Interstitial cystitis/bladder pain syndrome research: the answer may be just around the corner

Extracellular and intracellular organisms

There are many similarities between the lining of the genitourinary tract and gastrointestinal tract. Pathologic extracellular organisms have been identified on the cells lining the gastrointestinal tract, but have yet to be been found on the urothelial lining of the bladder. A search for other pathologic extracellular organisms on IC/BPS urothelium using modern investigative techniques may prove enlightening. It may hold the key to identifying at least some etiologies of IC/BPS and could lead to treatments that may dramatically reduce symptoms or possibly lead to a cure.

Familial Crohn’s Disease is a small subset of Crohn’s Disease. Although admittedly a small sample size was used, in 2017, researchers reported the presence of three organisms (Candida tropicalis, Escherichia coli, and Serratia marcescens) on thelining of the gastrointestinal tract, detected using DNA sequencing⁶. Many organisms stick to the lining of the intestines via fimbriae and produce biofilms to protect themselves; thus, allowing these organisms to escape the body’s normal protective immune responses and form an impenetrable barrier to antibiotics. Recently (April 2019), it was shown that the above three organisms were found in elevated amounts in a cohort of patients with Crohn’s Disease and that the use of specific probiotics significantly decreased the number of these pathologic organisms; thereby reducing the amount of inflammation that they caused⁷.

In additional to taking a bladder biopsy, urologic researchers could further investigate IC/BPS patients whose urine cultures are negative, despite the patients being clinically symptomatic. PCR is one such technique. Another would be to take a second sample from these patients, spin down the urine samples, pour off the supernatant, and look at the remaining urothelial cells using a confocal scanning laser microscope to determine whether there are any bacteria or fungi attached to the cells (personal communication with Dr. Mamoud Ghannoum, Case Western Reserve University). If this technique reveals that specific organisms are present on a large number of IC/BPS urothelial cells, and not in controls, larger studies should be reproduced at other medical centers in order to validate this technique.If positive, this may indicate that IC/BPS has an infectious etiology, despite negative urine cultures.

The next step could be to create specific phages (lytic viruses) that could penetrate the biofilms of specific organisms that might be found on these urothelial cells, followed by administration of appropriate antibiotics. This might be one way to cure IC/BPS if extracellular organisms are the cause^8,9.

Mast cells and mast cell activation disease

Mast cells reside in all vascularized tissues of the body, including the bladder. They are generally found in close proximity to blood vessels and nerves. Mast cells contain over 200 types of granules/mediators. The hypothesis that inappropriate chronic mast cell activation may be an integral element, and perhaps even the root cause of IC/BPS in at least some patients, should be considered and revisited employing updated techniques^10–13. The mast cell biopsy should be re-evaluated in the field of IC/BPS using the stain most specific for mast cells, CD117. In addition, an accurate measurement of the levels of these mast cell granules (e.g. tryptase, histamine, N-methylhistamine, heparin and prostaglandin D2, among others) many of which have quite short half-lives and great thermolability) in urine samples has been quite challenging to determine and should be re-assessed^14–16.

This hinders or even renders impossible, the ability to demonstrate in the IC/BPS population that mast cell activation exists. Laboratory techniques have improved with time and assessment of IC/BPS patients for biochemical evidence of mast cell activation is becoming more feasible, especially using CD117 staining^10–13. Although a paper published in 2015 addressed a great deal of research on mast cells and mast cell activation syndrome (MCAS), it was not specific for IC/BPS¹⁷.

If mast cell mediators can be consistently found in the urine of IC/BPS patients, then inappropriate mast cell content release might explain the etiology of IC/BPS patients, or at least one etiology of IC/BPS. This might provide additional means for diagnostic testing and/or be a marker for the condition. It may also point towards more effective treatment directed at specific inflammatory mast cell mediators, reduce time to diagnosis, and provide the basis for at least one component of a classification system for the disease.

Simply relying on the number of mast cells seen on biopsy is not enough. The number of mast cells may not be as important as their level of activation and/or degranulation. Mast cells may be hyper-responsive and degranulate more frequently in response to variable trigger stimuli or may selectively release specific inflammatory mediators in response to a certain type of stimulus. The release of inflammatory mediators without degranulation of the mast cell may also occur^10–13. Proper histochemical and/or immunohistochemical staining of biopsied tissue is critical for revealing the mast cells therein, as these cells usually cannot be recognized as mast cells with routine hematoxylin and eosin staining, instead being mistaken for other types of cells such as lymphocytes or macrophages. The best staining for mast cells is CD117 immunohistochemical staining, which is independent of the mast cell’s state of activation and is seen brightly on mast cells (a pattern seen on virtually no other cells). Certain other histochemical stains, such as tryptase and toluidine blue, have long been used by pathologists to identify mast cells. However, these stains principally target the mast cells’ granules; thus, they may not be as revealing for MCAS as CD117 can be, given that MCAS is a disease whose dominant feature is inappropriate mast cell activation and whose cellular-level pathology is dominated by mast cell degranulation, including complete degranulation which leaves an ‘empty’ cell that can be identified^10–13.

Mast cells and transgranulation

In addition to degranulation, mast cell contents are able to transgranulate to nerves via the formation of filipodia (thin, finger-like projections) that attach directly to the neuronal membranes of nerves, including nerves within the bladder. The contents of the mast cells empty directly into the nerve cells via endocytosis. Transgranulation of mast cell contents to nerves in the brain was shown via time-lapse photography using an electron microscope in 2005¹⁸. It is possible that sensory nerves in the bladder are triggered by mediators released from mast cells (either in the bladder, elsewhere or both), generating impulses that travel to the spinal cord and, from there, to the pain centers in the brain. This may be an explanation for the pelvic pain symptoms seen in many patients with IC/BPS.