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.患有新生儿胆汁淤积症的婴儿易出现神经发育缺陷，其中包括神经运动功能缺陷。血液中包括氨与胆汁酸在内的潜在神经毒性分子蓄积，以及脂质吸收不良，可能影响此类患者的神经发育。本研究通过胆管结扎（bile duct ligation, BDL）手术构建梗阻性新生儿胆汁淤积症仔猪模型，对其神经运动功能以及脑部胆汁酸与脂质组成展开分析。结果显示，与假手术（SHAM）组仔猪相比，胆管结扎组仔猪的平衡能力受损、肝酶水平升高，且出现肝纤维化与胆管增生。两组仔猪的血浆及小脑胆汁酸谱存在显著差异，其中猪胆酸与结合型胆汁酸为胆管结扎组的主导胆汁酸类型。两组仔猪的小脑脂质谱存在差异，但基因表达谱并无显著不同。本研究对8日龄仔猪实施胆管结扎（BDL）或假手术（SHAM），并连续随访3周，期间开展多项神经运动功能测试：平衡木实验（balance beam）、旷场实验（open field）、神经运动评分以及步态分析（gait analysis）。采集样本用于肝脏组织病理学检测、小脑的RNA测序（RNA sequencing）与qPCR分析，以及血浆和/或小脑的胆汁酸与脂质谱分析。