Liver-brain inflammation axis.

It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including chronic inflammatory liver diseases, are associated with changes in central neural transmission that result in alterations in behavior. These behavioral changes include sickness behaviors, such as fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. While such behaviors have a significant impact on quality of life, the changes within the brain and the communication pathways between the liver and the brain that give rise to changes in central neural activity are not fully understood. Traditionally, neural and humoral communication pathways have been described, with the three cytokines TNFα, IL-1β, and IL-6 receiving the most attention in mediating communication between the periphery and the brain, in the setting of peripheral inflammation. However, more recently, we described an immune-mediated communication pathway in experimentally induced liver inflammation whereby, in response to activation of resident immune cells in the brain (i.e., the microglia), peripheral circulating monocytes transmigrate into the brain, leading to development of sickness behaviors. These signaling pathways drive changes in behavior by altering central neurotransmitter systems. Specifically, changes in serotonergic and corticotropin-releasing hormone neurotransmission have been demonstrated and implicated in liver inflammation-associated sickness behaviors. Understanding how the liver communicates with the brain in the setting of chronic inflammatory liver diseases will help delineate novel therapeutic targets that can reduce the burden of symptoms in patients with liver disease.