Why Do Urinary Tract Infections (UTI) Recur?

May 3, 2024

Graphic of a bladder with a magnifying glass showing urine and bacteria inside
UTIs are among the most common infections worldwide.
Source: AlonzoDesign/iStock
If it hurts to pee, then it might be…a urinary tract infection (UTI). This is not an uncommon occurrence—roughly 400 million UTIs occur globally every year, primarily in people assigned female at birth. While antibiotics might initially get rid of a UTI, the infection will often come back again and again. 

Such recurrent UTIs (rUTIs) are, at best, a nuisance and, at worst, the seeds for serious health complications. To banish these infections for good, scientists are teasing apart why recurrent infections happen in the first place.

Why do UTIs Come Back?

UTIs typically occur when bacteria invade the urinary tract via the urethra and travel into the bladder. In 80% of cases, uropathogenic Escherichia coli (UPEC) is the culprit behind a UTI, though other bacteria (e.g., Proteus mirabilis and Klebsiella pneumoniae) cause them too. If someone has a UTI, there is a 25-50% chance their infection will return, with rUTIs specified as 3 or more infections in a year. What can explain this dismal cycle?

Susceptibility to rUTIs—and UTIs in general—depends on interactions between the host and bacteria. Indeed, not everyone has the same risk of getting a UTI, and “UPEC” itself encompasses a swath of E. coli strains with slight variations in their virulence and pathogenesis. The characteristics of a given E. coli strain must match up just right with the characteristics of a given host for an infection to occur, described as a sort of “lock-and-key” mechanism.  

The Host With the Most 

On the host side, there are multiple features that contribute to bacterial growth and survival. For instance, some conditions, like diabetes, predispose to rUTIs. People with diabetes tend to have elevated glucose concentrations in their urine. UPEC hoovers up this glucose as a food source, and research shows the bacteria exhibit enhanced growth in glucose-rich urine compared to normal urine.

Catheters (i.e., thin tubes inserted into the urethra to drain the bladder) are another key player. These devices create a scaffold for pathogen adherence and biofilm formation, and the biofilms can persist even after antibiotic treatment to prompt recurrence. rUTIs have additional ties to genetics, an inability to completely empty the bladder after urination—which creates persistent pool of urine to support pathogen growth—frequency of sexual activity and wiping after using the bathroom.

Why would the latter matter? UPEC largely resides in the gut, where it can exist as a transient or commensal member of the gut microbiota. After excretion in feces, the bacteria populate the skin close to the urethra or, in people assigned female at birth, the vagina. From these locations, UPEC can be physically introduced into the urinary tract through wiping (especially if wiping back-to-front), sex or catheterization. 

Diagram depicting how UPEC survives in gut and also invades bladder cells
UPEC lives in the gut. It can be introduced to the urinary tract in various ways, where it then invades host cells. The bacteria multiply and exist the cells to infect neighboring cells.
Source: Tamadonfar K.O., et al./Microbiology Spectrum, 2019

Within that vein, there are emerging associations between the gut microbiota and rUTIs. Researchers postulate that differences in gut microbial diversity and metabolic function in people assigned female at birth who have a history of rUTIs may alter host immune responses to bacterial bladder colonization by way of the "gut-bladder axis," predisposing to repeat infection. Such altered immunity can also be tied to rUTIs themselves. Scientists recently found that the epigenome of urinary stem cells derived from mice with either resolved or chronic UPEC infection differed. Specifically, cells from chronically infected mice had epigenetic modifications in genes that regulate rUTI-associated changes in cell morphology and inflammation. The findings indicate that UTIs trigger lasting changes to host molecular processes in ways that boost infection susceptibility. 

Ultimately, whether or not someone developes rUTIs depends on biological and behvaioral factors, and their risk may change over their lifetime. 

Unpacking UPEC's Role in rUTIs

Of course, a UTI doesn’t exist without the microbe causing the infection, and the infection dynamics of said microbe, like UPEC, are integral to rUTIs.  

During infection, UPEC adheres to and is then internalized into urothelial cells (the cells lining the bladder wall). In this intracellular haven, safe from host immune responses, the bacteria replicate. They eventually emerge from the cells to bind and infect neighboring cells. 

To deal with this unwelcome invasion, bladder epithelial cells undergo programmed cell death, and exfoliation (shedding) of the epithelium kicks into high gear. This battle between bacteria and bladder cells gives rise to UTI symptoms, like burning pain during urination, bloody urine and increased frequency of urination. While the exfoliation process molts infected cells, it also exposes underlying epithelial cells to UPEC. A few of these bacteria sneak into the newly uncovered bladder cells to form quiescent intracellular reservoirs (IQR) where they hang out for up to 12 weeks. As bladder cells turn over, the bacteria in IQRs can reemerge and jumpstart new infections

Diagram showing virulence factors in UPEC
UPEC is loaded with diverse fitness and virulence factors that facilitate its survival and pathogenesis in the urinary tract.
Source: Tamadonfar K.O., et al./Microbiology Spectrum, 2019

UPEC survival in the bladder is further bolstered by its physiological and metabolic bells and whistles. The bacteria come decked out in pili to stick to host cells, 2-component systems to sense and respond to the environment, toxins, secretion systems and an ability to acquire and use nutrients in urine (a liquid devoid of many compounds other bacteria like to eat). 

Although UPEC is the principal pathogen responsible for UTIs, other UTI-associated bacteria have their own qualities and quirks that facilitate survival and persistence. For example, P. mirabilis, a frequent cause of catheter-associated UTIs, is loaded with appendages called fimbriae that allow the bacteria to adhere to epithelial and catheter surfaces.

The Future of rUTI Prevention and Treatment

Getting rid of rUTIs is not just about comfort, but also health—pathogens can ascend from the bladder into the kidneys, and potentially the bloodstream, posing a risk for sepsis. The goal is to get a UTI under control before it reaches this point.

Antibiotics are currently the name of the game when it comes to UTI treatment, but the antimicrobial resistance (AMR) crisis has limited their reliability. Pivmecillinam, an antibiotic used in Europe to treat UTIs, is expected to become available in the U.S. in 2025—the first time in 2 decades the U.S. Food and Drug Administration (FDA) has approved a new drug for UTIs. Yet, health practitioners warn that the drug will have to be administered responsibly to avoid breeding resistance against it. There is a push for alternative options for managing UTIs. 

One facet of research focuses on developing vaccines to prevent rUTIs. Some promising candidates target different components of UTI pathogens. For instance, a phase 1b clinical trial showed that in patients with rUTIs, SEQ-400—a vaccine containing the E.coli FimH adhesin protein, which is essential for bacterial attachment and invasion of host cells—prompted a ~70% reduction in total rUTI and UTI caused by the bacterium

Other vaccines contain whole, heat-inactivated cells of common UTI-causing pathogens (e.g., E. coli, Enterococcus faecalis, Klebsiella pneumoniae and others). One such candidate, MV140 (Uromune), is a pineapple-flavored spray administered daily by mouth. A phase 3 trial showed that, among people assigned female at birth with rUTIs, 58% were free of UTIs after 6 months of MV140 treatment compared to 25% in the placebo group. The vaccine is approved for use in many European countries and is available via special access programs in other countries, though has yet to be approved in the U.S. 

Diagram showing how phages can be used to combat UTIs
Phage therapy, one of several emerging options for managing rUTIs, has several potential benefits, including an ability to synergize with antibiotics.
Source: Zulk J.J., et al./EcoSal Plus, 2024
Non-antibiotic medications to mitigate rUTIs are also being discovered and explored. These include molecules that mimic proteins on the host cell surface, thus binding up microbes before they infect cells, as well as compounds derived from diverse sources, like plants. A recent study identified 2 plant-derived compounds that disrupt host cell machinery needed for UPEC to enter bladder cells. The kicker: if the bacteria can’t enter cells, they can’t be protected from antibiotics. The study’s authors speculate that the plant-derived compounds could be administered alongside antibiotics to boost their activity. A similar rationale underlies scientists’ interest in phage therapy—the therapeutic use of bacteria-infecting viruses—for mitigating rUTIs. Often, bacteria develop resistance to phages that infect them but, when they do, they become more susceptible to antibiotics. Capitalizing on this tradeoff could be a way to preserve the efficacy of existing treatments. 

All this is to say that a future without rUTIs is not outside the realm of possibility. The more scientists learn about the mechanisms underlying rUTIs, the more options will become available for making the infections go away—for good.
How are UTIs diagnosed? Learn about the multi-step process in this next article.

Author: Madeline Barron, Ph.D.

Madeline Barron, Ph.D.
Madeline Barron, Ph.D. is the Science Communications Specialist at ASM. She obtained her Ph.D. from the University of Michigan in the Department of Microbiology and Immunology.