Recurrent UTIs as a possible explanation for Interstitial Cystitis

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Spencer is Co-Founder and COO of Uqora. Trained in biochemistry at UC Berkeley, Spencer leads Uqora’s research and development initiatives focusing on UTIs, urinary tract health, and non-antibiotic UTI treatments.

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Many researchers and leading clinicians now believe that recurring urinary tract infections, and the immune response driving inflammation and UTI symptoms, is at least one of if not the cause of Interstitial Cystitis (IC). IC is a general term for chronic bladder pain, and is a diagnosis based on exclusion, without a clear cause, that affects an estimated 3 to 8 million women in the US. IC may be a default diagnosis when a patient consistently presents with UTI symptoms but negative urine cultures. IC can possibly be explained by two types of recurrent UTIs: 1) UTIs caused by hidden bacteria and 2) UTIs caused by uncommon bacteria.

A negative urine culture does not necessarily mean that an infection is not present and causing the symptoms of Interstitial Cystitis. The bacteria could be hiding within biofilm or tissue and are not present in the urine.

It is now known that, through different mechanisms, bacteria from a single UTI can evade antibiotics and the immune system and lay dormant on the surface of the bladder or within the bladder cells themselves protected by something called biofilm. These bacteria can lead to cyclical, chronic infections called recurrent UTIs (rUTI). Bacteria housed within bladder cells can cause an immune response and inflammation without being present in the urine. These bacterial populations can also consist of several different types of bacteria. In this situation, the cells of the bladder might be screaming for help, but when the immune cells arrive to assist, they are unable to identify and eliminate the bacteria. You can read more about how acute UTIs lead to recurrent UTIs here. To learn more about bacterial biofilms and how they work, go here.

Although Type 1 is likely much more common, there is another scenario in which a person could have recurrent UTI symptoms but continue to test negative for infections. The infection described in Type 1 could be caused by E. coli, which is the most common bacteria that causes UTIs. E. coli is culturable, meaning it can be grown in a urine culture. However, the vast majority of potential pathogens actually cannot be cultured using a standard urine culture. With new DNA sequencing and testing techniques, there have been more and more case studies of UTIs caused by one of these pathogens that can’t be cultured and are difficult to identify.

In the ways described above, bacteria could be causing chronic bladder inflammation without a positive test for a UTI. Standard urine cultures may be inadequate for diagnosing the infections causing these symptoms. In addition to not being able to culture the majority of potential pathogens, cultures often report inaccurate results. If a culture presents with a combination of different bacteria, the culture is ruled out due to “contamination”. However, as researchers have identified, there are often several types of bacteria involved recurring UTIs in women. This would mean this isn’t contamination, but actual bacteria from the bladder. Finally, as mentioned above, because the bacteria may be “hidden” within the cells of the bladder wall, these bacteria may not be in the urine sample at all.

What about the immune response discussed in Type 1? White blood cells, or leukocytes, are a type of immune cell. During an infection, they are usually present in the urine trying to fight it off. This is a strong indication that there is an infection. However, these are often ignored in urine cultures either because they aren’t found in combination with other bacteria, or the white blood cell counts aren’t high enough to be clinically classified as an infection. The presence of white blood cells should be strongly considered when trying to determine if there is an infection present.

More and more experts that focus on IC are convinced that it is caused by rUTI, and are using new DNA sequencing techniques to try and isolate test for the presence of infection instead of standard urine cultures. These sequencing techniques can identify a wide range of potential pathogens. In addition, researchers and IC specialists are using microscopy to identify hard-to-culture pathogens. As a treatment, they are leaning on long-term antibiotic therapy using antibiotics targeted to the potential culprit pathogen(s). When using these techniques, it is very important that the samples are not contaminated and a proper, midstream urine sample is used. Finally, more experts are using enhanced quantitative urine cultures (EQUC), a type of urine culture that can identify a wider range of bacteria. You can read more about different UTI testing methods here.

There is now strong and growing evidence for the existence of a complex bacterial microbiome in the human urinary tract and bladder (1). This evidence alone may be suggestive that bacteria would be involved in chronic bladder inflammation. We now know there are measurable changes in the microbiome between healthy and unhealthy states. These changes could impact inflammation, and, with more research and better diagnostic tools, we could gain more insight on what the urobiome might mean for those with IC. For instance, other bacterial imbalances in the microbiome that are not yet understood may be additional causes of IC.

There is strong evidence that rUTI is at least a cause of IC. There have been many theories and possible explanations as to the cause of IC, but rUTI is emerging as the strongest. IC is diagnosed on chronic UTI symptoms but negative test results for UTI. As a result, this would mean that women diagnosed with IC are being told they don’t have an infection when they actually do. Those that suffer from IC should seek out care from a specialist that focuses on IC and/ or on rUTI, and rUTI should only be ruled out after extensive testing and consideration. More research on IC is needed.

1. Brubaker L, Wolfe A. The urinary microbiota: a paradigm shift for bladder disorders? Curr Opin Obstet Gynecol. 2016 Oct; 28(5):407-12.