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A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Cholestasis alters brain lipid and bile acid composition and compromises motor function in neonatal piglets
Nicole Lind Henriksen1, Svend Høime Hansen2, Matthew Domenic Lycas3
1Comparative Pediatrics and Nutrition, Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg C, Denmark.
Insights
Neonatal cholestasis in piglets impairs motor function and alters brain bile acid and lipid profiles. These molecular changes, including hydrophilic bile acids and altered lipids, may underlie neurodevelopmental deficits.
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Neonatal cholestasis is linked to neurodevelopmental deficits, but the causes are poorly understood.
- Bile acid and lipid dysregulation are potential, yet understudied, contributors to brain dysfunction in this condition.
Purpose of the Study:
- To investigate the impact of neonatal cholestasis on brain bile acid and lipid composition in a translational piglet model.
- To correlate these molecular brain changes with observed motor function deficits.
Main Methods:
- A piglet model of neonatal cholestasis was established using bile duct ligation.
- Brain tissue underwent comprehensive bile acid profiling and lipidomics analysis.
- Gene expression analysis was performed on cerebellar tissue.
Main Results:
- Bile duct-ligated piglets exhibited sensory-motor deficits.
- The brain showed a shift towards more hydrophilic and conjugated bile acids.
- Cerebellar lipidomics revealed decreased total lipids (e.g., phosphatidylinositols, phosphatidylserines) and increased lysophospholipids.
- Cerebellar gene expression indicated inflammation and tissue damage without significant transcriptome-wide changes.
Conclusions:
- Neonatal cholestasis induces significant alterations in brain bile acid and lipid profiles in piglets.
- These molecular changes are associated with motor deficits, suggesting a role in neurodevelopmental impairments.
- The findings highlight bile acids and lipids as potential mediators of brain dysfunction in neonatal cholestasis.
Abstract:
Infants with neonatal cholestasis are prone to neurodevelopmental deficits, however, the underlying pathogenesis is unclear. Lipid malabsorption and accumulation of potentially neurotoxic molecules in the blood such as bile acids are important yet relatively unexplored pathways. Here, we developed a translational piglet model to understand how the molecular bile acid and lipid composition of the brain is affected by this disease and relates to motor function. Piglets (8-days old) had bile duct ligation or sham surgery and were fed a formula diet for 3 weeks. Alongside sensory-motor deficits observed in bile duct-ligated animals, we found a shift toward a more hydrophilic and conjugated bile acid profile in the brain. Additionally, comprehensive lipidomics of the cerebellum revealed a decrease in total lipids including phosphatidylinositols and phosphatidylserines and increases in lysophospholipid species. This was paralleled by elevated cerebellar expression of genes related to inflammation and tissue damage albeit without significant impact on the brain transcriptome. This study offers new insights into the developing brain's molecular response to neonatal cholestasis indicating that bile acids and lipids may contribute in mediating motor deficits.
