Since LPS is a large molecule, it is unlikely that it crosses the BBB and has a direct effect on the brain [16]. Instead, LPS is thought to activate peripheral TLR4 signaling cascades (including TLR4 on cerebral endothelial cells) that initiate the release of pro-inflammatory cytokines and other immune mediators (Fig. 1) that then cross the BBB by diffusion or active transport mechanisms [12]. Alcohol compromises the tight junctions in the gut epithelium and increases its permeability to LPS [17] which initiates immune responses in liver, blood, and other tissues. In fact, intestinal permeability, LPS, and peripheral pro-inflammatory cytokines were largely increased in non-cirrhotic alcohol-dependent subjects compared to healthy controls and the increased pro-inflammatory cytokines in the alcohol-dependent subjects were correlated with alcohol craving [18*]. Once these cytokines have crossed the BBB, they affect the brain and have been linked to sickness behavior and depression in rodent models [14], suggesting a role for the gut-brain axis in alcohol dependence (Fig. 2).
