There is new(ish) evidence emerging that recurrent UTIs, also known as chronic cystitis, are not always caused by a reinfection with a new pathogen but rather can be a relapse of the same pathogen.
It turns out that pathogenic bacteria have the ability to invade the cells of the bladder and live there in a dormant sleep-like state.
This is called an ‘intracellular bacterial community’.
In this state, the bacteria remain undetected by standard urine testing and unaffected by antibiotic treatment. They also remain undetected by our own immune system.
Now and again they can leave the cells, causing a relapse of the urinary tract infection.
This is a similar scenario to biofilm infections and often both may be present at the same time.
How Intracellular Bacterial Communities form
- Coli are responsible for 70-90% of standard urinary tract infections.
- Coli bacteria are the main pathogens capable of forming intracellular bacterial communities but they may not be the only ones. S. saprophyticus, K. pneumoniae and Salmonella enterica have also been indicated, although the mechanism by which they do so may differ from E. coli.
The simplified mechanism of how intracellular bacterial communities of E. coli form looks like this:
- First, the bacteria replicate and change their shape from rod-shape to round cocci and penetrate down to the bladder lining (urothelium).
- Then, some of the bacteria enter the cells of the urothelium.
- Once the bacteria are in the cell, they stop dividing and enter into a state of hibernation.
- The cells that have become colonized send stress signals to the immune system.
- The immune system starts an inflammatory response and the bladder becomes inflamed.
- White blood cells arrive at the urothelium to deal with the infection but fail to detect a problem because the bacteria are hidden in the cells.
- The white blood cells tell the immune system that there’s no problem but the urothelial cells still signal that there is a problem.
- The result is chronic low-grade inflammation with pain and white blood cells detectable in the urine.
- The urothelium thickens to protect itself with a barrier (much like other skin thickens when constantly exposed to stress). This diminishes bladder capacity. Since the bacteria are still hidden in the cells, this is of little use.
- The urethra also thickens due to the constant state of inflammation, leading to obstruction and voiding problems.
- The bacteria may also develop biofilms under which they can hide.
- The bacteria may become filamentous, meaning they form long strands of bacteria that can interlink. This allows the bacteria more protection from the host’s immune system.
Not all pathogens are able to form intracellular communities. However, they may become able to do so in cases of mixed infections where a second pathogen is also present.
The Mechanism behind Relapsing UTIs
The immune systems tries to get rid of the intracellular infection by shedding the top layer of urothelial cells.
Unfortunately, some of the bacteria can actually get into the lower cells of the urothelium (which is about 5 cells deep). The lowest cells take around 100 days to get to the top and therefore shedding the top layer will not get rid of all the bacteria.
Furthermore, when a cell is shed the bacteria can detect that they are in a free floating cell that is dying. Therefore, they escape the cell, change their shape back to rod-shape and start to replicate again.
Continued division of the bacteria causes an acute flare of cystitis.
Moreover, the replicated bacteria can start the whole process of intracellular colonization afresh.
How Pathogens avoid the Immune System
Bacteria can adapt to ensure their best survival chances. Hence they tend to find ways around our immune systems that can allow them to survive in our body.
The bladder lining has receptors on it that detect certain molecules on pathogens and mount an immune response that includes the release of certain chemicals that deal with the elimination of pathogens.
Unfortunately, some pathogens are able to suppress these chemicals and are able to down-regulate a gene that plays a role in the production of these chemicals.
Pathogens may also have a special appendage (pili) that allows them to adhere to the urothelium.
Why are Intracellular Bacteria so hard to treat?
As soon as bacteria manage to enter the cells and/or produce biofilms, they are ‘shielded’ from both the host’s immune system and antibiotics.
When they are dormant they also stop reproducing. Bacteria that are reproducing are easier to kill with antibiotics.
Long-term antibiotic therapy with the same agent also often creates resistance, making the drug useless.
Testing and Treatment Options
The presence of white blood cells in the urine is the best indicator for hidden infections.
Short courses of broad-spectrum antibiotics may not be very effective in treating these types of infections.
They can wipe out all the bacteria in the bladder whilst leaving the intracellular bacteria unscathed.
The protective bacteria in the bladder may become weakened, allowing the re-emerging pathogens even better control over the situation.
This is still the standard treatment and most doctors may not know about intracellular bacteria or biofilms.
Some specialists advise early aggressive targeted antibiotics treatment that is continued until all symptoms are eradicated. The dosage is increased whenever the intracellular pathogens re-emerge.
If you can’t find a specialist that knows about these type of infections it may help to pass some of the below cited research on to your doctor.
Natural agents that inhibit bacterial adherence such as PACs from cranberry extract and D-Mannose may also help reduce the chance of bacteria getting into the cells.
Some natural antibiotics may also be helpful – this is something I will investigate in future articles.
Interstitial Cystitis, Overactive Bladder and Intracellular Bacterial Communities
Interstitial cystitis and overactive bladder are both symptom complexes, not diseases as such, that often rely on negative urine tests for diagnosis. They share the symptoms of urgency, frequency and nocturia. Pain is the hallmark symptom for interstitial cystitis.
Many sufferers of these conditions initially developed one or more UTIs or have suffered from UTIs in childhood.
In the chronic state of inflammation that arises from intracellular bacterial communities, the blood vessels in the urothelium become dilated, which is a normal part of the immune system’s inflammatory response.
This will make the bladder wall look red and inflamed – very much like the pictures we see of a bladder affected by interstitial cystitis.
In studies, quite a few sufferers of these ‘conditions’ have seen improvement on an intensive antibiotic treatment plan over several weeks, which hints at the possibility of hidden infections as the root cause.
However effective antibiotic therapy may be, it will usually also negatively affect the beneficial bacteria in our body.
I personally started having the worst problems after repeated broad-spectrum antibiotics. It took me years and a lot of money and time to get my bladder and gut back to baseline.
There is some evidence that beneficial bacteria help protect us against invading pathogens.
For example, by-products of Lactobacilli bacteria can downregulate the ability of pathogens to adhere to the urothelium.
Some probiotics for the urinary tract are already showing promise.
Some researchers suggest that in the future the approach for treating chronic UTIs could shift from antibiotic to probiotic therapy.
By boosting the good, we may be able to out crowd the bad!
Do you think you may be affected by intracellular infections? Let me know in the comments!
Pin it for later:
- Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ. Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med. 4:e329. doi:10.1371/journal.pmed.0040329.
- Elliott, T. S., L. Reed, R. C. Slack, and M. C. Bishop. Bacteriology and ultrastructure of the bladder in patients with urinary tract infections. J. In- fect. 11:191–199.
- S. Justice, C. Hung, J.A. Theriot, D.A. Fletcher, G.G. Anderson, M.J. Footer, S.J. Hultgren, Differentiation and developmental path- ways of uropathogenic Escherichia coli in urinary tract pathogenesis, Proc. Natl. Acad. Sci. USA 101 (2004) 1333–1338.
- D. Schilling, R.G. Lorenz, S.J. Hultgren, Effect of trimethoprim- sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli, Infect. Immun. 70 (2002) 7042–7049.
- Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ. Intracellular bacterial biofilm-like pods in urinary tract infections. Science 301:105–107.
- Mulvey, J.D. Schilling, S.J. Hultgren, Establishment of a persis- tent Escherichia coli reservoir during the acute phase of a bladder infection, Infect. Immun. 69 (2001) 4572–4579.
- Mysorekar IU, Hultgren SJ. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc. Natl. Acad. Sci. U. S. A. 103:14170–14175.
- Garofalo CK, Hooton TM, Martin SM, Stamm WE, Palermo JJ, Gordon JI, Hultgren SJ. Escherichia coli from urine of female patients with urinary tract infections is competent for intracellular bacterial community formation. Infect. Immun. 75:52–60.
- Rosen DA (2008) Utilization of an intracellular bacterial community pathway in Klebsiella pneumoniae urinary tract infection and the effects of fimK on type 1 pilus expression. Infect Immun 76: 3337-3345. doi: 10.1128/IAI.00090-08. PubMed: 18411285.
- Berry R E, Klumpp D J, Schaeffer A J. Urothelial cultures suppor intracellular bacterial community formation by uropathogenic Escherichia coli. Infection and Immunity. 2762-2772.
- Hultgren S J, Porter T N, Schaeffer A J, Duncan J L. Role of type 1 pili and effects of phase variation on lower urinary tract infections produced by Escherichia coli. 1985. Infection and Immunity. 50 (2) 370- 377.
- Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells.EMBO J. 19:2803–2812.
- Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn J L, Malone-Lee J. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract. 51(7) 2054-2062.
- Khasriya R, Ismail S, Wilson M, Malone-Lee J. Caught inflagrante- bacteria from OAB patients invade urothelial cell lines. International continence society abstracts. 443.
- Khasriya R, Ismail S, Wilson M, Malone-Lee J. A new aetiology for OAB: Intracellular bacterial colonization of urothelial cells. . 2011. International continence society abstracts. 438.
- Yige Bao, Blayne Welk, Gregor Reid & Jeremy P Burton Role of the microbiome in recurrent urinary tract infection Novel Insights into Urinary Tract Infections and their Management, Future Medicine 2014, p. 49-59
- Bladder Action UK How cUTI Forms 2007 http://www.bladderaction.org/about-cuti/how-cuti-forms/
- Justice SS, Hunstad DA, Seed PC, Hultgren SJ. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(52):19884-19889. doi:10.1073/pnas.0606329104.
- Scott VCS, Haake DA, Churchill BM, Justice SS, Kim J-H. Intracellular Bacterial Communities: A Potential Etiology for Chronic Lower Urinary Tract Symptoms. Urology. 2015;86(3):425-431. doi:10.1016/j.urology.2015.04.002.
Sheryl ChanApril 20, 2017
Such a good read, and so well researched. Seriously I don’t know else can make such a topic so interesting! Keep it up!
LaylaApril 22, 2017
Thanks Sheryl, that’s very kind as always!
Usha RaniApril 21, 2017
Very very thankful for such type of information regarding IC I m suffering till 17 yrs. But the treatment it nuisance disease.
LaylaApril 22, 2017
Sorry you’ve been suffering for so long,I hope some of the info helps!
Nicole McDonaldMay 29, 2017
It makes complete sense. I had recurrent UTI’s as a child and IC began 10 years ago for me after an UTI. Most IC treatments don’t work on me. This could be the problem.
LindsayJanuary 30, 2018
Omg my daughter has this!! We were just at her urologist today!!! Started low grade antibiotic therapy and a probiotic….will be having an ultrasound and seeing an infectious disease doctor at Duke in a few weeks. Her doctor thinks this is what may be happening with her…20 trips to ER since June….but it started six years ago with 8 trips to ER in 10 days….so looking forward to seeing where this leads….
LaylaJanuary 30, 2018
I hope you can resolve it!
JackieOctober 7, 2018
I live in South Carolina. Recently diagnosed with IC. Did you have any luck at Duke?
UnnVApril 10, 2018
I’m desperate. I’ve been suffering from constant urge for years now and it’s even gotten more painful. I’m hoping I’ll find a resolution after bringing this info to my doctor. They rarely know what to do after the urine tests are negative and none of the meds for IC works.
LaylaApril 12, 2018
Yes, official guidelines have not changed to reflect this. I’d take the studies to your doctor (rather than my blog post). Good luck!
ChazMay 9, 2018
Hi, could you possibly give me a little more information on the probiotics that can be used to help the urinary tract? When you say that it took you a long time after having repeated broad-spectrum antibiotics – how did you get your bladder and gut back to baseline? Also when you say you were at your worst after them – what do you mean by that? Do you mean that you were getting more infections p, symptoms were worse and felt ill etc? Sorry for all the questions, I’m just trying to see if I’m in the same place as you were and if intracelluar bacteria relate to me.
Thanks so much! XxxX
LaylaMay 9, 2018
Hi Chaz, have you read my post on probiotics? It gives more details on different strains that have been researched: http://bladder-help.com/probiotics-urinary-tract
My bladder went back to baseline after 6 months on the GAPS elimination diet, but my gut didn’t quite. I still have some issues now although am much better – mainly by still eating a paleo type diet and incorporating prebiotic fibres into my diet. Vitamin C has also helped quite a bit (high dose). It took a long time and a lot of trial and error.
After antibiotics I had really bad IBS – lots of bloating, diarrhoea or constipation, cravings, brain fog etc as well as a constant pain and pressure in the bladder (compared to normal UTIs that come and go).
Hope that helps!
KimberlyMay 24, 2018
Yes, this makes total sense to me! I would be interested in knowing more about natural antibiotics but something else came to mind also.
It seems as though some type of bladder irrigation using Anti Biofilms should be fairly easy to come up with. Has there been any trial studies of this type of therapy yet??
Cheryl VitulloFebruary 25, 2019
Since age 20, I would have 1-2 UTI’s a year. Now I have recurrent UTI’s. They always used to culture out as e.coli and were responsive to the usual antibx but about 3 yrs ago klebsiella pneumonai entered the picture. I am now colonized with it and it is resistant to all oral antibiotics and most IV antibiotics. 2 yrs ago I had 28 doses of IV Zosyn which provided about 6 mos. of glorious freedom from symptoms, that is once I got over the C. diff it caused. Cystoscopy showed follicular cystitis. Infectious disease doc says available IV meds will do more harm to my kidneys that the good they will provide since the problem will return. Some days are bearable, others are not. I live on pyridium, hydrocodone when I can get it, Ellura, and more recently CBD oil. It’s not a delightful scenario.
K SmithMarch 19, 2019
This has to be me! I have suffered for years and years, throughout my childhood and into adulthood. About 2 years ago I got so fed up of visiting the doctors and taking endless antibiotic treatments I just stopped and decided to live through the next ‘infection’ as long as I could even if it meant becoming so ill I’d need to be sent to hospital. It sounds ridiculously extreme but I just reached the end of my tether. I get flare ups, that are now much less frequent and can usually be associated with diet. I took a probiotic approach too which I do believe also supports me. What has changed for me in the last year is the urge to go. I don’t get those signals. I think years of ‘cystitis’ calling me to the loo meant I got so good a suppressing the urge it doesn’t happen. I tend to go regularly anyway bit if I do forget I get a massive headache, once I’ve had a wee it’s gone! I’m glad to finally find freedom from antibiotics and can live with my condition. I know what works for me.
Lisa MarieMarch 22, 2019
Hi, I share your pain. For me, everything started about 1 year ago after having sex with a new partner. I had a classic UTI, with pain, urgency, and frequency – a 3day course of Nitrofurantonin helped. Three month and a sad attempt at having sex later, another UTI which again was treated with Nitro – the urgency and frequency went away, but since then I’m having the most sensitive urethra ever. The bladder per se seems fine, but touching or pressing against the urethra (e.g. when taking a vaginal swab or contracting the muscles down there) results in a lot of pain that stays for days. Again, no urgency or frequency issues. Is that similar to what you have too? Doctors find nothing in my urine. My urethra feels inflamed and sensitive and I can’t have sex at all. I’m 34 and before that I’ve only ever had 2 UTIs my entire life, last one 10 years ago. I can’t stop but thinking that the dismissal of the contraceptive pill two years ago plays into my misery. I always had an intact bladder when on the pill, since I stopped, I felt that my urethra got more sensitive.
I’m scared to take long term antibiotics because I’m prone to getting thrush.
One more thing – has anyone of your ever been diagnosed with Ureaplasma Urealyticum? I’m positive but some docs say there’s no real evidence for a connection to recurrent UTIs. Any thoughts?
Carolyn FondrenJune 6, 2020
Hello I’ve had IC for over 30 years now. With age unfortunately the symptoms just get more intense. Still after so many years there is no cure. I actually had a male doctor tell me “ If this were a predominatly male disease, there would be a cure by now.” Sad but true. Antibiotics make it worse of course so I take viramins and probiotics to help. Your article if very interesting and spot on. Read something about this quite a while ago, others have come close just as you have. So it still baffles me as to why medical science isn’t finding a way around this nasty biofilm bacteria. Thank you for your intelligent and well informed article, this is a keeper!