Analysis of Multi-Site Bile Acid Metabolic Profile Reveals an Association Between Bile Acid–FXR Signaling and Visceral Hypersensitivity in Heterotypic Intermittent Stress-Induced IBS

Visceral hypersensitivity (VH) is a hallmark of irritable bowel syndrome (IBS), establishing a reliable VH model is vital for investigating the disorder. While the impact of chronic stress on bile acid (BA) metabolism remains unclear. The exploratory study aimed to evaluate a heterotypic intermittent stress (HIS)-induced rat model of VH and characterize associated alterations in BA metabolism and farnesoid X receptor (FXR) signaling. Rats underwent a 9-day HIS regimen, and VH was assessed by electromyographic recording of the visceromotor response to colorectal distension. BA profiles in feces, colon, and serum were quantified by HPLC-MS/MS, and colonic FXR and CGRP expression were examined by Western blot, immunohistochemistry, and three-dimensional confocal reconstruction. HIS induced significant VH without organic colonic pathology, accompanied by increased CGRP-positive nerve fibers. The bile acid pool composition region-specific alterations in feces, colon, and serum. Specifically, the free-to-conjugated BA ratio was significantly increased in the colon and decreased in the serum of HIS rats, whereas no significant difference was detected in feces, while species-level changes were compartment-specific. Colonic FXR was upregulated and spatially associated with CGRP-positive fibers; in a preventive guggulsterone-treated group, both signals were reduced. These findings indicate that HIS-induced VH is associated with region-specific alterations in BA metabolism and colonic FXR signaling change, identifying the BA–FXR axis as a candidate pathway meriting functional validation as a potential therapeutic target for IBS.