Negative Urine Cultures And The Science Behind UTIs. An Interview With Dr. Krystal Thomas-White

The issue around negative urine cultures is a big topic in the UTI community. You may have found yourself struggling with UTI symptoms, only to be told your urine culture was negative.

In this video series, Dr. Krystal Thomas-white, Live UTI Free’s scientific advisor, discusses the bladder microbiome and explains that the bladder is not the sterile environment it was once believed to be. This old belief can impact the interpretation of urine cultures and the treatment you may receive.

Rather, the bladder is home to pathogenic, beneficial, and unoffending bacteria, viruses, and fungi that are still being explored and understood. 

Jump To Section:

• The Science Behind Probiotics  >>>>
• How Negative Urine Cultures Can Be Misleading  >>>>
• The Far-Reaching Effects Of Oral Probiotics  >>>>
• A Negative Urine Culture Does Not Confirm A Healthy Microbiome  >>>>

Dr. Thomas-White addresses the relationship between the urinary and vaginal microbiomes and why Lactobacillus is so important to both. Additionally, the challenges of determining what bacteria is causing what urinary tract symptoms is discussed. 

What about the gut microbiome and how it influences other systems of the body? The gut microbiome can impact UTI rate and recovery. Dr. Thomas-White explains the indirect way that oral probiotics can affect bladder health. 

Watch the video interview on our YouTube channel or browse summaries of the videos below to learn more about the microbiomes of the body, issues with both positive and negative standard urine cultures, and how this inadequate testing method became so widely used. 

Many people with chronic UTI do not feel they receive adequate information from their doctors. Therefore, they often do their own research. 

In your own research, you may have come across ‘in vitro’ and ‘in vivo’ in the scientific literature. But what do these mean and what significance do they have to your treatment methods? 

Dr. Thomas-White explains that ‘in vitro’ refers to what happens in a test tube. In comparison, ‘in vivo’ is what happens in a live organism, such as a mouse.

Dr. Thomas-White explains that ‘in vitro’ refers to what happens in a test tube. In comparison, ‘in vivo’ is what happens in a live organism, such as a mouse.

The difference is important because sometimes an experiment will produce one set of results in vitro and another set of results in vivo.

Similarly, an experiment may produce one set of results in a mouse and a different set of results in a human. Dr. Thomas-White describes how, when it comes to the microbiome, these differences can apply to human demographics as well. 

Diet, antibiotic exposure, and living in an urban versus a rural area all impact a person’s microbiome.

A microbiome is like an ecosystem. One small change produces a series of changes, like a domino effect. 

Consequently, the same experiment performed on people in various parts of the world may lead to different results. 

What This Means For Your Treatment

Probiotics are often used alongside antibiotic treatment. When it comes to overseeing your own microbiome treatment, Dr. Thomas-White notes that the probiotics commonly sold as supplements are safe to try.

However, depending on the quality and your own microbiome, they may not help. 

“If you are looking to apply an idea from a study to your own treatment, your personal results may not be the same as those described in the literature.”

Because probiotics are live organisms and prone to mutation, they are practically impossible to regulate by the Food and Drug Administration (FDA). Therefore, as with many natural supplements, what’s in the product may not match what’s on the label. 

It’s important to look into the companies producing probiotics and other supplements to determine whether or not the product they provide is high quality.

While probiotics are an unregulated product, there are third-party companies that test supplements and other natural products and post their findings online.

Dr. Thomas-White recommends selecting a probiotic that is refrigerated, as only Clostridia and Bacillus organisms are shelf-stable.

As many people with recurrent UTI have likely suspected, there is a high rate of false negative urine cultures. But if the bladder is not sterile, then why are so many standard urine cultures negative?

Dr. Thomas-White explains that in the 1950’s, Dr. Edward Kass, an epidemiologist, designed a test (the same urine culture used today) to determine which patients were at risk of a kidney infection during or after surgery.

He did this by placing a drop of urine in a specific environment and noting what grew in 24 hours. 

While this test was successfully able to identify the risk of kidney infections in patients, it was only useful for growing E. coli bacteria. The test failed to accurately grow and identify other organisms. 

If E. coli is not present in high enough levels, a patient may receive a negative urine culture, despite possibly having imbalances of other bacteria.

“The reason E. coli is used as a model organism across the world since the 50’s is because it grows just about anywhere. It’s the microbial weed of the scientific community.”

Unfortunately, this urine culture was introduced into other areas of healthcare and used as a test for all UTIs, despite the fact that it did not successfully detect other bacteria. 

For people who have UTI symptoms but receive negative urine culture results, the test can only determine that they are negative for E. coli.

The test cannot confirm that they are negative for a UTI caused by other organisms.

If Urine Cultures Are Unreliable, How Do We Know What Organism Is Causing Symptoms?

Dr. Thomas-White describes how, contrary to popular belief, urine is not sterile. To add to that misheld belief, the same urine sample tested under different conditions will culture different organisms. 

This means that you could receive a negative urine culture as well as a positive urine culture from the same urine sample if different testing conditions are used.

While everybody has microorganisms in their urinary tract, not all of these organisms are harmful, and many of them have yet to be studied. This means that even if you test positive for one bacteria, that does not necessarily mean that it is the cause of your symptoms. 

Studies and literature about how certain bacteria respond to specific antibiotics can help to direct treatment recommendations, but how your symptoms respond to the treatment can also provide insight.

To further complicate matters, symptoms and recurrent infections can also be triggered or intensified by specific combinations of bacteria. 

Even if an organism is not directly causing symptoms, the effect that bacteria has on the bladder tissue can contribute to additional bacteria dominating the microbiome. This well-known study on Gardnerella vaginalis and E. coli demonstrates this phenomenon. 

If you test positive for two uropathogens, Dr. Thomas-White generally recommends treating both at the same time.

Meanwhile, Lactobacillus is a beneficial microorganism that kills off harmful pathogens like E.coli. It occurs in both the vaginal and urinary microbiomes, which are interconnected in women. There may be other healthy pathogens, but – as with many elements of the urinary system – more research is needed.

Oral probiotics typically contain Lactobacillus, but are they delivered all the way to the bladder? 

“There is no evidence that the same strains that you consume in an oral probiotic end up in the bladder or the vagina. But that doesn’t mean there aren’t benefits.”

There is much to still be explored in this area of interconnectedness between the gut microbiome and other areas of the body. As Dr. Thomas-White points out, these are the current assumptions in science, and they have the potential to change over time. 

Let’s take a look at this evolving area of research!

Through taking oral probiotics and influencing the gut microbiome, a cycle emerges. Not only can the gut microbiome affect the bladder, but also the vagina, brain, kidneys, hormone levels, blood stream, and metabolism. All of these regions of the body can play a preventative role in UTI. 

How Do Oral Probiotics Affect Kidney Health?

Because the kidneys are also part of the urinary tract, their health is important in preventing and treating UTI. You’re likely familiar with the concept of kidney stones, but were you aware that oral probiotics can help to prevent kidney stones?

One of the causes of kidney stones is the buildup of oxalates. Within the body, certain metabolizers work to break down oxalates and discourage stones. Probiotics can be beneficial in encouraging production of these metabolizers. 

In very simplified terms, oral probiotics may improve the health of the kidneys and prevent the formation of kidney stones. 

The gut microbiome also impacts the health of the immune system in a significant way. But we’ll let you listen to Dr. Thomas-White’s explanation of this in the attached video because her illustration is too valuable to miss.

The gut microbiome in constantly training your immune system to learn what to attack and what to leave alone. This is why it’s crucial to maintain a healthy balance in your own gut microbiome.

Bacteria are often the cornerstone of UTI discussions. But what about other organisms such as fungi and viruses? How do they influence the bladder microbiome, and are urine cultures at all beneficial in identifying them?

The microbiomes of the male and female bladder are typically very different. Due to the connection between vaginal and urinary microbiomes, the dominant bacteria in the female bladder is Lactobacillus. 

In the male bladder, streptococcus and staphylococcus dominate, but very little research has been completed into male bladder microbiomes. 

Other Influences of The Bladder Microbiome

Fungi

When it comes to fungi, research has shown that 100% of women have had a fungus identified. Compared to only 50-75% of women demonstrating bacteria in the bladder, this is a surprising finding. 

While these fungi appear to be harmless, we ultimately have no idea of their impact on the microbiome or immune system. We know we sound like a broken record, but more research is needed into how fungi may be shaping bladder health.

Viruses

The bladder biome includes two types of viruses: one that infects the person and another that infects the bladder-dwelling bacteria. 

Viruses that can infect bacteria are known as bacteriophages, or simply phages. Phages and bacteria evolved side by side, with bacteria mutating to better protect itself against phages

In turn, phages have mutated to better side-step the bacteria’s defenses. 

Phage therapy is based on the principle that, since specific phages attack specific bacteria, introducing that phage into an infected microbiome will eradicate the problematic bacteria without harming the beneficial organisms the way antibiotics do. 

However, the rate of mutation of both the bacteria and the phages is a major challenge to phage therapy. 

We recently wrote an in-depth article about bacteriophages, including how they work and ways to access phage therapy. We’d love to hear your thoughts on the topic!

Hormones

Many women have noted that they are more vulnerable to UTIs during specific times of their menstrual cycle, such as ovulation or menstruation, or after beginning hormonal birth control. 

Detailed research into female hormone levels is significantly lacking. The information we do have provides only a broad overview, and studies on hormone levels during UTI are non-existent. 

But, we do know that hormones can impact the immune system, which then impacts the microbiomes of the body. More directly, some hormones are produced in the gut. 

In this way, hormones are influenced by the gut microbiome – as Dr. Thomas-White discussed earlier. We’re learning that the gut microbiome is not to be underestimated.

Furthermore, since Lactobacillus feeds on estrogen, there is a direct link between estrogen levels and bladder health. 

When women experience a drop in estrogen during menopause, their Lactobacillus levels drop and they become more vulnerable to UTI. This can be addressed with hormone replacement therapy, if your doctor agrees that it is right for you. 

It is standard practice to treat urinary pathogens in pregnant women, regardless of whether they are symptomatic. But will this practice change now that it has been determined that urine is not sterile? 

Dr. Thomas-White says that until more information is obtained and guidelines are updated, probably not. 

Hormonal and other changes during pregnancy can cause genetic switches in bacteria that cause asymptomatic bacteriuria (ASB) to become pathogenic. UTIs can be extremely dangerous to unborn babies. In these situations, the benefits of treating the ASB outweigh the risks.

Difficulties Of Negative Urine Cultures In Research

Given the high rate of false negative standard urine cultures and their unreliability, is it possible to determine the type of infection based on symptoms? 

“Urinary incontinence is characterized by frequency, urgency, nocturia. UTIs are characterized by frequency, urgency, nocturia, pain, and sometimes blood. Who’s to say that someone diagnosed with urinary urgency incontinence doesn’t actually have a UTI without pain?”

In research studies, urinary tract study participants are often selected based on a collection of symptoms as opposed to a clear diagnosis drawn from conclusive test results. After all, if negative urine cultures are so common, it can be unclear which study group participants fall into. 

This is namely because most people with urinary tract symptoms do not receive a well defined diagnosis. If these presumed diagnoses are incorrect, then the data from the studies becomes difficult to interpret. 

Secondly, as previously mentioned, certain symptoms may be the result of not only individual bacteria but potentially specific combinations of bacteria. 

Infection often begets infection – as in the case of recurrent infection – as a person’s bladder lining is vulnerable until it heals completely. 

In many recurrent UTI cases, this process of reinfection has little to do with the specific bacteria present, and more to do with the individual person’s health history. 

Dr. Thomas-White hypothesizes that certain bacteria have likely evolved to infect different areas of the urinary tract, although research has not yet explored this idea.

Acknowledgements

As you may have gathered, more scientific research is desperately needed into these various areas that affect bladder health. The bladder microbiome is still a recent discovery, and unfortunately, many physicians are still reliant on testing methods that align with the outdated concept of a sterile bladder.

Because non-E. coli bacteria, fungi, and viruses may be contributing to UTI symptoms, a negative urine culture cannot be relied upon to rule out UTI. 

We want to thank Dr. Krystal Thomas-White for sharing her scientific insights with the UTI community, and we look forward to reviewing her future research into the microbiomes of the body. As a reminder, Live UTI Free does not endorse a specific approach to treating chronic or recurrent UTI.

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To get answers to commonly asked questions about chronic and recurrent UTI, visit our FAQ page. If you have questions or comments, share them below, or reach out to our team directly.