Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity

TLDR: Altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome 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 systemic auto-inflammatory and metabolic disorders.

Abstract: 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, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome 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 systemic auto-inflammatory and metabolic disorders. An expansion of Porphyromonadaceae in the gut is linked to the pathogenesis and progression of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in the mouse. Using a mouse model, Richard Flavell and co-workers study the inflammatory processes associated with progression from non-alcoholic fatty liver disease — the leading cause of chronic liver disease in developed countries — to the more severe non-alcoholic steatohepatitis, which often leads to cirrhosis and hepatocellular carcinoma. They find that alterations of the intestinal microbiota associated with the NLRP6 and NLRP3 inflammasomes enhance disease in mice with diet-induced non-alcoholic fatty liver syndrome. These findings highlight the pivotal role of the microbiota in the development of autoinflammatory and metabolic disorders, and point to the manipulation of host–microflora interactions as a focus for new therapies.