1. Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non‐alcoholic steatohepatitis
- Author
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Luo, Zhenlong, Ji, Yudong, Zhang, Dinghong, Gao, Hong, Jin, Zhongmou, Yang, Meixiang, and Ying, Wei
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Prevention ,Liver Disease ,Chronic Liver Disease and Cirrhosis ,Hepatitis ,Nutrition ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Inflammatory and immune system ,Good Health and Well Being ,Animals ,DNA ,Bacterial ,Disease Models ,Animal ,Fibrosis ,Hepatocytes ,Inflammation ,Liver ,Mice ,Mice ,Inbred C57BL ,Non-alcoholic Fatty Liver Disease ,Nucleotidyltransferases ,liver fibrogenic activation ,liver inflammation ,microbial DNAs ,microbiota-derived extracellular vesicles ,Vsig4+macrophages ,Vsig4+ macrophages ,Human Movement and Sports Sciences ,Physiology ,Medical physiology - Abstract
AimLow-grade inflammation is the hallmark of non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH). The leakage of microbiota-derived products can contribute to liver inflammation during NAFLD/NASH development. Here, we assessed the roles of gut microbial DNA-containing extracellular vesicles (mEVs) in regulating liver cellular abnormalities in the course of NAFLD/NASH.MethodsWe performed studies with Vsig4-/- , C3-/- , cGAS-/- , and their wild-type littermate mice. Vsig4+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut mEVs were adoptively transferred into Vsig4-/- , C3-/- , cGAS-/- , or littermate WT mice, and hepatocyte inflammation and HSC fibrogenic activation were measured in these mice.ResultsNon-alcoholic fatty liver diseases and non-alcoholic steatohepatitis development was concomitant with a diminished liver Vsig4+ macrophage population and a marked bacterial DNA enrichment in both hepatocytes and HSCs. In the absence of Vsig4+ macrophages, gut mEVs translocation led to microbial DNA accumulation in hepatocytes and HSCs, resulting elevated hepatocyte inflammation and HSC fibrogenic activation. In contrast, in lean WT mice, Vsig4+ macrophages remove gut mEVs from bloodstream through a C3-dependent opsonization mechanism and prevent the infiltration of gut mEVs into hepatic cells. Additionally, Vsig4-/- mice more quickly developed significant liver steatosis and fibrosis than WT mice after Western diet feeding. In vitro treatment with NASH mEVs triggered hepatocyte inflammation and HSC fibrogenic activation. Microbial DNAs are key cargo for the effects of gut mEVs by activating cGAS/STING.ConclusionAccumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.
- Published
- 2022