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If it hurts to pee, then it might be…a urinary tract infection (UTI). This is not an uncommon occurrence—roughly , 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, , 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—. 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, .  

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 . UPEC hoovers up this glucose as a food source, and research shows the 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  to prompt recurrence. rUTIs 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. 

Within that vein, there are emerging associations between the gut microbiota and rUTIs. Researchers postulate that 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 of urinary stem cells . 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 , 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 (IQR) where they hang out for up to 12 weeks. As bladder cells turn over, the bacteria in IQRs can . 

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, to sense and respond to the environment, toxins, secretion systems and and nutrients in urine (a liquid devoid of ). 

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 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 —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—. 

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, (Uromune), is a pineapple-flavored spray administered daily by mouth. A phase 3 trial showed that, among people assigned female at birth with rUTIs, compared to 25% in the placebo group. The vaccine is in many European countries and is available via special access programs in other countries, though has yet to be approved in the U.S. 

Non-antibiotic medications to mitigate rUTIs are also being discovered and explored. These include molecules that mimic proteins on the host cell surface, thus , as well as compounds derived from diverse sources, like plants. A recent study identified 2 plant-derived compounds . 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. 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.

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How are UTIs diagnosed? Learn about the multi-step process in this next article.