In the past decade, research on the biology of the gut-liver axis has assisted in understanding the basic biology of nonalcoholic fatty liver disease (NAFLD). High mobility group box 1 (HMGB1) protein, in its role as a crucial injury-related molecule, displays a substantial correlation with the degree of liver steatosis. However, its underlying molecular mechanism remains unclear. In the current study of ASC(-/-) mice on a high-fat diet (HFD), we observed disorder of the gut microbiota along with abnormal increases in the Firmicutes:Bacteroidetes ratio and in Streptomyces, both of which were detected by 16S rDNA sequencing. Therefore, we investigated the intestinal mucosal injury and analyzed the NAFLD activity score and found that the ASC(-/-)-HFD group was more severely impaired than the others. Moreover, HMGB1 increased significantly in the intestinal tissue and was co-localized with an exosomal marker. We revealed that HMGB1 was significantly elevated in the exosomes of the ASC(-/-)-HFD group. It transported by exosomes from the intestine to the liver, thereby triggering hepatic steatosis when dysbiosis. In conclusion, the findings indicated that HMGB1 plays a crucial role in the gut-liver axis mechanism. (C) 2019 Elsevier Inc. All rights reserved.