Acyloxyacyl Hydrolase Is a Host Determinant of Gut Microbiome-mediated Pelvic Pain

Afrida Rahman-Enyart, Wenbin Yang, Ryan E. Yaggie, Bryan A. White, Michael Welge, Loretta Auvil, Matthew Berry, Colleen Bushell, John M. Rosen, Charles N. Rudick, Anthony J. Schaeffer, David J. Klumpp

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)R396-R412
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume321
Issue number3
DOIs
StatePublished - Aug 25 2021

Keywords

  • Acyloxyacyl hydrolase
  • Gut dysbiosis
  • Interstitial cystitis
  • Microbiome
  • Pelvic pain

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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