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The leakage of microbiota\u2010derived products can contribute to liver inflammation during NAFLD\/NASH development. Here, we assessed the roles of gut microbial DNA\u2010containing extracellular vesicles (mEVs) in regulating liver cellular abnormalities in the course of NAFLD\/NASH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed studies with Vsig4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , C3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , cGAS\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , and their wild\u2010type 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\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , C3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , cGAS\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , or littermate WT mice, and hepatocyte inflammation and HSC fibrogenic activation were measured in these mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Non\u2010alcoholic fatty liver diseases and non\u2010alcoholic 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\u2010dependent opsonization mechanism and prevent the infiltration of gut mEVs into hepatic cells. Additionally, Vsig4\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Accumulation of microbial DNAs fuels the development of NAFLD\/NASH\u2010associated liver abnormalities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.13827","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T15:28:56Z","timestamp":1651505336000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non\u2010alcoholic steatohepatitis"],"prefix":"10.1111","volume":"235","author":[{"given":"Zhenlong","family":"Luo","sequence":"first","affiliation":[{"name":"Division of Endocrinology &amp; Metabolism Department of Medicine University of California  San Diego California USA"},{"name":"Department of Gastroenterology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudong","family":"Ji","sequence":"additional","affiliation":[{"name":"Division of Endocrinology &amp; Metabolism Department of Medicine University of California  San Diego California USA"},{"name":"Department of Anesthesiology Institute of Anesthesiology and Critical Care Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinghong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology &amp; Metabolism Department of Medicine University of California  San Diego California 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