TY - JOUR
T1 - Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain
AU - Rahman-Enyart, Afrida
AU - Yang, Wenbin
AU - Yaggie, Ryan E.
AU - White, Bryan A.
AU - Welge, Michael
AU - Auvil, Loretta
AU - Berry, Matthew
AU - Bushell, Colleen
AU - Rosen, John M.
AU - Rudick, Charles N.
AU - Schaeffer, Anthony J.
AU - Klumpp, David J.
N1 - Funding Information:
This work was supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Award R01 DK103769 (B.A.W., A.J.S., and D.J.K.) and by NIH/NIDDK T32 DK062716 postdoctoral fellowship to A.R.-E. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory which is supported by National Cancer Institute (NCI) P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/8/25
Y1 - 2021/8/25
N2 - 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 comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. 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 gastrointestinal (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. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAHdeficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAHdeficient 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.
AB - 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 comorbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in patients with IC/BPS. 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 gastrointestinal (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. Cohousing AOAH-deficient mice with wild-type mice resulted in converged microbiota and altered predicted metagenomes. Cohousing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAHdeficient mice with stool slurry of wild-type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAHdeficient 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.
KW - Acyloxyacyl hydrolase
KW - Gut dysbiosis
KW - Interstitial cystitis
KW - Microbiome
KW - Pelvic pain
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UR - http://www.scopus.com/inward/citedby.url?scp=85113947581&partnerID=8YFLogxK
U2 - 10.1152/ajpregu.00106.2021
DO - 10.1152/ajpregu.00106.2021
M3 - Article
C2 - 34318715
AN - SCOPUS:85113947581
SN - 0363-6119
VL - 321
SP - R396-R412
JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
IS - 3
ER -