Inflammasome-mediated dysbiosis regulatesprogressionofNAFLDandobesity

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause ofchronicliverdiseaseintheWesternworld.TwentypercentofNAFLDindividualsdevelopchronichepaticinflammation(non-alcoholicsteatohepatitis,NASH)associatedwithcirrhosis,portalhypertensionandhepatocellularcarcinoma,yetthe causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multipleaspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal thatinflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated withexacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation,leading to enhanced hepatic tumour-necrosis factor (TNF)-a expression that drives NASH progression. Furthermore,co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis andobesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities,highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemicauto-inflammatory and metabolic disorders.The prevalence of non-alcoholic fatty liver disease (NAFLD) rangesfrom 20–30% in the general population and up to 75–100% in obeseindividuals