Stool-based biomarkers of interstitial cystitis/bladder pain syndrome

Abstract

Interstitial cystitis/bladder pain syndrome (IC) is associated with significant morbidity, yet underlying mechanisms and diagnostic biomarkers remain unknown. Pelvic organs exhibit neural crosstalk by convergence of visceral sensory pathways, and rodent studies demonstrate distinct bacterial pain phenotypes, suggesting that the microbiome modulates pelvic pain in IC. Stool samples were obtained from female IC patients and healthy controls, and symptom severity was determined by questionnaire. Patients with urologic chronic pelvic pain syndromes (UCPPS) suffer chronic pelvic pain and dramatically lower quality of life, yet diagnostic markers and effective therapies remain elusive for these costly syndromes 1 . Interstitial cystitis/bladder pain syndrome (IC/BPS or IC) is a debilitating UCPPS condition of pelvic pain and voiding dysfunction that afflicts as many as 8 million U.S. women where depression is a common co-morbidity 2-5 . IC etiology remains unknown, but urothelial lesions and lamina propria mast cells are associated with patient symptoms [6][7][8] . HPA axis dysfunction has been implicated in female and male patients and cats with feline IC 9-13 , and thus may be common among UCPPS, but mechanisms that integrate pelvic pain, voiding dysfunction, HPA activity, and depression are lacking. Because of these long-standing questions, NIDDK has launched its flagship urology study, the Multi-Disciplinary Approaches to Chronic Pelvic Pain (MAPP) Research Network with the most comprehensive studies to date of UCPPS including clinical characterization and epidemiologic and mechanistic studies 14,15 . Operational taxonomic units (OTUsThe microbiome is increasingly appreciated as driving diverse physiologic processes in both health and disease 16,17 . With the notable exception of C. difficile colitis, early studies implicated pathogenic dysbioses primarily at the phylum and genus levels, but more recent studies identify individual species associated with disease. Moreover, individual species within the microbiome have recently been associated with driving disease through altered innate metabolism or altered pharmaceutical metabolism 18 . Despite these advances, it remains unclear whether microbiota contribute to pain syndromes generally and to UCPPS in particular. Consistent with the recent finding of a normal female urinary microbiome 19 , the MAPP Network is also exploring UCPPS microbiota with a focus on the urinary microbiome. MAPP Network studies have identified an association between fungi

Questions and challenges associated with studying the microbiome of the urinary tract

“…The mechanisms of OAB are not fully elucidated but there are potential links to microbiome involvement. These include potential contributions at the global level, where constipation is often associated with the condition and that there may be "cross talk" between gut and the bladder (26). It is interesting that UTI's caused by different bacterial types such Enterococcus faecalis, seemingly invoke different pain responses, perhaps indicative of bacterial interference with nociceptive signaling.…”

Gut microbiome and chronic prostatitis/chronic pelvic pain syndrome

“…Whereas bacterial pain phenotypes have been identified in murine models of urinary tract infection, a group from Northwestern University hypothesized that the microbiome of adjacent organs, namely the gut and reproductive tract, might modulate pelvic pain through organ crosstalk visceral sensory pathways (90,91). While analysis of the vaginal microbiome did not yield significant differences between IC/BPS patients and controls, analysis of the stool (gut) microbiome revealed differential representation of specific bacterial species, suggesting that these characteristic changes in the microbiome may lead to use as potential biomarkers for the disease state (92). In an earlier study by the same group, female patients classified as having urologic CPPS were classified by self-report as currently having symptom "flares" (acute worsening of symptoms) versus no flares, and initial and mid-stream urine specimens were collected and microbiomes of urethral and mid-stream urine were analyzed.…”

The effect of the urinary and faecal microbiota on lower urinary tract symptoms measured by the International Prostate Symptom Score: analysis utilising next‐generation sequencing

“…Past studies have seen a relationship between urinary microbiota and urinary symptoms, most of these in females, but very little has been investigated into the effect of the faecal microbiome on urination. Braundmeier‐Fleming et al obtained stool samples from female patients with IC and healthy controls, and determined symptom severity by questionnaire. The authors then used quantitative PCR of stool DNA with species‐specific primer pairs to demonstrate significantly reduced levels of Eggerthella sinensis , Colinsella aerofaciens , Faecalibacterium prausnitzii , Odoribacter splanchnicus , and Lactonifactor longoviformis in microbiota of patients with IC.…”