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

ABSTRACT Gut 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 (PPAR γ ), alleviate anxiety/depressive and voiding phenotypes of AOAH-deficient mice. Here, we examined the effects of AhR and PPAR γ in CRF-expressing cells on the dysbiosis of AOAH-deficiency. AOAH-deficient mice with cKO of PPAR γ and AhR/PPAR γ exhibited reduced pelvic allodynia compared to AOAH-deficient mice, suggesting a role for PPAR γ in regulating pelvic pain. 16S rRNA sequencing of fecal stool from female AOAH-deficient mice with a cKO of AhR and/or PPAR γ in CRF-expressing cells identified altered gut microbiota distinct from AOAH-deficient stool. The cKO of AhR and PPAR γ showed improved cecum barrier function in females compared to AOAH-deficient mice, whereas males were primarily affected by PPAR γ , 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 PPAR γ . Our findings suggest that the dysbiosis and leaky gut of AOAH deficiency is mediated by AhR and PPAR γ in CRF-expressing cells and reveal a novel mechanism and therapeutic targets for pelvic pain.