Rahman-Enyart, AfridaYang, WenbinYaggie, Ryan E.White, Bryan A.Welge, MichaelAuvil, LorettaBerry, MatthewBushell, ColleenRosen, John M.Rudick, Charles N.Schaeffer, Anthony J.Klumpp, David J.2023-09-012023-09-012021Rahman-Enyart A, Yang W, Yaggie RE, et al. Acyloxyacyl hydrolase is a host determinant of gut microbiome-mediated pelvic pain. Am J Physiol Regul Integr Comp Physiol. 2021;321(3):R396-R412. doi:10.1152/ajpregu.00106.2021https://hdl.handle.net/1805/35297Dysbiosis 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 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.en-USPublisher PolicyAcyloxyacyl hydrolaseGut dysbiosisInterstitial cystitisMicrobiomePelvic painArticle