Obstructive cholestasis compromises balance and alters brain lipid composition in neonatal piglets

Infants with neonatal cholestasis are prone to neurodevelopmental deficits including neuromotor function. Accumulation of potentially neurotoxic molecules in the bloodstream including ammonia and bile acids and malabsorption of lipids may affect neurodevelopment in these patients. This study examined neuromotor function and bile acid and lipid composition of the brain in a piglet model of obstructive neonatal cholestasis via bile duct ligation (BDL) surgery. Results showed that BDL piglets had compromised balance and increased liver enzyme levels, liver fibrosis and bile duct proliferation compared to SHAM piglets. Plasma and cerebellum bile acid profiles differed between BDL and SHAM piglets with hyocholic acid and conjugated bile acid forms dominating in the BDL group. In the cerebellum there were different lipid profiles, but similar gene expression profiles between the two groups. Eight-day old piglets underwent bile duct ligation (BDL) or sham surgery (SHAM) and were followed for three weeks during which neuromotor functional tests (balance beam, open field, neuromotor score, gait analysis) were conducted. Samples were collected for liver histopathology, RNA sequencing and qPCR analysis of the cerebellum, and bile acid and lipid profiling of the plasma and/or cerebellum.