Why do some women experience UTI pain with no clear infection? A mouse study offers clues

Each year, more than 400 million urinary tract infections occur in people around the globe. And researchers have long been puzzled by a medical mystery: Some women susceptible to recurrent UTIs experience symptoms without any signs of bacteria, or after an infection has supposedly been cleared with antibiotics.

A new study provides a potential molecular mechanism behind the phenomenon. Researchers at Duke University found that, in mice with recurrent UTIs, the immune response in the bladder acted too strongly to build back nerves lost in shedding the infection. This overgrowth of nerves caused pelvic pain and frequent urination, some of the same symptoms people with recurrent UTIs experience.

“This study seems to suggest an alternative approach to the management of these cases,” said Soman Abraham, a senior author on the study, published Friday in Science Immunology. “Maybe you do not need to continue to give antibiotics to these patients, particularly when you do not see bacteria in the urine, but instead maybe think about treating the pathology, the symptoms.”

UTIs are most common in women — at least half of all cisgender women will get one in their lifetime. Doctors have a couple crude methods to diagnose them. First, a patient can pee in a cup, into which doctors dip a piece of paper that turns a different color if it detects white blood cells, signs of bacteria, or blood. But the test isn’t very sensitive, so infections can easily go undetected. Afterward, a doctor might send urine to a lab, where a drop is spread out in a Petri dish and inspected for signs of bacterial growth.

But what if that test, too, comes back negative? Experts say it’s common for this to happen in women with UTI symptoms, though they don’t know the exact frequency. They also don’t know what leads someone to get recurrent UTIs, or to then experience symptoms outside of active infections. The lack of understanding reflects a historical struggle to capture attention and funds for a disease that mainly affects women, experts say.

“It’s a perfect storm of neglect,” said Jennifer Rohn, head of the Centre for Urological Biology at University College London.

In the recent study, scientists set out to answer some of those long-standing questions. Before inducing UTIs in mice, researchers analyzed bladder biopsies from women with a history of recurrent UTIs who were experiencing symptoms (pelvic pain and frequent urination) without detectable bacteria in their urine, and a control group without a history of recurrent UTIs. They found that the women with UTIs showed signs of increased nerve activity — “like night and day,” Abraham said — compared to the control group. The urine of the women who get UTIs also contained a neuropeptide that’s made when neurons are activated.

But the samples were small and not well-preserved, so the team couldn’t look for other clues and turned to mice to investigate further. Mice with recurrent UTIs experienced the same symptoms and showed the same increased nerve activity seen in people. But the researchers found something else, too, in their bladders: mast cells, immune cells that play a role in allergies and asthma by releasing the chemical histamine. Here, the researchers found that mast cells were creating nerve growth factor, a protein that can drive the regrowth and increased sensitivity of nerves after they’ve been destroyed by an infection. This is what led to the overgrowth of nerves in the mouse bladder, making it more sensitive to pain and the presence of urine than usual.

The discovery worked backward, too: When researchers treated the mice with an antibody that neutralized the nerve growth factor, it alleviated the symptoms.

For Rashmi Kaul, a UTI researcher and professor at Oklahoma State University who did not work on the study, the new research arrived as if on cue. That same week, she received the results of her own UTI culture — negative, despite her persistent pain and frequent need to urinate. Even she, an expert in the field with a history of recurrent UTIs, was not sure what to do next. As someone who studies the role of estrogen in UTIs, she considered taking the hormone or other supplements. When she asked her nurse for a suggestion for a painkiller, the nurse recommended AZO, a typical over-the-counter remedy. Her doctor suggested she get a cystoscopy, a procedure in which a physician inserts a small tube into the urethra to examine the bladder.

“This whole picture gives you a fair idea how little we have researched to deal with UTIs in women,” she wrote in an email.

Doctors use a round of antibiotics as the go-to treatment for UTIs, often even if a test comes back negative, Abraham said. But clinicians and researchers are growing more concerned about this approach as antibiotic resistance becomes a greater threat. If the new findings are correct, he added, perhaps doctors could treat a UTI with both a standard antibiotic and a drug that addresses nerve growth factor, which could then prevent lingering symptoms and subsequent, ineffective rounds of antibiotics.

“The most obvious question is how long does this hyperinnervation last after the last UTI, and is it possible to reverse it?” he asked. As the team continues the research, they’ve seen the nerve overgrowth last at least a month in mice, and hope to follow up as far as six months after the last infection. If the high density of nerves continues, then researchers should think of approaches to limit the production of nerve growth factor in the bladder, he said.

More overall research is needed on the mechanisms behind recurrent UTIs, experts say. A 2016 study also in mice suggested that E. coli left a “molecular imprint” in the mucus layer of the bladder that affects subsequent infections, but it’s currently a small area of focus, said Rohn, who wasn’t involved in either study.

Of course, mice are not humans and can’t communicate their pain levels quite as well. Even though Abraham’s study did include some evidence from women, it did not break the results down by age. Pre-menopausal and post-menopausal women have different susceptibility to UTIs, and their estrogen receptor levels in the bladder differ, meaning that their mast cells could act differently, Kaul noted.

Experts also say that even more basic research and resources are needed: better tests that can detect different types of E. coli, which makes up most UTIs, and other bacterial species. Various populations or sociodemographic groups may have their own patterns of transmission with different bacteria due to common diets, genetics, and other factors, Kaul said.

And more data is needed on just how common it is for people to experience symptoms without an active infection — a gap that may be related to the shoddy tests available, Rohn said.

“How many of those people actually have bona-fide low-grade UTIs that are just being let down by the poor testing that’s available at the moment?” she asked. It’s possible that women are having symptoms without any bacteria in their system, she said, but without better tests, it’s impossible to know.