Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol

• Published in: Nature communications Vol. 14; no. 1; p. 228
• Main Authors: Yang, Ming, Qi, Xiaoqiang, Li, Nan, Kaifi, Jussuf T., Chen, Shiyou, Wheeler, Andrew A., Kimchi, Eric T., Ericsson, Aaron C., Rector, R. Scott, Staveley-O’Carroll, Kevin F., Li, Guangfu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 14/1; 14/63; 38/23; 38/77; 64; 64/60; 692/4020/4021/1607/1605; 692/4020/4021/1607/2751; Animals; Blautia; Cell activation; Choline; Diet; Diet, High-Fat - adverse effects; Diet, Western - adverse effects; Disease Models, Animal; Fatty liver; Fibrosis; Gastrointestinal Microbiome; High fat diet; Humanities and Social Sciences; In vivo methods and tests; Inflammation; Inflammation - pathology; Intestinal microflora; Liver; Liver - metabolism; Liver diseases; Low fat diet; Macrophages; Male; Males; Metabolism; Metabolites; Metabolomics; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Microorganisms; multidisciplinary; NF-κB protein; Non-alcoholic Fatty Liver Disease - metabolism; Nutrient deficiency; Pathogenesis; Priming; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Signal transduction; Steatosis; TAK1 protein; Transforming growth factor-b1
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-35861-1

The interplay between western diet and gut microbiota drives the development of non-alcoholic fatty liver disease and its progression to non-alcoholic steatohepatitis. However, the specific microbial and metabolic mediators contributing to non-alcoholic steatohepatitis remain to be identified. Here, a choline-low high-fat and high-sugar diet, representing a typical western diet, named CL-HFS, successfully induces male mouse non-alcoholic steatohepatitis with some features of the human disease, such as hepatic inflammation, steatosis, and fibrosis. Metataxonomic and metabolomic studies identify Blautia producta and 2-oleoylglycerol as clinically relevant bacterial and metabolic mediators contributing to CL-HFS-induced non-alcoholic steatohepatitis. In vivo studies validate that both Blautia producta and 2-oleoylglycerol promote liver inflammation and hepatic fibrosis in normal diet- or CL-HFS-fed mice. Cellular and molecular studies reveal that the GPR119/TAK1/NF-κB/TGF-β1 signaling pathway mediates 2-oleoylglycerol-induced macrophage priming and subsequent hepatic stellate cell activation. These findings advance our understanding of non-alcoholic steatohepatitis pathogenesis and provide targets for developing microbiome/metabolite-based therapeutic strategies against non-alcoholic steatohepatitis. Interplay of western diet and gut microbiota has been reported to be involved in the development of nonalcoholic steatohepatitis (NASH). Here the authors report that Blautia producta and 2-oleoylglycerol are bacterial and metabolic mediators that promote liver inflammation and hepatic fibrosis in male mice.