
Urinary tract infections (UTIs) account for almost 25% of infections in women, and most are caused by bacteria, the authors wrote. The standard of care is a course of antibiotics, but even after clearance of the bacteria, patients can still have symptoms. “Many are recurrent UTIs, with patients frequently complaining of chronic pelvic pain and urinary frequency, even after a round of antibiotics,” Abraham said.
Currently, clinicians may treat these vestiges of infection with more antibiotics. “In patients with frequent recurrences, the off-label prophylactic antibiotic course could be in excess of 6 months,” the team noted.
To try and understand what might underly these continued symptoms, Abraham, together with colleagues, including first author Byron Hayes, PhD, who is previously a postdoctoral fellow in Duke’s Department of Pathology, collected bladder biopsies from recurrent UTI patients who were experiencing pain despite no culturable bacteria in their urine. They analyzed biopsies from eight female patients, and urine samples from 25 female patients, aged from 29–79 years. Using biopsies from people without UTIs as a comparison, they found evidence that sensory nerves were highly activated in the UTI patients, explaining the persistent sense of pain and urinary frequency.
Their investigation showed that, although the rUTIs were gone, the patients’ bladders still had elevated levels of a SP, a peptide that directly supports growth of pain-sensing nerves in the genitourinary tract. “Our studies of bladder biopsies and urine of patients with rUTI revealed not only enhanced SP staining in the lamina propria but also elevated levels of urinary SP, suggesting that sensory nerves in the bladder of patients with rUTI are in an activated state,” they wrote.
To better understand why substance P remained, the researchers turned to rUTI mouse models. They saw that, in these animals, following infection, monocytes and mast cells kept secreting nerve growth factor (NGF). That factor aided sprouting of pain-sensing nerves, thereby increasing substance P levels. The team commented, “This finding of sensory nerve modulation after UTI was recapitulated in our mouse model of rUTI … Evidence for the role of NGF comes from our finding that NGF specifically was elevated in bladder tissue of rUTI mice.”
Hayes added, “Typically, during every bout of UTI, epithelial cells laden with bacteria are sloughed off, and significant destruction of nearby nerve tissue occurs. These events trigger a rapid repair program in the damaged bladder involving massive regrowth of destroyed nerve cells.”
The researchers were able to address these symptoms by treating study mice with molecules that suppress production of the mast-cell generated nerve growth factor. “… antagonists to the NGF receptor TrkA and neutralizing antibodies targeting NGF were found to block neuronal sprouting in vitro and in vivo when administered during rUTI,” they noted.
Further, the team’s study found, mice lacking mast cells did not display visible signs of pain and bladder incontinence in this rUTI model. “Mast cell–deficient mice exposed to multiple UTIs failed to exhibit either pain-like behavior or aberrant bladder voiding,” they wrote. Strikingly, we observed that depleting mast cells after exposing these mice to rUTIs prevented both pelvic pain–like behavior and aberrant voiding responses in the hyperinnervated bladder, suggesting that mast cells were necessary for triggering these bladder pathologies.”
Overall, the findings indicate that a pathway between immune cells and pain-sensing nerves emerges during rUTIs—and that this pathway’s continuation post-rUTI may depend on mast cells The authors further noted that their study “… supports SP released from stimulated sensory nerves as a likely candidate causing mast cell activation.“
Abraham said, “Our study, for the first time, describes an underlying cause and identifies a potential new treatment strategy … This work helps illuminate a puzzling clinical condition that drives medical costs and affects the quality of life of millions of people, primarily women. Understanding the crosstalk between mast cells and nerves is an essential step toward effective treatments for people suffering repeat urinary tract infections.”
The authors concluded, “In view of our findings that neutralization of NGF signaling and mast cell mediator receptor blockade can markedly reduce pain-like behavior in rUTI, it may be appropriate to introduce therapy targeted at preventing sensory nerve sprouting and activation, which should offer better and early relief from the most pressing symptoms experienced y the rUTI patient population.”
