Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non-alcoholic steatohepatitis

Zhenlong Luo; Yudong Ji; Dinghong Zhang; Hong Gao; Zhongmou Jin; Meixiang Yang; Wei Ying

doi:10.1111/apha.13827

Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non-alcoholic steatohepatitis

Acta Physiol (Oxf). 2022 Jul;235(3):e13827. doi: 10.1111/apha.13827. Epub 2022 May 10.

Authors

Zhenlong Luo^{1

2}, Yudong Ji^{1

3}, Dinghong Zhang¹, Hong Gao¹, Zhongmou Jin⁴, Meixiang Yang^{5

6}, Wei Ying¹

Affiliations

¹ Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, California, USA.
² Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Anesthesiology, Institute of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Division of Biological Sciences, University of California, San Diego, California, USA.
⁵ Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, California, USA.
⁶ Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Biomedical Translational Research Institute, Jinan University, Guangzhou, China.

Abstract

Aim: Low-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.

Methods: We 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.

Results: Non-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.

Conclusion: Accumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.

Keywords: Vsig4+ macrophages; liver fibrogenic activation; liver inflammation; microbial DNAs; microbiota-derived extracellular vesicles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA, Bacterial
Disease Models, Animal
Fibrosis
Hepatocytes / pathology
Hepatocytes / physiology
Inflammation / pathology
Liver / pathology
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / prevention & control
Nucleotidyltransferases

Substances

DNA, Bacterial
Nucleotidyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding