Cholestasis alters brain lipid and bile acid composition and compromises motor function in neonatal piglets

Authors: HENRIKSEN, NICOLE - University Of Copenhagen; HANSEN, SVEND - Rigshospitalet - Copenhagen University Hospital; LYCAS, MATTHEW - University Of Copenhagen; PAN, XIAOYU - University Of Copenhagen; ERIKSEN, THOMAS - University Of Copenhagen; JOHANSEN, LARS - Rigshospitalet - Copenhagen University Hospital; SPRENGER, RICHARD - University Of Southern Denmark; EJSING, CHRISTER - University Of Southern Denmark; Burrin, Douglas - Doug; SKOVGAARD, KERSTIN - Technical University Of Denmark; CHRISTENSEN, VIBEKE - University Of Copenhagen; THYMANN, THOMAS - University Of Copenhagen; PANKRATOVA, STANISLAVA - University Of Copenhagen

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/6/2022
Publication Date: 7/12/2022
Citation: Henriksen, N.L., Hansen, S.H., Lycas, M.D., Pan, X., Eriksen, T., Johansen, L.S., Sprenger, R.R., Ejsing, C.S., Burrin, D.G., Skovgaard, K., Christensen, V.B., Thymann, T., Pankratova, S. 2022. Cholestasis alters brain lipid and bile acid composition and compromises motor function in neonatal piglets. Physiological Reports. 10(13). Article e15368. https://doi.org/10.14814/phy2.15368.
DOI: https://doi.org/10.14814/phy2.15368

Interpretive Summary: Biliary atresia (BA) is a rare liver disease in infants that leads to jaundice, liver injury and often requires a liver transplant. The liver injury in BA infants occurs because the ducts that drain bile from the liver into the intestine do not form correctly prior to birth due to unknown reasons. Another adverse side effect of jaundice in BA infants is poor neurodevelopment which is thought be caused by accumulation of bile acids in the blood and brain tissue. In this study, we used neonatal piglets to model biliary atresia by ligated the bile duct (BDL group) soon after birth and then measuring motor function and tissue development in the piglets after one month. Piglets in the BDL group developed jaundice and evidence of liver injury at the end of one month similar to what occurs in infants with BA. We also found that BDL piglets showed evidence of poor coordination and brain tissue markers of damage and inflammation that was associated with accumulation of bile acids in the brain. This model of BDL in newborn piglets provides a new animal model to study the effects of severe jaundice and liver injury during infancy.

Technical 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 three weeks. Alongside sensory-motor deficits observed in bile duct-ligated animals, we found a shift towards 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.