Figure 6.

The gut–liver axis. A major factor in the initiation of the inflammatory response by resident macrophages of the liver (i.e., Kupffer cells) is endotoxin or lipopolysaccharide (LPS), a cell-wall component of Gram-negative bacteria that translocates from the gut lumen into the portal circulation to reach the liver. Enhanced circulating endotoxin levels in alcoholic hepatitis are caused by alcohol-induced qualitative and quantitative changes in the bacteria that inhabit the gut (i.e., gut microbiota) and increased gut leakiness. In the liver, LPS activates Kupffer cells and hepatic stellate cells by interacting with toll-like receptor 4 (TLR4). These cells produce reactive oxygen species (ROS) as well as proinflammatory cytokines and chemokines that together with alcohol contribute to hepatocyte damage. Other factors contributing to hepatocyte damage include alcohol-induced activation of various immune cells (i.e., neutrophils, T cells, and other leukocytes) as well as alcohol’s effects on the fat (i.e., adipose) tissue, which results in the production of damage-associated molecular pattern (DAMP) molecules.