Is chronic prostatitis/chronic pelvic pain syndrome an infectious disease of the prostate?

For over a hundred years chronic prostatitis was considered an infectious disease of bacterial origin and when antibiotics became available it was believed that it would probably be relegated to the wastebasket of cured diseases [1]. However, despite this promise, antibiotics did not cure most of the patients with prostatitis and with better understanding of microbiology, uropathogenicity and the condition itself, we came to the conclusion that perhaps it was not caused by bacteria or other infectious agents after all. We finally defined the condition of National Institutes of Health (NIH) category III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) by the absence of bacterial infection by a recognized uropathogen identified using traditional culture techniques as a cause for the chronic pain and urinary symptoms. This left the door open to further discoveries that infection might play a role in the etiology or pathogenesis of CP/CPPS (using other methods etc). In fact, it has only been several decades when a disease believed to be due to genetics, increased gastric acidity and stress, was discovered to be due to Helicobacter pylori and gastritis is now treated with appropriate antimicrobial therapy instead of radical surgery. Could there be a microorganism cause for CP/CPPS, but we just cannot identify it? Clinically we isolate uropathogens from voided urine or expressed prostatic secretion on specific nutritive media and under environmental conditions that do not support growth of many possible bacterial species. Chronic bacterial infections have been shown to be associated with a biofilm mode of growth that is highly recalcitrant to antibiotic therapy and difficult to culture [2]. Or could we be missing an unknown (never discovered) or unrecognized organism (perhaps an organism not recognized as a uropathogen) as the cause. Molecular techniques, that do not rely on bacterial growth in vitro, including molecular-phylogenetic approaches based on 16S RNA PCR techniques have resulted in conflicting conclusions regarding the contributions of infectious agents in CP/CPPS [345678910]. We recently reported [11] on the use of next-generation molecular diagnostic Ibis T-5000 Universal Biosensor technology which provides universal and comprehensive identification of all bacterial species present at >1%–3% of the microbiome, to characterize the microbiota of CP/CPPS patients and asymptomatic control subjects recruited within the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network Epidemiological/Phenotyping Study [12]. The Ibis T-5000 Universal Biosensor technology [13] is able to generate a definitive species-level diagnostic for all known bacterial species. In addition, the system allows for a powerful discovery-based approach that was not subject to restrictions based on a priori assumptions of microbial profiles, including a “most-closely-related match” for unknown organisms.

We noted no differences at the species or genus level between CP/CPPS and control participants for VB2 or VB3 samples (or even VB3 - VB1+2 samples). We believe the clinical significance of minor microbiome differences in VB1 remain unclear. The observed specific microbiome differences for Burkholderia cenocepacia (more prevalent in VB1 in CP/CPPS participants compared to controls) and minor differences observed in VB1 for Propionibacterium acnes and Staphylococcus capitis/capare (both under represented in CP/CPPS participants compared to controls) may or may not be clinically insignificant, but they could also indicate a change in the overall species balance. Others have described B. cenocepacia as a pathogen [14], possibly involved in the etiology of CP/CPPS [1516]. Nevertheless, we did not find a putative organism identified with a significant presence in the segmented specimens to identify an important prostatitis pathogen that could account for this condition.

Although we clearly did not identify, the “smoking gun” pathogen, we cannot necessarily say that microbiome differences are not important in CP/CPPS. We did not address microbial immunological memory since chronic inflammation and pain may persist after an offending organism has been cleared [1718]. Various organisms or combinations of organisms, might influence various symptom changes (e.g., flare status) or are associated with select urologic chronic pelvic pain syndrome patients with differing symptom profiles, natural history, and/or underlying biological characteristics. Without biopsy, we may have missed a major impact of biofilm bacteria which in theory may only be detected if there is better mechanical disruption of the biofilm than that obtained by prostate massage. Finally, the microbiome in areas other than the urinary tract, for example in the bowel, may influence the symptoms or clinical phenotypes of men with CP/CPPS [19]. We are addressing some of these issues in the ongoing NIH/National Institute of Diabetes and Digestive and Kidney funded MAPP-2 Clinical Patterns study in which we will be identifying the bacterial, viral and fungal microbiota in the urine and the rectum of CP/CPPS patients and correlating that with symptom patterns, inflammatory biomarkers and even neuroimaging studies over a 2-year period. The story of the role of the microorganism in the men suffering from CP/CPPS is not over yet.