Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes

Abstract

Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies. Graphical Abstract

Microbiota-gut-liver-brain axis and hepatic encephalopathy

“…At present, HE therapies targeting the brain are still in the preclinical stage [ 108 ] . For instance, gamma-aminobutyric acid-benzodiazepine receptor agonists reduced peripheral inflammation and neuroinflammation which was associated with improved cognitive and motor functions in hyperammonemic rats [ 109 ] .…”

“…Serum homocysteine and BA levels were also identified as promising markers for the diagnosis of HE [106] . Additionally, it is possible to target brain dysfunction as a potential diagnostic criterion in HE, as the brain default mode network based on resting-state functional magnetic resonance imaging (MRI) scanning was shown to be a valuable method to identify HE [107] . All of these diagnostic indicators for clinical laboratory are closely related to the microbiome-gut-liver-brain axis.…”