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. To test the role of inflammasomes on progression of steatohepatitis (NAFLD/NASH) and other features of the metabolic syndrome (such as obesity and glucose intolerance), we employed the three major small animal models of this disease. Our most striking finding in the current study is that the NLRP6 and NLRP3 inflammasomes, through activation of the effector protein IL-18, negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome such as obesity and glucose homeostasis via a cell-extrinsic effect of modulation of the gut microbiota. In addition, we showed that that 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, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. But perhaps more interestingly, we demonstrated that wild-type mice co-housed with inflammasome-deficient mice also developed exacerbated Metabolic Syndrome. Finally, we recognize two family level taxa, Prevotella and Porphyromonadaceae that are expanded in inflammasome-deficient mice and their cohoused WT partners. The latter is only expanded in the context of dietary induction of the metabolic syndrome. In a general sense, these findings highlight the role of the microbiota in the pathogenesis of chronic liver disease and other seemingly gut-unrelated systemic auto-inflammatory and metabolic disorders.
Furthermore, Our results may offer one potential explanation as to why a large number of treatments in NASH have failed to yield beneficial effects on disease progression and outcome.
Finally, we have recently found another interesting role for infmammasomes as a sensor in the regulation of IL-22 driven repair of tissue damage. These results will be discussed.