Gut-brain axis and alcohol dependenceLipopolysaccharide (LPS), a gram-negative bacterial endotoxin, is normally localized to the gut. Ethanol jeopardizes the tight junctions of the intestinal mucosa allowing LPS to enter systemic circulation. Once in the bloodstream, LPS binds to TLR4 receptors on liver macrophages, Kupffer, and stellate cells and activates signaling cascades that result in an increase of pro-inflammatory genes (cytokines, chemokines, proteases, ROS) via activation of the transcription factor NF-κB. This process is known to be a key factor in the development of alcoholic liver disease. These cytokines then enter the bloodstream, cross the BBB, and activate microglia, the brain’s resident macrophages. Microglial activation increases the expression of pro-inflammatory genes in the brain which is hypothesized to increase alcohol consumption behavior.
