The study investigates the role of inflammasomes in the progression of non-alcoholic fatty liver disease (NAFLD) and obesity. It demonstrates that the NLRP6 and NLRP3 inflammasomes, along with the effector protein IL-18, negatively regulate NAFLD/NASH progression and metabolic syndrome by modulating the gut microbiota. Inflammasome deficiency leads to changes in the gut microbiota, which exacerbates hepatic steatosis and inflammation through the influx of TLR4 and TLR9 agonists into the portal circulation, resulting in increased TNF-α expression and NASH progression. Co-housing inflammasome-deficient mice with wild-type mice exacerbates hepatic steatosis, glucose intolerance, and obesity. The study also shows that altered interactions between the gut microbiota and the host, caused 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 systemic auto-inflammatory and metabolic disorders.The study investigates the role of inflammasomes in the progression of non-alcoholic fatty liver disease (NAFLD) and obesity. It demonstrates that the NLRP6 and NLRP3 inflammasomes, along with the effector protein IL-18, negatively regulate NAFLD/NASH progression and metabolic syndrome by modulating the gut microbiota. Inflammasome deficiency leads to changes in the gut microbiota, which exacerbates hepatic steatosis and inflammation through the influx of TLR4 and TLR9 agonists into the portal circulation, resulting in increased TNF-α expression and NASH progression. Co-housing inflammasome-deficient mice with wild-type mice exacerbates hepatic steatosis, glucose intolerance, and obesity. The study also shows that altered interactions between the gut microbiota and the host, caused 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 systemic auto-inflammatory and metabolic disorders.