1).[18, 19] Several studies in humans and mouse models suggest that endotoxin promotes liver disease by driving Kupffer cell activation.[20] Accordingly, endotoxin-mediated liver injury could be prevented by antibiotic treatment,[21] by eliminating Kupffer

cells,[22] or by neutralizing TNF-α with antibody[23] or by using TNF-α knockout mice.[24] In a rat model, treatment with polymyxin B, an antibiotic that directly prevents endotoxin from activating TLR4, prevented liver disease induced by ethanol treatment.[21] Moreover, absence of the TLR4 gene in bone-marrow cells (including Kupffer cells)-derived or somatic cells (including hematopoietic stem cell and hepatocytes) reduced the extent of alcohol-induced steatohepatitis in mice.[25] The mechanism by which alcohol increases gut permeability

appears to be driven by modification of tight junction protein expression during alcohol exposure, such as zona-occludens Selleck NVP-BKM120 protein-1 Pexidartinib molecular weight (ZO-1),[26] as well as cytoskeleton protein, such as microtubule.[27] Importantly, this increased intestinal permeability is likely not specific for endotoxin but would likely increase the load of a variety of microbial products that can result in excessive activation of both TLR- and NLR-mediated pathways, suggesting a broad but central role of gut-derived microbial products in alcohol-induced liver pathology.[28] Evidence that such mechanisms are operative in humans include that intestinal permeability and LPS load were largely increased in alcohol-dependent subjects compare to controls.[29]

Interestingly, a 3-week detoxification program is sufficient to restore normal levels of intestinal permeability and LPS load.[29] Another means by which alcohol can promote activation of liver TLRs/NLRs is by altering microbiota composition. Indeed, the colonic microbiome is altered during alcoholism,[30] and alcoholic subjects exhibiting reduced abundances of Bacteroidetes and increased levels of Enterobacteriaceae and Proteobacteria.[30, 31] Proteobacteria are elevated in a variety of chronic inflammatory diseases and are thought to be potent activators of innate immunity.[32] In accordance, the observed alterations in microbiota composition Methamphetamine in alcoholic subjects correlate with endotoxemia in a subgroup of alcoholics.[30] In addition to directly promoting increased TLR/NLR activation, the increased in Proteobacteria, and gram-negative bacteria in general, promoted by alcohol also results in accumulation of acetaldehyde, leading to an increased tyrosine phosphorylation of tight junction and adherent junction proteins, that can in turn increase intestinal permeability to bacterial products.[33] Importantly, it is very difficult to define the extent to which alterations in microbiota composition associated with alcoholism are a cause of inflammation and/or are a consequence of disease.