MP07-18 ACYLOXYACYL HYDROLASE REGULATES GUT DYSBIOSIS-MEDIATED PELVIC PAIN AND DEPRESSIVE-LIKE BEHAVIOR

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.

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

10.1101/2021.03.04.433950 ◽

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.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00106.2021 ◽

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.

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

10.1101/2021.02.26.433087 ◽

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.

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MP85-20 ACYLOXYACYL HYDROLASE MODULATES PELVIC PAIN SEVERITY

The Journal of Urology ◽

10.1016/j.juro.2017.02.2682 ◽

2017 ◽

Vol 197 (4S) ◽

Author(s):

Wenbin Yang ◽

Ryan Yaggie ◽

Mingcheng Jiang ◽

Charles Rudick ◽

Joseph Done ◽

...

Keyword(s):

Pelvic Pain ◽

Pain Severity ◽

Acyloxyacyl Hydrolase

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Chronic Pelvic Pain and Irritable Bowel Syndrome: Is Subclinical Inflammation Bridging the Gap?

Revista de Chimie ◽

10.37358/rc.19.10.3634 ◽

2019 ◽

Vol 70 (10) ◽

pp. 3634-3637

Keyword(s):

Irritable Bowel Syndrome ◽

Abdominal Pain ◽

Pelvic Pain ◽

Inflammatory Markers ◽

Chronic Pelvic Pain ◽

Young Female ◽

Cross Sectional ◽

Gut Dysbiosis ◽

Inflammatory Status ◽

Irritable Bowel

Irritable bowel syndrome (IBS) is characterized by a multitude of symptoms digestive and extra- digestive that need at some point a multidisciplinary approach. This study aimed at profiling IBS associated with chronic pelvic pain (CPP) in young females. A cross sectional observatory study on 40 consecutive young female patients (under 45 years) with IBS (Rome III) was performed. Patients were assigned in two groups, as matched pairs, based on the presence of chronic pelvic pain (CPP) symptoms: cystalgia, urinary urge and dyspareunia: CPP(+) vs. CPP(-) and undertook clinical examinations with special protocols related to migraine disability, fibromyalgia, temporo-mandibular joint dysfunction, as well as assessment of anxiety and severity of abdominal pain. Laboratory work-up (blood, urine and stool) as well as multiple exams: digestive endoscopy, abdominal and pelvic ultrasound//CT were performed. Results: CPP (+) group displayed higher CRP, TNF-alpha, gut dysbiosis (DB) and abdominal pain severity, as well as associated fibromyalgia, migraine and anxiety mood disorder. DB positively correlated with inflammatory markers and symptoms characterizing CPP. In conclusion, young female IBS patients with concurrent CPP symptoms often experienced other associated functional pain conditions like FM and migraine along with anxiety, more severe abdominal complaints as well as higher gut DB and consecutively subclinical pro-inflammatory status. Strong positive correlations of gut DB to inflammatory markers as well as to CPP symptoms give the relationship IBS-CPP a new perspective. Keywords: CPP, IBS, inflammation, gut dysbiosis

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

10.1101/2021.01.27.428290 ◽

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.

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