What Causes Chronic Urinary Tract Infections in Women
Chronic recurrent urinary tract infections (UTIs) affect nearly 20% of women after their first episode of UTI. However, the diagnosis of what constitutes a UTI or recurrent UTI remains controversial.
Some well-known factors that contribute to a chronic UTI are:
- Imbalanced vaginal flora for women.
- Bacterial dysbiosis that may manifest as constipation or diarrhea.
- Inability to fully void the bladder.
Other less-researched factors might be bacterial biofilms or intracellular bacterial communities. Opportunistic bacteria can hide in biofilms to avoid the attack of antibiotics or the host’s immune system response and thus cause the infections to recur. Therefore, bacterial biofilms could be a reason why it is challenging to detect and to cure a chronic urinary tract infection.
Bacterial Biofilms in Chronic UTI
Bacterial biofilms are pod-like structures that bacteria create in order to avoid being killed by your immune system or antibiotics. After the danger of an antibiotic attack is gone, bacteria emerge from the biofilm to start a new infection.
So it’d be nice to know if you have bacterial biofilms, right? Unfortunately, it’s a tough problem to solve, and there is still no consensus in the medical community whether a chronic UTI could be caused by biofilms in the bladder.
While physicians agree that biofilms can form on foreign bodies (such as catheters, stones, and IUDs, for example) there is still very little research on biofilms in the urinary tract.
Paul Sturman, Ph.D., a researcher from the Center for Biofilm Engineering, proposes: “A catheter is where biofilms typically start to form. But then they could move into the urinary tract and the following infections could certainly be caused by a biofilm. Generally speaking, when you’ve got a persistent infection inside somebody’s body it’s often a biofilm that is causing that.”
In fact, biofilms are currently estimated to be responsible for up to 80% of all microbial infections.
Urologist Dr. Melissa Kaufman is doubtful that biofilm could form on a bladder surface given that, especially during an acute infection, bladder sheds epithelial cells to get rid of invading bacteria. However, it is a known fact that opportunistic bacteria can create intracellular communities and avoid antibiotics and immune defenses that way. Dr. Kaufman says, “Bacteria can take advantage of a normal process that bladder cells undergo when recycling parts of their cell membranes. The bacteria are perhaps willing participants, or perhaps bystanders that become internalized [in a structure of a bladder cell], but their role in recurrent UTIs remains a mystery since they are not growing but persisting in that environment.”
There is now research that perhaps can merge both opinions. For example, Gregory Anderson et al. observed that intracellular bacteria mature into biofilms, creating pod-like bulges on the bladder surface. Other research also shows that in vitro biofilm production is independently associated with UTI relapse.
Unfortunately, there aren’t really great methods to detect biofilms, especially in hard-to-reach places, such as the bladder. “In fact, in many cases, you don’t necessarily know if biofilm is present other than you have a persistent infection and inflammation despite antibiotic treatment,” explains Dr. Sturman.
Here are the signs that an infection could be caused by a biofilm:
- An infection is persistent even with repeated courses of antibiotics.
- The infection seems to subside during the active use of antibiotics.
- The infection appears to return as soon as the antibiotic course is completed.
Moreover, urinary culture tests capture only free-floating bacteria, not the bacteria that hide in biofilms.
“Clearly, bacterial biofilms can exist on bladder epithelium, without being detected in urine samples and without giving rise to symptoms,” postulates another researcher.
However, “if microorganisms are present, you can assume that they might have originated in a biofilm and that the biofilm is still there,” says Dr. Sturman. Of course, it’s much easier if you can simply scrape off a sample directly from the surface where you suspect biofilms are and analyze them in a lab. However, it’s going to be an invasive and probably unnecessary test for a patient with a UTI because biofilms or not, the treatment approach will likely not change.
Chronic UTI Testing
In the past, researchers used culture-based techniques to identify bacteria in the samples.
You are probably familiar with a urine culture test, which used to be a go-to solution to identify bacteria in a biofilm. A culture test is when you take a specimen (for example, urine) and you grow it on a variety of different types of agar. The problem is that many bacteria don’t like to grow on agar. This is when researchers call them viable but not culturable. “If you happen to have this situation, you are not going to know the exact microbial composition [of the biofilm]. Maybe you only going to be able to culture 10% of the organisms that are present,” clarifies Dr. Sturman. “DNA-based techniques such as PCR do a much better job in identifying organisms.”
The nice thing about using molecular techniques is that you find genetic material from most of the organisms that are there if not all. Such tests will give you an idea of the complexity of the community, and with even more advanced molecular techniques, you can gain insights into the activity of those organisms. Dr. Sturman explains: “You’re looking at not only who’s there but you’re also looking at what are they doing. You know what genes are turned on, what proteins and enzymes are they making, and which are the ones that are growing the most rapidly. We call this transcriptomics.”
While transcriptomics is a fascinating way to explore the microbial community in action, Dr. Sturman says a good first step is simply ordering a PCR test, which allows for researchers to precisely identify the bacteria in an infection.
However, besides PCR, there are even more advanced testing opportunities for those who are ready to pay. For example, a company called Aperiomics provides testing services based on metagenomic sequencing that is able to identify up to 37,000 various microorganisms and viruses.
“PCR technique, while more accurate than culture, is limited by the types of bacteria it can screen at a time. Unfortunately, you must decide beforehand what type of organisms you are looking for prior setting up a PCR test panel,” explains Crystal Icenhour, Ph.D., CEO of Aperiomics, “The [PCR] test doesn’t provide a complete picture of all microorganisms in a sample and can result in findings that are not driving clinical disease. For example, the presence of E. coli in urine does not necessarily mean E. coli is causing an infection, especially if it is in very low levels.”
Dr. Icenhour believes that even the more advanced 16S sequencing test is also inferior to Aperiomics technology. First of all, this test can only identify bacteria down to the genus level while Aperiomics’ tests can pinpoint bacterial profile down to species. Secondly, it cannot identify viruses, while Aperiomics can. Moreover, when comparing tests results from a competitor who is using the 16S technique to the results achieved by Aperiomics, they found that the abundance of bacteria and types of bacteria reported differing significantly.
So how does the Aperiomics team know that their tests work? For example, when they mixed 400 microorganisms and put it through their analysis, Aperiomics’ technology was able to identify all 400 microbes with 99% sensitivity and 97% specificity, which is pretty astonishing.
“Some autoimmune conditions may actually be undiagnosed infections,” proposes Dr. Icenhour. She gives an example of her mother, who was diagnosed with chronic interstitial cystitis (IC). They ran her urine sample through Aperiomics’ testing and were able to identify high levels of a virus and several pathogenic bacteria in her urine. Once the virus was suppressed and bacteria targeted with treatment, the IC symptoms cleared. While this might sound like an odd case of a misdiagnosed problem, Dr. Icenhour states that they have at least 75 more cases of patients diagnosed with IC who were able either to resolve their symptoms or lessen them after a treatment protocol was developed based on the findings that Aperiomics provided.
In fact, in about 100% of patients that were diagnosed with IC, Aperiomics’ tests were able to identify either a virus or various bacteria that were not targeted in prior treatment.
She mentions that in some cases when the results come back, the treating physicians argue that the identified bacteria are not known to cause UTI. However, “just because it doesn’t grow in culture doesn’t mean it’s not a culprit since only 10% of microbes can grow in urine culture, so right there you are excluding 90% of possibilities from your consideration,” argues Dr. Icenhour. “The reality is what causes infections can be different from one person to the next. And what’s known to be a pathogen is somewhat fluid. What we know about infection has been limited by our ability to identify microorganisms, thus genomic tools such as Aperiomics’ are changing what we know. Infection is a dynamic and a complicated process—it’s rarely just one microbe, but rather a complex community of microorganisms driving disease.”
While we still don’t know what the normal bladder microbiome should be, in 100% of UTI patients, Aperiomics finds bacteria in urine that was either not expected to be there or at levels that are high compared to other microbes in the urine sample.
Once a precise set of bacteria is identified, a physician can develop a treatment to target them. After the treatment, Aperiomics recommends retesting to see how the picture has changed and if the treatment protocol needs to be further adjusted.
For those who are worried about false positive based on DNA fingerprint, Dr. Icenhour reassures that they utilize numerous layers of quality controls to prevent and filter out artifacts and only show the bacteria that are currently present in samples tested.
At the same time, Dr. Kaufman points out that “the data from Loyola [suggests that] the vast array of bacteria—not to mention other types of organisms such as viruses—are likely present in everyone’s bladder as part of our symbiotic community. Enhanced methods to detect these organisms, whether it involves specific culture mechanisms or genetic expansion techniques, does not always correlate to the clinical symptoms of a patient. The overall utility in patient care remains a question.”
Treating Chronic UTI
To prescribe an effective treatment, it is important to know what type of bacteria are present in biofilms and what these microorganisms are susceptible to. Since a simple urine culture only captures the free-floating bacteria, it’s better if you can run a DNA-based test and identify pathogenic bacteria that way. Besides antibiotic treatment, there are also some experimental options such as iron-chelating Lactoferrin and bacteriophages.
Biofilms & Supplements
You might know that naturopaths frequently prescribe acetylcysteine, Lactoferrin, and some biofilm-targeting enzymes in combination with antimicrobials in hope to destroy bacterial biofilms.
Dr. Sturman, however, is skeptical about supplements that have not gone through extensive clinical trials. “I’d encourage patients to ask for evidence-based medications, not just something that is based on anecdotal evidence. Often naturopathic treatment lacks clinical research behind it. As for Lactoferrin, I’m not personally familiar with any work here in our center, but that being said, it has been shown as an effective agent in controlling bacterial growth,” Dr. Sturman says.
Bacteriophages & Biofilms
Bacteriophages (or phages) are viruses that attack bacteria. Phages have been around forever since bacteria and viruses coexisted and evolved together over eons.
“There is some work being done using phages to try to control bacterial biofilms, but it’s still pretty experimental. The hard part of it is that phages are specific to the type of bacteria. The problem is that the biofilm could be comprised of many different organisms and so it’s really a challenge logistically when you think about it. No one has really successfully met this challenge to add a phage to a polymicrobial biofilm and be able to control all the different species that might be present in it. Unfortunately, the vast [majority] of biofilms are polymicrobial,” explains Dr. Sturman.
Interesting fact: Using phage cocktails to treat chronic infections is a popular method in the country Georgia where the technique has been perfected since the ‘60s. Currently, there are several facilities that provide treatment for patients with a variety of chronic infections, including UTI.
Prolong Cycles of Antibiotics For Chronic UTI
Recently, new research suggests using a long-term cyclic antibiotic treatment over several years and even for patients with negative culture for up to a year.
“I think it’s devastating. I believe that that would promote a general state of dysbiosis and poor health. I think it will provoke a worsening of different metabolic functions of the body. There’s news all the time about what are bacterial communities are contributing to our general health…So I think a year-long treatment with antibiotics might provoke more problems than it may alleviate.”
In fact, your body is composed of more microorganisms than your own cells and we are still learning about their role in our health. “Our understanding and the conversation has been based on the microorganisms that we can culture while the vast majority of the time they may coexist with us without any problem. Symptomatic patients might as well have the same composition of bladder microbiome as the patients who have no symptoms at all,” continues Dr. Kaufman.
Instead of killing or suppressing microorganisms that have been evolving with us for thousands of years, creating a more diverse microbiome might be a better solution. “I think bacteria in the bladder are directly correlated to bacteria in the gut. What I believe is actually happening is that you have an overgrowth and dysbiosis of your gut bacteria and that’s provoking part of the disease process that occurs in the bladder. So I think to target the gut first [is a better approach for UTI treatment].”
“We do not have a reliable way to say what are commensal organisms in the bladder.
What we tend to do in a western medicine is to look at a human as a bunch of different organ systems that are separated and it is not true, they all work in coordinated fashion. So if you change your gut bacteria you may change the nutrients that are required for bacteria in the bladder to grow,” says Dr. Kaufman.
According to Dr. Kaufman, antibiotics are the first step which leads a bladder to not being able to protect itself, and it is a common occurrence.
Therefore, focusing on restoring your gut and vaginal microbiome could prove crucial in turning around chronic UTI.
Once she rules out any structural or functional abnormalities, to make sure that patients are emptying their bladder completely, Dr. Kaufman assess the vaginal health of her patients.
“Vaginal treatment, for example, topical estrogen, can improve the protective layer of Lactobacilli and can help make the urethra more robust to resist the ascending infections that come from gut bacteria.”
What can we do now?
While we still trying to understand the role of bacterial biofilms in chronic UTIs, the fact that the infection might be caused by biofilms that are already in the bladder is an important discovery for how patients feel about the disease. Chronic UTI patients sometimes think that they did something wrong to provoke another recurrence. Therefore, discussing biofilms as a possible contributing factor can help release the feeling of guilt and shame and improve doctor-patient relationships.
Even perfect hygiene and adherence to all UTI prevention tips recommended by a physician do not guarantee that a patient will be UTI-free. In fact, as more evidence suggests, inviting more bacteria in your life via a diverse diet and less sanitization can prove beneficial in the long run.