The Pathophysiology of Hepatic Encephalopathy at the Level of Gut-Liver-Brain Axis: The Role of Resident Innate Immune Cells

Abstract

Hepatic encephalopathy (HE) reflects a wide spectrum of frequent and complex neurological complications that are associated with advanced liver diseases. It significantly impacts the quality of life and daily activities of those affected. Despite many investigations, the precise pathophysiology of HE is still under discussion. One contributing factor believed to be responsible for HE is the accumulation of neurotoxic substances in the brain such as ammonia, mercaptans, short-chain fatty acids, and lipopolysaccharides, originating from the dysfunctional liver. Strong data, however, suggests that HE is a complex symptom, and inflammation interacts synergistically with ammonia to worsen gliopathy and neuronal destruction. Recent data suggests that HE might come from the intestines. Increased activity of gut innate immune cells, especially macrophages and dendritic cells, can initiate inflammatory signals from the gut to systemic circulation, liver tissue, and finally the central nervous system. In this chapter, all inflammatory mechanisms at the levels of the gut-liver-brain axis following cirrhosis and HE are presented in detail. The chapter highlights the role of intestinal innate immune cells, liver Kupffer cells, and brain microglia in cirrhosis and the progression of HE.