Interestingly, the recent report that mice lacking the negative regulator of TLR signaling IRAK-M exhibit increased alcohol-induced TLR4 signaling and microbiota alteration indicate that microbiota composition alteration and inflammation are likely highly intertwined Selleckchem RAD001 coregulating events.[34] Together, these data support the concept that microbiota products, especially endotoxin, play a central role in alcohol-induced liver disease,

and suggest that antagonizing TLR4-mediate recognition of endotoxin might be a means of treating/preventing alcohol-induced liver injury.[21] Following alcoholism, the most well-established classic cause of liver disease is infection, especially with hepatitis viruses.

Although less well studied, similar paradigms may be relevant to mechanisms by which alcoholism and viral infection cause chronic inflammatory disease of the liver. For example, hepatitis B virus (HBV), which is thought to be responsible for a considerable portion of the worldwide liver disease burden, is Selleckchem FK866 associated with both altered gut permeability and alterations in the gut microbiota composition, either of which can be envisaged to result in increased activation of liver TLR/NLR.[35, 36] In a mouse model of viral-induced liver disease, germfree mice are protected from disease and conventional mice can be protected by the antibiotic/TLR4 antagonist polymixin B.[37] Thus, although the myriad of ways in which microbiota and viruses interact have only begun

to be deciphered, it seems likely that mechanisms by which HBV and perhaps hepatitis C virus (HCV) promote liver disease are mediated, in part, by way of the gut microbiota. While alcoholism and infection remain major causes of liver disease, perhaps the most alarming increase in liver disease click here is occurring in the form NAFLD. Twenty percent of NAFLD individuals develop chronic hepatic inflammation, i.e., nonalcoholic steatohepatitis (NASH) associated with cirrhosis, portal hypertension, and/or hepatocellular carcinoma (HCC). The rapidity of increased incidence of NAFLD over the last half-century, amidst relatively constant human genetics, indicates that environmental and/or lifestyle factors are driving this alarming trend. This is, of course, not occurring in isolation but rather is associated with the constellation of metabolic abnormalities including obesity, insulin resistance/type 2 diabetes, hyperlipidemia, and hypertension collectively referred to as metabolic syndrome. Like NAFLD and other chronic liver diseases, metabolic syndrome is increasingly appreciated to be a chronic inflammatory disease in which gut microbial products are prime suspects to be drivers of inflammation. Thus, it is possible that NAFLD and other aspects of metabolic syndrome are promoting each other and/or that both have related underlying causes.