Inflammasome-mediateddysbiosis.pdfVIP

ARTICLE doi:10.1038/nature10809 Inflammasome-mediated dysbiosis regulatesprogressionofNAFLDandobesity 1 1 1,2 3 4 1 1 Jorge Henao-Mejia *, Eran Elinav *, Chengcheng Jin *, Liming Hao , Wajahat Z. Mehal , Till Strowig , Christoph A. Thaiss , 5,6 7 4 4 4,8 5 Andrew L. Kau , Stephanie C. Eisenbarth , Michael J. Jurczak , Joao-Paulo Camporez , Gerald I. Shulman , Jeffrey I. Gordon , Hal M. Hoffman9 Richard A. Flavell1,8 Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation,