scholarly journals Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain

2021 ◽  
Author(s):  
Afrida Rahman-Enyart ◽  
Wenbin Yang ◽  
Ryan E. Yaggie ◽  
Bryan White ◽  
Michael Welge ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Pelvic Pain ◽  
Gut Microbiome ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Wild Type ◽  
Oral Gavage ◽  
Bladder Pain ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

ABSTRACTDysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or “IC”) is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a “leaky gut” phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

scholarly journals Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain

2021 ◽  
Author(s):  
Afrida Rahman-Enyart ◽  
Wenbin Yang ◽  
Ryan E. Yaggie ◽  
Bryan A. White ◽  
Michael Welge ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Pelvic Pain ◽  
Gut Microbiome ◽  
Bladder Pain Syndrome ◽  
Wild Type ◽  
Oral Gavage ◽  
Bladder Pain ◽  
16S Sequencing ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We identified the locus encoding acyloxyacyl hydrolase, Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and a "leaky gut" phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.

scholarly journals Acyloxyacyl Hydrolase Regulates Microglia-Mediated Pelvic Pain Through Toll-Like Receptor-4

2021 ◽  
Author(s):  
Afrida Rahman-Enyart ◽  
Ryan E. Yaggie ◽  
Wenbin Yang ◽  
Justin L. Bollinger ◽  
Deborah R. Winter ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pelvic Pain ◽  
Microglial Activation ◽  
Pain Syndrome ◽  
Brain Regions ◽  
Bladder Pain Syndrome ◽  
Bladder Pain ◽  
Tlr4 Activation ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

ABSTRACTInterstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating condition of chronic pelvic pain and urinary dysfunction. We have shown that mice deficient for the lipase acyloxyacyl hydrolase (AOAH) develop pelvic allodynia and exhibit symptoms and comorbidities consistent with IC/BPS, as well as gut dysbiosis. Microglia are resident immune cells of the central nervous system (CNS) that respond to changes in the gut microbiome, and studies have linked microglial activation to neuropathic pain. Additionally, microglia express toll-like receptors (TLRs), including TLR4, which are activated by microbial components. We have previously shown that AOAH-deficient mice exhibit increased gut permeability, suggesting a possible mechanism of microglial TLR4 activation via translocation of microbial products across the intestinal barrier to the brain. Here, we assessed the role of AOAH and TLR4 in microglial activation and pelvic pain. AOAH immunoreactivity co-localized with the microglial marker P2YR12 but not astrocytes, suggesting a functional role for AOAH in microglia. Pharmacologic ablation of CNS microglia with PLX5622 resulted in decreased pelvic allodynia in AOAH-deficient mice and resurgence of pelvic pain upon drug washout. Aligned with microglial activation, we observed altered cytokine abundance in Aoah−/− cortex that was reduced in Aoah/Tlr4−/− cortex. Consistent with our hypothesis of TLR4 activation by gut microbes, we observed microbiome-dependent activation of cultured BV2 microglial cells. Skeletal analyses revealed that AOAH-deficient mice have an activated microglia morphology in brain regions associated with neuropathic pain, independent of TLR4. Compared to Aoah−/− mice, Aoah/Tlr4−/− mice exhibited decreased pelvic pain and microglial cytokine expression. Together, these findings demonstrate differential roles for AOAH and TLR4 in microglial activation and pelvic pain and thus identify novel therapeutic targets for IC/BPS.

scholarly journals Acyloxyacyl Hydrolase Modulates the Gut Microbiome Through Transcriptional Regulators of Corticotropin-Releasing Factor

2021 ◽  
Author(s):  
Afrida Rahman-Enyart ◽  
Lizath M. Aguiniga ◽  
Wenbin Yang ◽  
Ryan E. Yaggie ◽  
Bryan White ◽  
...  
Keyword(s):  
Sex Differences ◽  
Pelvic Pain ◽  
Gut Microbiome ◽  
Transcriptional Regulators ◽  
Corticotropin Releasing Factor ◽  
Conditional Knockout ◽  
Peroxisome Proliferator ◽  
Bladder Pain ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

ABSTRACTGut microbiome-host interactions play a crucial role in health and disease. Altered gut microbiome composition has been observed in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), a disorder characterized by pelvic pain, voiding dysfunction, and often co-morbid with anxiety/depression. We recently showed that mice deficient for acyloxyacyl hydrolase (AOAH) mimic pelvic pain symptoms and comorbidities of IC/BPS and also exhibit gut dysbiosis. In addition, we previously identified that the conditional knockout (cKO) of two transcriptional regulators of the gene encoding corticotropin-releasing factor, Crf, that are downstream of AOAH, aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ (PPARγ), alleviate anxiety/depressive and voiding phenotypes of AOAH-deficient mice. Here, we examined the effects of AhR and PPARγ in CRF-expressing cells on the dysbiosis of AOAH-deficiency. AOAH-deficient mice with cKO of PPARγ and AhR/PPARγ exhibited reduced pelvic allodynia compared to AOAH-deficient mice, suggesting a role for PPARγ in regulating pelvic pain. 16S rRNA sequencing of fecal stool from female AOAH-deficient mice with a cKO of AhR and/or PPARγ in CRF-expressing cells identified altered gut microbiota distinct from AOAH-deficient stool. The cKO of AhR and PPARγ showed improved cecum barrier function in females compared to AOAH-deficient mice, whereas males were primarily affected by PPARγ, suggesting sex differences in gut responses. Pair-wise comparison of microbiota also suggested sex differences in response to AOAH-deficiency and conditional knockout of AhR and PPARγ. Our findings suggest that the dysbiosis and leaky gut of AOAH deficiency is mediated by AhR and PPARγ in CRF-expressing cells and reveal a novel mechanism and therapeutic targets for pelvic pain.

scholarly journals Acyloxyacyl hydrolase modulates pelvic pain severity

2018 ◽  
Vol 314 (3) ◽  
pp. R353-R365 ◽  
Author(s):  
Wenbin Yang ◽  
Ryan E. Yaggie ◽  
Mingchen C. Jiang ◽  
Charles N. Rudick ◽  
Joseph Done ◽  
...  
Keyword(s):  
Pelvic Pain ◽  
Chronic Pelvic Pain ◽  
Cell Activation ◽  
Pseudorabies Virus ◽  
Allelic Variation ◽  
Pain Severity ◽  
Mast Cell Activation ◽  
Bladder Pain ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxBprogeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

scholarly journals Microbiota of Chronic Prostatitis/Chronic Pelvic Pain Syndrome are Distinct from Interstitial Cystitis/Bladder Pain Syndrome

2021 ◽  
Author(s):  
Bryan White ◽  
Michael Welge ◽  
Loretta Auvil ◽  
Matthew Berry ◽  
Colleen Bushell ◽  
...  
Keyword(s):  
Interstitial Cystitis ◽  
Pelvic Pain ◽  
Chronic Prostatitis ◽  
Chronic Pelvic Pain ◽  
Chronic Pelvic Pain Syndrome ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Unknown Etiology ◽  
Pelvic Pain Syndrome ◽  
Bladder Pain

Urologic chronic pelvic pain syndrome patients include men chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and patients, mainly women, with interstitial cystitis/bladder pain syndrome (IC/BPS or IC). CP/CPPS is marked by severe chronic pelvic pain of unknown etiology that is differentially associated with prostatic inflammation. Microbes are known to modulate sensory responses, and microbiota are increasingly understood to drive normal biological processes and pathogenesis, including inflammation. Recent studies have linked fecal dysbiosis with chronic pelvic pain in IC/BPS, suggesting a role for microbiota in modulating UCPPS pain. Similarly, dysbiosis has been reported in CP/CPPS patients, but the relationship between with the dysbiosis of IC/BPS patients is unclear. Here, we characterized the fecal microbiota of men with CP/CPPS and women and men with IC/BPS. Similar to recent reports, we identified fecal dysbiosis in men with CP/CPPS relative to healthy controls among specific phyla and overall differences in diversity and richness. Interestingly, we also observed differences between CP/CPPS microbiota and IC/BPS microbiota that were not likely due to sex differences. These findings suggest that CP/CPPS is marked by changes in the gut microbiome, but these changes differ from IC/BPS. Taken together, UCPPS appears associated with distinct dybioses among CP/CPPS and IC/BPS, raising the possibility of distinct contributions to underlying pelvic pain mechanisms and/or etiologies.

scholarly journals Autonomic neurophysiologic implications of disorders comorbid with bladder pain syndrome vs myofascial pelvic pain

2019 ◽  
Vol 38 (5) ◽  
pp. 1370-1377 ◽  
Author(s):  
Gisela G. Chelimsky ◽  
Sheng Yang ◽  
Tatiana Sanses ◽  
Curtis Tatsuoka ◽  
C. A. Tony Buffington ◽  
...  
Keyword(s):  
Pelvic Pain ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Bladder Pain

Interstitial Cystitis/Bladder Pain Syndrome

2018 ◽  
Vol 36 (02) ◽  
pp. 123-135 ◽  
Author(s):  
Ioana Marcu ◽  
E. Campian ◽  
Frank Tu
Keyword(s):  
Interstitial Cystitis ◽  
Pelvic Pain ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Bladder Pain ◽  
Painful Bladder ◽  
Bladder Symptoms ◽  
The Many ◽  
American Urological Association ◽  
Underlying Pathophysiology

AbstractInterstitial cystitis/bladder pain syndrome is an uncommon but potentially devastating pelvic pain disorder affecting both women and men. This condition is often confusable and comorbid with other pelvic pain disorders. Although our understanding of the underlying pathophysiology is growing, the exact longitudinal course by which peripheral and central aberrations involving the bladder mucosa, peripheral inflammation, and central dysregulation of bladder sensitivity create painful bladder symptoms remains an area in need of further study. Only a limited number of drugs have been approved for treatment by the Food and Drug Administration, and overall durable efficacy of the many treatments reviewed in recent American Urological Association guidelines remains suboptimal, making awareness, early diagnosis, and use of effective treatments early in the disease course, where neural changes may still be reversible, imperative.

Chronic pelvic pain in benign and functional urological conditions: A review and comparison of the UK and European guidelines

2018 ◽  
Vol 11 (2) ◽  
pp. 115-121 ◽  
Author(s):  
Sophia Cashman ◽  
Suzanne Biers
Keyword(s):  
Pelvic Pain ◽  
Chronic Pelvic Pain ◽  
Chronic Pelvic Pain Syndrome ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Current Evidence ◽  
Pelvic Pain Syndrome ◽  
Bladder Pain ◽  
European Guidelines ◽  
Relative Paucity

We aim to provide a general overview of the available UK and European guidelines on non-oncological causes of chronic pelvic pain, and highlight any differences in practice. We have reviewed the current guidelines on chronic pelvic pain syndrome (defined as chronic pelvic pain with no identified underlying cause and/or the pain is non-specific or involves more than one organ) and other specific organ pain syndromes particularly relevant to urological clinical practice, including prostate pain syndrome, bladder pain syndrome and gynaecological causes of chronic pelvic pain. We have identified a relative paucity of UK guidelines, and accept that the European Association of Urology provides a comprehensive and current evidence based reference and guide which is utilised and regarded by most urologists as the ‘gold standard’ in UK practice.

Nerve stimulation for chronic pelvic pain and bladder pain syndrome: a systematic review

2013 ◽  
Vol 92 (8) ◽  
pp. 881-887 ◽  
Author(s):  
Seema A. Tirlapur ◽  
Antonis Vlismas ◽  
Elizabeth Ball ◽  
Khalid S. Khan
Keyword(s):  
Systematic Review ◽  
Pelvic Pain ◽  
Nerve Stimulation ◽  
Chronic Pelvic Pain ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Bladder Pain

scholarly journals A MAPP Network study: overexpression of tumor necrosis factor-α in mouse urothelium mimics interstitial cystitis

2018 ◽  
Vol 315 (1) ◽  
pp. F36-F44 ◽  
Author(s):  
Wenbin Yang ◽  
Timothy J. Searl ◽  
Ryan Yaggie ◽  
Anthony J. Schaeffer ◽  
David J. Klumpp
Keyword(s):  
Interstitial Cystitis ◽  
Transgenic Mouse ◽  
Voiding Dysfunction ◽  
Visceral Pain ◽  
Ex Vivo ◽  
Pain Syndrome ◽  
Bladder Pain Syndrome ◽  
Tactile Allodynia ◽  
Wild Type ◽  
Bladder Pain

Interstitial cystitis/bladder pain syndrome is a chronic bladder condition associated with pain and voiding dysfunction that is often regarded as a neurogenic cystitis. Patient symptoms are correlated with the presence of urothelial lesions. We previously characterized a murine neurogenic cystitis model that recapitulates mast cell accumulation and urothelial lesions, and these events were dependent on TNF. To further explore the role of TNF in bladder inflammation and function, we generated a transgenic mouse model with chronic TNF overexpression in urothelium under the control of the uroplakin II (UPII) promoter. Transgenic mouse lines were maintained by backcross onto wild-type C57BL/6J mice and evaluated for pelvic tactile allodynia as a measure of visceral pain, urinary function, and urothelial lesions. TNF mRNA and protein were expressed at greater levels in bladders of UPII-TNF mice than in those of wild-type mice. UPII-TNF mice showed significantly increased urinary frequency and decreased void volume. UPII-TNF mice had increased urothelial apoptosis and loss of urothelial integrity consistent with urothelial lesions. Overexpression of TNF was also associated with pelvic tactile allodynia. Consistent with these findings, UPII-TNF mice exhibited increased bladder afferent activity in response to stretch ex vivo. In summary, UPII-TNF mice display significant pelvic pain, voiding dysfunction, urothelial lesions, and sensory input. Thus UPII-TNF mice are a model for characterizing mechanisms of interstitial cystitis symptoms and evaluating therapies.

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