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 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 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 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 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 regulates voiding activity

2020 ◽  
Vol 318 (4) ◽  
pp. F1006-F1016 ◽  
Author(s):  
Lizath M. Aguiniga ◽  
Timothy J. Searl ◽  
Afrida Rahman-Enyart ◽  
Ryan E. Yaggie ◽  
Wenbin Yang ◽  
...  
Keyword(s):  
Brain Area ◽  
Neuronal Firing ◽  
Conditional Knockout ◽  
Bladder Function ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Void Volumes ◽  
Acyloxyacyl Hydrolase ◽  
Deficient Mice

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington’s nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington’s nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH- Crf axis is a therapeutic target for treating voiding dysfunction.

scholarly journals Pgc1a is responsible for the sex differences in hepatic Cidec/Fsp27β mRNA expression in hepatic steatosis of mice fed a Western diet

2020 ◽  
Vol 318 (2) ◽  
pp. E249-E261 ◽  
Author(s):  
Luis V. Herrera-Marcos ◽  
Sara Sancho-Knapik ◽  
Clara Gabás-Rivera ◽  
Cristina Barranquero ◽  
Sonia Gascón ◽  
...  
Keyword(s):  
Sex Differences ◽  
Mrna Expression ◽  
Oleanolic Acid ◽  
Dietary Cholesterol ◽  
Western Diet ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Experimental Conditions ◽  
Hepatic Expression ◽  
Deficient Mice

Hepatic fat-specific protein 27 [cell death-inducing DNA fragmentation effector protein C ( Cidec)/ Fsp27] mRNA levels have been associated with hepatic lipid droplet extent under certain circumstances. To address its hepatic expression under different dietary conditions and in both sexes, apolipoprotein E ( Apoe) -deficient mice were subjected to different experimental conditions for 11 wk to test the influence of cholesterol, Western diet, squalene, oleanolic acid, sex, and surgical castration on Cidec/Fsp27 mRNA expression. Dietary cholesterol increased hepatic Cidec/Fsp27β expression, an effect that was suppressed when cholesterol was combined with saturated fat as represented by Western diet feeding. Using the latter diet, neither oleanolic acid nor squalene modified its expression. Females showed lower levels of hepatic Cidec/Fsp27β expression than males when they were fed Western diets, a result that was translated into a lesser amount of CIDEC/FSP27 protein in lipid droplets and microsomes. This was also confirmed in low-density lipoprotein receptor ( Ldlr)-deficient mice. Incubation with estradiol resulted in decreased Cidec/Fsp27β expression in AML12 cells. Whereas male surgical castration did not modify the expression, ovariectomized females did show increased levels compared with control females. Females also showed increased expression of peroxisome proliferator-activated receptor-γ coactivator 1-α ( Pgc1a), suppressed by ovariectomy, and the values were significantly and inversely associated with those of Cidec/Fsp27β. When Pgc1a-deficient mice were used, the sex differences in Cidec/Fsp27β expression disappeared. Therefore, hepatic Cidec/Fsp27β expression has a complex regulation influenced by diet and sex hormonal milieu. The mRNA sex differences are controlled by Pgc1a.

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