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

Ming Yang, Xiaoqiang Qi, Nan Li, Jussuf T. Kaifi, Shiyou Chen, Andrew A. Wheeler, Eric T. Kimchi, Aaron C. Ericsson, R. Scott Rector, Kevin F. Staveley-O’Carroll () and Guangfu Li ()
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Ming Yang: University of Missouri
Xiaoqiang Qi: University of Missouri
Nan Li: University of Missouri
Jussuf T. Kaifi: University of Missouri
Shiyou Chen: University of Missouri
Andrew A. Wheeler: University of Missouri
Eric T. Kimchi: University of Missouri
Aaron C. Ericsson: University of Missouri
R. Scott Rector: University of Missouri
Kevin F. Staveley-O’Carroll: University of Missouri
Guangfu Li: University of Missouri

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-35861-1

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