The TL;DR for this article
- What IC/BPS actually is, and why "cystitis without a classic urinary tract infection" is a condition in its own right
- The two subtypes (Hunner vs. non-Hunner) and what distinguishes them
- Bacterial or not? What the research says about the bladder microbiome
- Why the bladder is full of (activated) mast cells, and how this leads to a particular kind of pain
- The cycle question: why "estrogen is to blame" falls short
- Distinguishing IC/BPS from MCAS
- Workshop info on recurrent cystitis
In clinical practice, women in particular, but also men (though less often), repeatedly present with recurrent cystitis and chronic bladder pain. Usually multiple treatments have already taken place, such as repeated courses of antibiotics, sometimes even long-term continuous use of an antibiotic, and yet the situation still cannot be brought under control. Sometimes it only feels like classic bacterial inflammation, but no bacteria are (any longer) detectable... and that is where two possible suspects come in: histamine as a tissue hormone on the one hand, and mast cells as an immunological first-line defense with multiple mediators on the other.
This article is about a lot of "whys": Why are people with MCAS or histamine intolerance affected by bladder problems at an above-average rate? What actually happens in the bladder wall when too many mast cells are present and too much histamine is released? And why is there an overlap with "chronic bladder pain syndrome" / interstitial cystitis (abbreviated IC/BPS for interstitial cystitis / bladder pain syndrome)?
It also briefly addresses why, pathophysiologically, bacterial infections too could be more common in people with MCAS than in the rest of the population. Important: as always, this is prepared scientifically for your information, but does not replace treatment by qualified medical professionals.
What exactly is IC/BPS?
IC/BPS is a diagnosis of exclusion and means chronic bladder pain or pressure lasting at least six weeks, accompanied by urinary urgency or frequent urination, without an infection or another identifiable cause (stones, tumor, radiation cystitis, etc.) being present. The name still dates back to a time when a uniform inflammation of the bladder tissue was assumed. By now, even interstitial cystitis can be divided into at least two types.
Hunner lesion vs. non-Hunner
During cystoscopy, that is, examination of the bladder with a scope, a portion of those affected show so-called Hunner lesions, meaning a reddened area of mucosa with characteristic vascular changes that tear and bleed easily when the bladder is distended. According to current understanding, this subtype is an inflammatory disease with detectable B-cell infiltration and epithelial damage. How commonly it occurs varies strongly between studies. In most investigations, however, the majority of IC/BPS patients show no Hunner lesion, but rather often barely visible abnormalities on cystoscopy. In this latter group, central nerve sensitization appears to be in the foreground. [1-4]
Interesting for us: one histopathological study found the stronger mast cell infiltration and fibrosis rather in the non-Hunner type, while the Hunner type stood out above all through pronounced inflammation and epithelial damage, though many other investigations produced exactly the opposite picture. [4] This shows, once again, how complex these syndromes are, and it seems plausible that each person likely has an individual disease process with an inflammatory signature that is particular to them.
Prof. Theoharides and other authors described, as early as the early 2000s, a probable increased mast cell activation and mast cell count in both types, and pointed out that it also depends on where the mast cell count is measured, that is, for example in the muscle (detrusor) versus the mucosa. [4, 10]
Bacterial cystitis or not?
Classically, IC/BPS is also referred to as "abacterial cystitis," because the diagnosis requires a negative standard urine culture. But this does not mean the bladder is actually sterile. With more sensitive, culture-independent methods (16S rRNA sequencing, extended culture techniques), a distinct "female urinary microbiome" can by now be detected in around 80% of all women. [5]
Similar to, for example, people with gut complaints in the broader sense, people with bladder pain sometimes show a lower microbial diversity and an altered composition of the microbiome compared to controls. However, no single germ can be found that could be blamed for the problem: the results vary between studies, sometimes an altered Lactobacillus frequency stands out, sometimes other genera, sometimes there is no significant difference from controls at all. [6,7]
The origin is presumably often the gut-bladder axis: with a disrupted gut barrier, immunosuppression, frequent antibiotic use, or surgical procedures, bacteria from the gut (and, via proximity, also from the vaginal flora) can migrate into the urinary tract, whereby repeated antibiotic use can itself contribute to the problem, because it also reduces the protective microbiota. [8] Concrete, guideline-based treatment approaches for this dysbiosis do not exist so far; individual approaches currently under research are addressed in the article on the treatment of chronic cystitis.
Histamine-producing gut flora and recurrent urinary tract infections: a recent study
Interesting for people with histamine intolerance or MCAS: a recent investigation of 188 women found a direct connection between histamine-producing gut dysbiosis and recurrent lower urinary tract infections. The actual histamine producers were bacteria like E. coli, Enterobacter spp., and Clostridium spp. (via the enzyme histidine decarboxylase), alongside a simultaneous decline in the protective Lactobacillus and Bifidobacterium strains. Candida albicans did occur more frequently within the same dysbiosis, but according to current knowledge does not itself produce histamine: the study describes its contribution as indirect, via metabolic products and a promoted gut permeability that can facilitate the uptake of histamine into the blood. [9] The altered microbiota may therefore supply additional histamine here, as a further driver of the ongoing inflammation.
IC/BPS is by definition an inflammation without pathological germs, but there is also an increased susceptibility to genuine bacterial, culturally detectable urinary tract infections in people with immune systems that are not functioning optimally. For example, the same cycle-dependent immunosuppression described further below in the hormone section, or indeed the altered microbiome described in the previous paragraph, could play a role in recurrent bacterial cystitis.
Nonetheless, the connections between hormones, mast cells, and immune defense, as well as the bladder microbiome, can therefore also be of interest for the bacterial urinary tract infection group, and may possibly provide starting points for a conversation with urological professionals.
Mast cells in the bladder
Mast cells are located throughout the body, but unevenly distributed. Particularly densely populated, "infiltrated" in medical jargon, are often mucous membranes and certain organs.
In people with IC/BPS, this density is not simply "increased," but, based on several investigations, actually markedly higher than in control subjects. The European specialist society ESSIC has even made a diagnostic criterion out of this: more than 28 mast cells per mm² in the detrusor are considered typical for IC/BPS with Hunner lesions. [11]
What is decisive here is not just the sheer number, but the activation state. In an older but widely cited investigation, over 90% of the mast cells in IC patients were activated or already degranulated, while in control subjects the mast cells were almost exclusively intact. [12]
How histamine amplifies pain signals
Here it becomes concrete for understanding the symptoms. When mast cells in the bladder wall degranulate, they release histamine: here histamine does not act as in an allergy, with itching or wheals, but directly on the nerve endings that supply the bladder. It is easy to imagine how this also helps explain the painfulness and burden of this condition.
For anyone interested in more detail: a previous article, written several years ago, covers the connection and above all the unfavorable "collaboration" between mast cells and nerve cells in itching.
Via the histamine H1 receptor, so-called TRPV1 channels on the sensory nerve fibers of the bladder are sensitized. The result: these nerves react even at normal bladder filling, which should not yet represent a distension perceived as painful. [13, 14] The bladder, in a sense, "learns" to respond to lower stimulus thresholds with pain.
On top of this comes a self-reinforcing cycle: sensitized nerves themselves release substance P and other neuropeptides, which in turn can stimulate mast cells to degranulate: mast cells and nerve cells egg each other on. [15] In the specialist literature this is called neurogenic inflammation, and it is one of the reasons IC/BPS pain is so persistent and difficult to break.
The hormone question is complicated
Women are affected by IC/BPS considerably more often than men, and many report a worsening before or around menstruation. The obvious explanation, which one often reads or which is spread via social media, goes roughly as follows: "estrogen activates mast cells, so high estrogen is the problem." However, this often falls short.
If pure estrogen were the driver, the follicular phase, that is, the first half of the cycle, with its estrogen peak, would actually have to be the most symptom-rich... Clinically, however, the opposite is often the case.
Two lines of explanation seem more plausible, though the state of research here is anything but settled:
For one, the histamine buffering capacity itself could fluctuate cyclically. An investigation in healthy women found higher diamine oxidase values (DAO, the enzyme that breaks down histamine) in the luteal phase compared to the follicular phase, in keeping with the rise in progesterone. [16] If progesterone drops perimenstrually, the DAO buffering capacity could drop in parallel at exactly the moment when, locally in the pelvis, prostaglandins rise for menstruation itself and are known to be able to irritate mast cells and pain nerves.
For another, progesterone is locally immunosuppressive and shifts the immune response toward a Th2-dominated, overall less defensively robust profile. A systematic review even finds a "window of vulnerability" after ovulation, in which immune defense is dampened overall by progesterone. [17] This could plausibly explain why, in this phase of the cycle, more room arises for pathogenic or opportunistic germs in the gut, vaginal, and bladder flora, which could in turn trigger mast cells... But precisely for the hypothesis relating to the bladder, no scientific investigation has yet been found; and at the same time, progesterone can also stabilize mast cells... Our biology is, unfortunately, genuinely complex.
Both models do not exclude one another, and explain better than the pure "estrogen-triggers-mast-cells narrative" why the follicular phase, despite high estrogen, often runs with fewer symptoms for patients. The actual interplay of cycle, hormones, and mast cells will be given its own, deeper article.
Ideas or questions about this? Then please write in the comments... and the gentlemen have not been forgotten either: chronic prostatitis, which can likewise be connected to mast cell disorders, will also be examined.
Where IC/BPS and MCAS overlap, and where they do not
Mast cell involvement in IC/BPS is well documented. Nonetheless, it is important not to equate the two: not every interstitial cystitis is an expression of a mast cell activation syndrome, and not every MCAS leads to bladder symptoms. What the literature shows is a clear clustering of comorbidities: quite a few IC/BPS patients additionally name irritable bowel syndrome as one of their most common accompanying conditions, and migraine is also very common. [18] This fits the typical MCAS picture of multiple affected organ systems, but is not proof of a common mechanism in every individual case.
In practice, it is therefore worth watching the overall picture: do the bladder complaints occur together with other histamine- or mast-cell-associated symptoms, such as flushing, irritable bowel, or intolerances that worsen in flares? Does the bladder react to the same triggers as other organs (certain foods, stress, infections)? These are the indications that justify a differentiated workup in the direction of MCAS, rather than treating the symptoms in isolation as "just urological."
What this means for treatment
If the disease mechanism is based on increased, activated mast cells and histamine-driven nerve sensitization, then it could therapeutically be concluded that one should address the mast cell activity itself, lower the stimulus threshold of the nerves, and support the damaged protective layer of the bladder. What this could concretely look like in an evidence-based, naturopathic way can be found in the article on the treatment of interstitial cystitis.
References
[1] Whitmore KE, Fall M, Sengiku A, Tomoe H, Logadottir Y, Kim YH. Hunner lesion versus non-Hunner lesion interstitial cystitis/bladder pain syndrome. Int J Urol. 2019;26(Suppl 1):26-34. doi:/10.1111/iju.13971
[2] Maeda D, Akiyama Y, Morikawa T, et al. Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation. PLoS One. 2015;10(11):e0143316. doi:10.1371/journal.pone.0143316
[3] Horie M, Akiyama Y, Katoh H, et al. APRIL/BAFF upregulation is associated with clonal B-cell expansion in Hunner-type interstitial cystitis. J Pathol. 2024;264(4):383-395. doi:/10.1002/path.6353
[4] Kim A, Han JY, Ryu CM, et al. Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion. Histopathology. 2017;71(3):415-424. doi:10.1111/his.13235
[5] Jacobs KM, Price TK, Thomas-White K, Halverson T, Davies A. Cultivable Bacteria in Urine of Women With Interstitial Cystitis: (Not) What We Expected. Female Pelvic Med Reconstr Surg. 2021;27(5):322-327. doi:10.1097/SPV.0000000000000854
[6] Nickel JC, Stephens-Shields AJ, Landis JR, et al; MAPP Research Network. A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network. J Clin Med. 2019;8(3):415. doi:10.3390/jcm8030415
[7] Fu C, Zhang Y, Liang L, Lin H, Shan K, Liu F, Feng N. The microbiota in patients with interstitial cystitis/bladder pain syndrome: a systematic review. BJU Int. 2024;134(6):869-880. doi:10.1111/bju.16439
[8] Choi HW, Lee KW, Kim YH. Microbiome in urological diseases: Axis crosstalk and bladder disorders. Investig Clin Urol. 2023;64(2):126-139. doi:10.4111/icu.20220357
[9] Ruța F, Avram C, Mardale E, Maior R, Filip C, Nemeth S. Histamine-Producing Intestinal Dysbiosis and Its Role in Lower Urinary Tract Infections and Irritable Bowel Syndrome in Young Women. Nutrients. 2026;18(1):16. doi:10.3390/nu18010016
[10] Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology. 2001;57(6 Suppl 1):47-55. doi:10.1016/s0090-4295(01)01129-3
[11] Regauer S. Mast cell activation syndrome in pain syndromes bladder pain syndrome/interstitial cystitis and vulvodynia. Transl Androl Urol. 2016;5(3):396-397. doi:10.21037/tau.2016.03.12
[12] Theoharides TC, Sant GR, el-Mansoury M, Letourneau R, Ucci AA Jr, Meares EM Jr. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol. 1995;153(3 Pt 1):629-636.
https://pubmed.ncbi.nlm.nih.gov/7861501/
[13] Grundy L, Caldwell A, Garcia Caraballo S, et al. Histamine induces peripheral and central hypersensitivity to bladder distension via the histamine H1 receptor and TRPV1. Am J Physiol Renal Physiol. 2020;318(2):F298-F314. doi:10.1152/ajprenal.00435.2019
[14] Shan H, Zhang EW, Zhang P, Zhang XD, Zhang N, Du P, Yang Y. Differential expression of histamine receptors in the bladder wall tissues of patients with bladder pain syndrome/interstitial cystitis – significance in the responsiveness to antihistamine treatment and disease symptoms. BMC Urol. 2019;19(1):115. doi:10.1186/s12894-019-0548-3
[15] de Groat WC, Yoshimura N. Afferent Nerve Regulation of Bladder Function in Health and Disease. Handb Exp Pharmacol. 2009;(194):91-138. doi:10.1007/978-3-540-79090-7_4
[16] Hamada Y, Shinohara Y, Yano M, et al. Effect of the menstrual cycle on serum diamine oxidase levels in healthy women. Clin Biochem. 2013;46(1-2):99-102. doi:10.1016/j.clinbiochem.2012.10.013
[17] Zwahlen M, Stute P. Impact of progesterone on the immune system in women: a systematic literature review. Arch Gynecol Obstet. 2024;309(1):37-46. doi:10.1007/s00404-023-06996-9
[18] Jhang JF, Kuo HC. Pathomechanism of Interstitial Cystitis/Bladder Pain Syndrome and Mapping the Heterogeneity of Disease. Int Neurourol J. 2016 Nov;20(Suppl 2):S95-104. doi: 10.5213/inj.1632712.356. Epub 2016 Nov 22. PMID: 27915472; PMCID: PMC5169097.
