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.
|Status||Udgivet - jul. 2022|
Bibliografisk noteFunding Information:
This work was supported by the Danish Dairy Research Foundation and the Novo Nordisk Foundation (NNF18OC0052834).
The authors acknowledge Karoline Aasmul-Olsen, Jane Povlsen, Britta Karlsson, Simone M. Offersen and Karina S. Asmussen from Comparative Pediatrics and Nutrition at the University of Copenhagen for their help with animal procedures. We thank Betina Andersen and Elisabeth Petersen from the Veterinary Pathology group at the University of Copenhagen for preparing histological slides, and Gemma Chavarria-Ventura from Comparative Pediatrics and Nutrition at the University of Copenhagen as well as Karin Tarp and Betina L. Henriksen from the Department of Biotechnology and Biomedicine at the Technical University of Denmark for their support in running qPCR analyses. Furthermore, we thank Henrik E. Jensen from the Veterinary Pathology group at the University of Copenhagen for his guidance in evaluating histological slides. The graphical abstract was created with BioRender.com.
© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.