Mechanistic insights into the liver–brain axis during chronic liver disease

The liver is a metabolically flexible tissue, adapting its functions to changes in nutrient availability and physiological states. This adaptability is crucial for maintaining metabolic homeostasis and likely involves communication with the central nervous system through the liver–brain axis. The liver also receives a constant influx of nutrients, hormones and microbial metabolites from the gastrointestinal tract in a multifaceted communication network, the gut–liver–brain axis. Dysregulation of this communication can lead to hepatic encephalopathy and cognitive impairments in early-stage chronic liver disease, such as metabolic dysfunction-associated steatotic liver disease, substantially affecting patient quality of life. This Review examines key signalling pathways along the liver–brain axis: humoral signalling, including metabolites, hepatokines, toxins and inflammation, and neural pathways, focusing on afferent signalling through the common hepatic branch of the vagus nerve. We discuss how each pathway might contribute to behavioural and mood changes in chronic liver disease and the development of hepatic encephalopathy. Although the humoral effects have been studied more extensively, we propose that the afferent vagus nerve is central to liver disease-associated cognitive and behavioural complications. Finally, we highlight how new techniques and tools could advance our understanding of the gut–liver–brain communication that affects behaviour.