Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. The study shows that the NLRP6 and NLRP3 inflammasomes, along with the effector protein IL-18, negatively regulate the progression of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), as well as multiple aspects of metabolic syndrome through modulation of the gut microbiota. Inflammasome deficiency leads to altered gut microbiota composition, which results in exacerbated hepatic steatosis and inflammation through the influx of TLR4 and TLR9 agonists into the portal circulation, increasing hepatic TNF-α expression and driving NASH progression. Co-housing inflammasome-deficient animals with wild-type mice exacerbates hepatic steatosis, glucose intolerance, and obesity. Altered interactions between the gut microbiota and the host, caused by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of metabolic syndrome-associated abnormalities. The study highlights the central role of the microbiota in the pathogenesis of systemic auto-inflammatory and metabolic disorders. The results indicate that the transmissible colitogenic microbiota present in inflammasome-deficient mice is a major contributor to their enhanced NASH. The study also shows that the gut microbiota of inflammasome-deficient mice negatively impacts NAFLD progression and glucose homeostasis. The findings suggest that dysbiosis in inflammasome-deficient mice can lead to increased weight gain, steatosis, and impaired glucose homeostasis. The study provides evidence that the gut microbiota plays a critical role in the progression of NAFLD and NASH, and that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases. The study also highlights the importance of the gut-liver axis in the pathogenesis of metabolic disorders. The results suggest that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases. The study provides evidence that the gut microbiota plays a critical role in the progression of NAFLD and NASH, and that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases.Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. The study shows that the NLRP6 and NLRP3 inflammasomes, along with the effector protein IL-18, negatively regulate the progression of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), as well as multiple aspects of metabolic syndrome through modulation of the gut microbiota. Inflammasome deficiency leads to altered gut microbiota composition, which results in exacerbated hepatic steatosis and inflammation through the influx of TLR4 and TLR9 agonists into the portal circulation, increasing hepatic TNF-α expression and driving NASH progression. Co-housing inflammasome-deficient animals with wild-type mice exacerbates hepatic steatosis, glucose intolerance, and obesity. Altered interactions between the gut microbiota and the host, caused by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of metabolic syndrome-associated abnormalities. The study highlights the central role of the microbiota in the pathogenesis of systemic auto-inflammatory and metabolic disorders. The results indicate that the transmissible colitogenic microbiota present in inflammasome-deficient mice is a major contributor to their enhanced NASH. The study also shows that the gut microbiota of inflammasome-deficient mice negatively impacts NAFLD progression and glucose homeostasis. The findings suggest that dysbiosis in inflammasome-deficient mice can lead to increased weight gain, steatosis, and impaired glucose homeostasis. The study provides evidence that the gut microbiota plays a critical role in the progression of NAFLD and NASH, and that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases. The study also highlights the importance of the gut-liver axis in the pathogenesis of metabolic disorders. The results suggest that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases. The study provides evidence that the gut microbiota plays a critical role in the progression of NAFLD and NASH, and that the inflammasome is a key regulator of gut microbiota composition and its impact on metabolic diseases.