Conditions, Cystitis, Interstitial Cystitis, Overactive Bladder

Intracellular Bacteria: The Hidden Cause of Bladder Problems

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

  1. Coli are responsible for 70-90% of standard urinary tract infections.
  2. 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:

  1. First, the bacteria replicate and change their shape from rod-shape to round cocci and penetrate down to the bladder lining (urothelium).
  2. Then, some of the bacteria enter the cells of the urothelium.
  3. Once the bacteria are in the cell, they stop dividing and enter into a state of hibernation.
  4. The cells that have become colonized send stress signals to the immune system.
  5. The immune system starts an inflammatory response and the bladder becomes inflamed.
  6. 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.
  7. The white blood cells tell the immune system that there’s no problem but the urothelial cells still signal that there is a problem.
  8. The result is chronic low-grade inflammation with pain and white blood cells detectable in the urine.
  9. 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.
  10. The urethra also thickens due to the constant state of inflammation, leading to obstruction and voiding problems.
  11. The bacteria may also develop biofilms under which they can hide.
  12. 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.

Future Treatments

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:

Sources

  • 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.

 

 

5 Comments

  • Reply

    Sheryl Chan

    April 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!

    • Reply

      Layla

      April 22, 2017

      Thanks Sheryl, that’s very kind as always!

  • Reply

    Usha Rani

    April 21, 2017

    Very very thankful for such type of information regarding IC I m suffering till 17 yrs. But the treatment it nuisance disease.

    • Reply

      Layla

      April 22, 2017

      Sorry you’ve been suffering for so long,I hope some of the info helps!

  • Reply

    Nicole McDonald

    May 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.

Leave a Reply