A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation

Sci Rep. 2022 Oct 20;12(1):17558. doi: 10.1038/s41598-022-22423-6.


Hepatic encephalopathy (HE) is a common complication of chronic liver disease, characterized by an altered mental state and hyperammonemia. Insight into the brain pathophysiology of HE is limited due to a paucity of well-characterized HE models beyond the rat bile duct ligation (BDL) model. Here, we assess the presence of HE characteristics in the mouse BDL model. We show that BDL in C57Bl/6j mice induces motor dysfunction, progressive liver fibrosis, liver function failure and hyperammonemia, all hallmarks of HE. Swiss mice however fail to replicate the same phenotype, underscoring the importance of careful strain selection. Next, in-depth characterisation of metabolic disturbances in the cerebrospinal fluid of BDL mice shows glutamine accumulation and transient decreases in taurine and choline, indicative of brain ammonia overload. Moreover, mouse BDL induces glial cell dysfunction, namely microglial morphological changes with neuroinflammation and astrocyte reactivity with blood-brain barrier (BBB) disruption. Finally, we identify putative novel mechanisms involved in central HE pathophysiology, like bile acid accumulation and tryptophan-kynurenine pathway alterations. Our study provides the first comprehensive evaluation of a mouse model of HE in chronic liver disease. Additionally, this study further underscores the importance of neuroinflammation in the central effects of chronic liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / metabolism
  • Animals
  • Bile Acids and Salts
  • Bile Ducts / metabolism
  • Bile Ducts / surgery
  • Brain / metabolism
  • Choline
  • Disease Models, Animal
  • Glutamine / metabolism
  • Hepatic Encephalopathy*
  • Hyperammonemia* / etiology
  • Kynurenine
  • Liver Diseases* / complications
  • Mice
  • Microglia / metabolism
  • Neuroinflammatory Diseases
  • Rats
  • Taurine
  • Tryptophan


  • Ammonia
  • Kynurenine
  • Glutamine
  • Tryptophan
  • Taurine
  • Choline
  • Bile Acids and Salts