Below you can find our ‘Ask me anything’ series with our scientific advisor, Dr. Krystal Thomas-White. We collected questions from our community all about UTI science, and Dr. Thomas-White has helped explain many of the mechanisms and terminology. We’ll continue with our expert Q&A series, and you can contribute questions over on our Instagram account.
Check back in here regularly, for more answers. We’ll add the most recent answers at the top of the post. Dr Krystal Thomas-White provided more insights into the science behind UTIs, in her video interview about negative urine culture and other issues with diagnosis. Read more from Dr Thomas-White in her article on UTI and estrogen therapy.
Question: What is the difference between colonized vs. embedded vs. pathogen vs. opportunistic infection?
Dr. Thomas-White’s response:
These terms all mean very different things, but it can be confusing because some of them are used interchangeably. Any bacteria (good or bad) that has taken hold in an environment has colonized that environment. So you can be colonized with benign bacteria or with pathogenic bacteria. A pathogenic bacterium that has colonized long term is said to be an embedded infection.
There are also 2 types of infection: infection from a pathogen or an opportunistic infection. A bacteria known to always cause symptoms is known as a pathogen, something like malaria, or covid is a known pathogen. When it colonizes a human it always causes symptoms, it is never (or rarely) benign.
There are some bacteria that can be involved in opportunistic infections. They can coexist in humans, are benign most of the time, and only cause symptoms under certain circumstances.
E. coli is an opportunistic pathogen. In your gut it is a perfectly harmless component of your normal flora. But if it gets into the bladder it can cause symptoms.
But remember, I am a microbiologist and I think from a bacterial perspective. So for me, I care just as much about the good bacteria as I do about the pathogenic bacteria.
Physicians tend to think about this from a host’s perspective, where the bacteria that matter are the ones that cause symptoms (aka pathogenic). Therefore when a doctor uses the term “colonized” it usually refers to the long-term presence of pathogenic bacteria and very rarely refers to benign or commensal bacteria.
Question: Can you explain Gram positive and Gram bacteria? Do Gram negative bacteria build a slimy matrix that antibiotics can’t penetrate?
Dr. Thomas-White’s response:
Gram positive vs Gram negative refers to the result from a lab test called a Gram stain. The Gram stain was developed a long time ago to allow humans to visualize bacteria under a microscope. Some bacteria stain pink (Gram negative), while others stain purple (Gram positive).
Before sequencing technology it was one of the primary methods for classifying bacteria. We have learned that this test actually stains the outer component of the cell called peptidoglycan which makes up the cell wall.
Gram positive organisms have a thick layer of peptidoglycan and therefore stain darker purple, while Gram negative organisms have a thinner layer and stain a lighter pink color. But the Gram stain doesn’t necessarily correlate with the slimy matrix you asked about.
Bacteria can do so many different things. Some Gram positive and some Gram negative organisms secrete slimy matrixes, and some do not. Some bacteria form biofilms (which prevent antibiotics from penetrating) and some do not, but that is not necessarily correlated with the cell wall (or Gram stain).
The Gram stain is primarily used to help classify bacteria. It can only be used for identification and gaining information about the cell wall. It can not be used to infer biofilm formation or any other activity of a bacteria.
Question: Do bacteria enter the bladder from the kidney?
Dr. Thomas-White’s response:
No, bacteria are entering the bladder from the urethra. There is no way that bacteria should be travelling from the bloodstream into the kidneys. In fact, you shouldn’t have any bacteria in your bloodstream at all, that can lead to a robust inflammatory response called sepsis and it can be fatal.
Question: Can oral probiotics directly reach the bladder?
Dr. Thomas-White’s response:
That is controversial. It is assumed that the probiotics are being digested, travelling through the gut microbiome, then moving externally from the gut to the vagina and then into the bladder. But the evidence for this is controversial.
There is conflicting evidence that any orally consumed probiotic actually ends up *in* the vagina, let alone the bladder. But due to FDA regulations, supplement companies are only allowed to market orally consumed probiotics, so consumers don’t have much of a choice.
Question: If there is a dense bacterial community in the bladder, wouldn’t it be easy to detect?
Dr. Thomas-White’s response:
The urobiome (urinary microbiome) is not a very dense population. The levels of bacteria are orders of magnitude smaller than the levels in the gut or the vagina.
Most people are familiar with the microbiome in the gut. Which is a very dense community. There are 100 billion (100,000,000,000) bacteria per gram of human feces. Compare that to about 100 million (100,000,000) bacteria per milliliter of vaginal secretion.
The bladder is even orders of magnitude smaller, about 100-100,000 bacteria per milliliter of urine. That is almost nothing in comparison to the gut. And most of those bacteria do not grow under standard laboratory conditions, so until the advent of sequencing, we couldn’t prove they were there.
Question: Why is my UTI test negative, despite my symptoms?
Dr. Thomas-White’s response:
Remember that a negative standard urine culture (SUC) only means that you are negative for E. coli (and other closely related organisms). There are a lot of uropathogens that don’t grow in standard culture, and 20% of women who have symptoms are SUC negative. You should get treatment anyways. If your doctor doesn’t believe you have symptoms, try getting a second opinion.
Question: Which organisms can standard urine culture (SUC) detect?
Dr. Thomas-White’s response:
Below is a graph* showing the bacterial diversity within the bladder. Each tip of the tree is a bacterium. The closer 2 organisms are on the tree, the more related they are, and the farther apart, the less related they are.
The tree represents all cultivatable bacteria from the bladder (sampled via catheter, not voided urine). Culturing or sequencing from voided urine does contain other bacteria from the vagina or even the skin, so there will be a greater diversity of organisms found in voided samples.
Expanded culture protocols used here are better than standard culture but not perfect. Many anaerobic organisms are missed by expanded culture and are therefore not represented below. One common example is Prevotella. Sequencing can sometimes detect these organisms.
The red arrows show organisms that SUC detects. The yellow arrows show known uropathogens that are not detected by SUC. The orange stars are bacteria known to be associated with UTIs or to make UTIs worse, and they are also not detected by SUC.
We don’t know much about the unmarked organisms. Some of them might be beneficial (like the other Lactobacillus species), some benign (neither good nor bad), and some might be undiscovered uropathogens. We simply don’t know and more research is needed.
Bacteria like Enterococcus and even sometimes Lactobacillus can sometimes be cultured by SUC, but not reliably. In comparisons between SUC and expanded culture protocols, we find those organisms are missed more often than they are detected.
Organisms SUC detects:
– E. coli
– Klebsiella pneumoniae
– Pseudomonas aeruginosa
– Proteus mirabilis
– Citrobacter freundii
– Citrobacter koseri
Known uropathogens not detected by SUC:
– Serratia marcescens
– M. morganii
– O. urethralis
– C. riegelii
– C. urealitycum/sp
– S. anginosus
– S. agalacticae
– Enterococcus faecalis (see note above the graph)
– A. urinae
– A. sanguinicola
– A. omnicolens
– A. schaalii
– Staphylococcus aureus
– Staphylococcus ludgunensis
UTI-associated bacteria not detected by SUC:
– Lactobacillus iners (see note above the graph)
– Gardnerella vaginalis
*Graph modified from Thomas-White & Forster et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat Commun. 2018 Apr 19;9(1):1557. doi: 10.1038/s41467-018-03968-5. PMID: 29674608, Using data generated in Price et al. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms. J Clin Microbiol. 2016 May;54(5):1216-22. doi: 10.1128/JCM.00044-16. Epub 2016 Mar 9. PMID: 26962083.
Read more about the limitations of standard urine culture.
Question: Is there a primary bacterium that infects the bladder?
Dr. Thomas-White’s response:
It is generally recognized that E. coli causes, or is involved in, 80% of all UTIs. But I say that with one major caveat… the standard urine culture (SUC) was designed to detect E. coli, and not much else.
The SUC was designed to determine who was at risk of dying of a kidney infection caused by E. coli. A specific threshold was set for the amount of E. coli that needed to be present for a kidney infection to be confirmed. This was decades ago (1950s), and it was so good at what it was designed to do that this same test ended up being used for everything involved with urine.
The problem is, the test was designed for a specific use, and has been applied to absolutely everything. And it has flaws. It can grow some organisms that are closely related to E. coli, like Klebsiella and Proteus (see the question above for an explanation of this), but it is terrible at growing most organisms that live in and on the human body.
So while the SUC can technically grow some other organisms, this still represents just a handful of the organisms that can be found in the bladder. The test is not only bad at detecting beneficial bacteria (Lactobacillus), but it also does not detect other pathogenic bacteria (Aerococcus, Actinotingum, and often not Staphylococcus and Streptococcus). These bacteria have been shown to cause serious urinary tract infections, but are not routinely detected by SUC.
Price et al 2017* showed that compared to expanded culture protocols, SUC missed 50% of pathogenic bacteria in patients with UTI symptoms. This shows that just because E. coli is the most commonly found bug, it doesn’t mean there aren’t other bacteria there, physicians just never had the technology to look for them.
Now, using different methods, researchers have been able to identify different bacteria in the bladder and we are discovering that these bugs are a lot more prevalent than we thought. We now know that the urine is not sterile.
The possibility that the standard test is wrong is one of the biggest reasons that clinicians should take patient symptoms into account. A negative test result does not necessarily mean no UTI is present.
* Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C, Brubaker L, Wolfe AJ, Mueller ER, Schreckenberger PC. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms. J Clin Microbiol. 2016 May;54(5):1216-22. doi: 10.1128/JCM.00044-16. Epub 2016 Mar 9. PubMed PMID: 26962083; PubMed Central PMCID: PMC4844725.
Question: What are the known contributing factors to frequent UTIs?
Dr. Thomas-White’s response:
1. Biofilm
Bacteria in the bladder form a dense 3D community. The bacteria on the outer layers are killed by the antibiotics, but bacteria on the inner layers may survive.
2. Internalization
Some pathogens, like E. coli, can invade the cells of the bladder and live internally. Antibiotics can’t penetrate the cell, so the bacteria are protected and can re-infect.
3. Secondary reservoir
E. coli might be re-infecting the bladder from an outside environment. Maybe coming from the gut, or maybe from another person (like after intercourse).
4. A secondary pathogen
Antibiotics might kill the E. coli, but not kill a secondary pathogen in the bladder, so symptoms remain. This has been shown to happen with Gardnerella. Gardnerella doesn’t cause symptoms itself, but it does cause changes in the epithelium that release internalized E. coli.
5. Your own immune system
Remember, the symptoms don’t come from the bacteria directly. The symptoms are caused by your immune system reacting to what it perceives as a threat. During the first infection, your immune system is learning, and it might respond more strongly the second time around. And if it keeps happening your immune system might be on such a hair trigger that the smallest thing will set it off.
6. Any combination of the above scenarios can happen
And medical science has no way to figure out what is going on in any one person. Yet.
Question: Why are there so few treatment options available for chronic UTI?
Dr. Thomas-White’s response:
In the US, antibiotics are currently the only approved treatment for UTIs. And that is a problem for many reasons. To be clear, I’m a PhD, not an MD, and I can’t give treatment advice. But I can comment on where I think the field needs to go in order to develop more useful therapeutics.
- Testing needs to get more sensitive and a lot faster. To give more targeted treatment, providers need to have better information about the underlying cause of the UTI (exactly which bacterial species) and the underlying cause of the recurrence (biofilm, second reservoir, immune response, etc). Our testing is currently a long way from understanding any of these nuances.
- Once we know that information, we can organize UTIs into different buckets (different etiologies), and treat them individually. Someone in made a comment that “we can treat cancer but we can’t treat UTIs”. Actually, we can treat some cancers, and that is because we have recognized that there are different types of cancer. Governments and the medical community have put a lot of money and research into finding therapies for each type of cancer. So doctors have very specific tools depending on the specific diagnosis. Right now the UTI field has one tool because the assumption is that there is one cause, and we are learning that is simply not the case.
- I would love to give specific information about what to do in a given scenario, but the honest truth is that we don’t know. I recognize how frustrating that answer is to those who are suffering now. But unfortunately, I have no answers, and that won’t change unless more research and more money is dedicated to the problem.
But I am happy to explain the science in any way that I can. I truly believe that the more information a patient has, the better they are at advocating for their own care.
Question: Is there such a thing as a urinary microbiome? If so, what does a healthy urinary microbiome look like?
Dr. Thomas-White’s response:
Yes there is! For decades urine was thought to be sterile, but recent research has shown that there are viable bacteria in the bladders of women. Even women without symptoms.
We are just at the beginning, and more research is needed, but we do know that certain species of Lactobacillus seem to be beneficial. Other bacteria, like E. coli, Staphylococcus, and Streptococcus are more associated with symptoms. And we know that Lactobacillus can kill many UTI-causing bacteria like E. coli.
It is measured using bacterial DNA sequencing of urine, or by using an expanded culture protocol (not standard culture).
Question: Why does a healthy vaginal biome impact UTI?
Dr. Thomas-White’s response:
Because the vaginal and urinary microbiomes are linked. Just like in the bladder a healthy vaginal microbiome is usually composed of Lactobacillus, and if you have Lactobacillus in the vagina, chances are you have Lactobacillus in the bladder.
I like to think of the microbiome as an ecosystem, like a mountain valley, and the bacteria are the plants. The vagina has a lot of nutrients so it is going to have the highest biomass, like the plants that cluster around the stream in a valley.
The bladder is a bit harsher of an environment, say the slopes of the mountains of that valley. Some plants can live both in the valley and on the slopes. And if you plant a flower in the valley, its seed will travel on the wind up the slope and there is a good chance that next spring those same flowers will be found on the slopes.
It is the same idea with the vagina and bladder. If you improve vaginal health by providing Lactobacillus, then there is a good chance that those Lactobacillus bacteria will also get into the bladder.
Question: Is it a UTI or overactive bladder (OAB)?
Dr. Thomas-White’s response:
OAB is thought to be caused by the misfiring of neurons from the brain while UTI symptoms are caused by an immune response to an infection. Symptoms of overactive bladder and symptoms of UTI overlap. Both have frequency, urgency, nocturia, but UTIs are supposed to have signs of inflammation (Leukocytes), pyuria (blood in urine), pain, and a positive urine culture.
But remember, you can still have a UTI even if you have a negative culture. However, if your doctor thinks that your symptoms of urgency are coming from a non-infection source, it might be worth trying OAB medication. Talk to your doctor to be sure.
Question: Which carries more risk: leaving a UTI untreated or taking antibiotics for an extended period?
Dr. Thomas-White’s response:
Believe it or not, untreated UTIs can be fatal. If the bacteria get from your bladder into the kidneys (pyelonephritis) and then cross over into the bloodstream, that can cause sepsis and death. I know antibiotics have terrible side effects on your microbiome, and as a society we need to be careful about them, but the risk of not taking antibiotics is too great! While you are taking antibiotics you can also take steps to strengthen and re-populate your microbiome using prebiotics and probiotics.
Special thanks to Dr Thomas-White for taking the time to answer questions from our community! Sign up to our newsletter below for more updates on UTI research, and watch our expert interviews on YouTube.
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