Chronic corticosterone exposure disrupts bile acids homeostasis associated with circadian dysfunction in the liver of chickens.

Enterohepatic bile acid metabolism displays robust diurnal rhythmicity governed by the hepatic circadian clock, yet how chronic stress reshapes this rhythmic process in poultry remains poorly defined. We hypothesized that chronic corticosterone exposure disrupts bile acid homeostasis in association with hepatic circadian clock dysfunction. This study therefore investigated the diurnal alterations of hepatic bile acid metabolism and its linkage with core clock dysregulation under corticosterone-induced chronic stress. Seventy-two 63-day-old male yellow-feathered dwarf broilers were randomly assigned to vehicle (Con) or corticosterone-treated (Cort) groups. Cort group received daily subcutaneous injections of corticosterone (4 mg/kg) for 10 consecutive days. On day 11, tissues were sampled every 4 hours from 09:00 (ZT2) to 05:00 the following day (ZT22), with feed and water provided ad libitum. Separately, AML12 hepatocytes were cultured with vehicle, dexamethasone (DEX), or DEX plus RU486, and bile acid transport activity was assessed using a Transwell system. Results indicated that chronic corticosterone exposure disrupted the hepatic circadian clock in chickens, reducing BMAL1 and REV-ERBβ mesors to 0.75- and 0.65-fold of control levels, respectively (P < 0.05), suppressing REV-ERBβ amplitude to 0.27-fold (P < 0.0001), and inducing significant phase delays in multiple core clock genes. Corticosterone increased CYP8B1 mesor and amplitude by 3.04- and 6.42-fold, respectively (P < 0.05), and advanced the acrophases of FXR and SHP by 10.37 h and 9.49 h, respectively (P < 0.05). Hepatic (P < 0.01) and plasma (P < 0.05) total bile acid levels decreased at ZT18, whereas gallbladder bile acid levels increased at ZT22 (P < 0.01). Correlation analysis revealed corticosterone eliminated diurnal negative correlations between clock and bile acid genes, shifting to persistent positive associations. In vitro, dexamethasone upregulated MRP2 expression (1.39-fold, P < 0.05) and promoted its membrane translocation via the glucocorticoid receptor, enhancing apical bile acid efflux. These findings indicate that chronic stress disrupts bile acid homeostasis via hepatic clock dysregulation, while glucocorticoids enhance MRP2-mediated efflux, linking stress to enterohepatic bile acid remodeling.