Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, California, USA.
Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Acta Physiol (Oxf). 2022 Jul;235(3):e13827. doi: 10.1111/apha.13827. Epub 2022 May 10.
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.
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.
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.
Accumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.
低度炎症是非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的标志。微生物衍生产物的渗漏可能导致 NAFLD/NASH 发展过程中的肝炎症。在这里，我们评估了肠道微生物 DNA 包含的细胞外囊泡（mEVs）在调节 NAFLD/NASH 过程中肝脏细胞异常的作用。
我们对 Vsig4、C3、cGAS 及其野生型同窝仔鼠进行了研究。通过流式细胞术或免疫组织化学分析，在小鼠和人肝中检测了 Vsig4+巨噬细胞群体和细菌 DNA 丰度。将肠道 mEVs 过继转移到 Vsig4、C3、cGAS 或同窝 WT 小鼠中，并在这些小鼠中测量肝细胞炎症和 HSC 纤维生成激活。
非酒精性脂肪肝和非酒精性脂肪性肝炎的发展伴随着肝 Vsig4+巨噬细胞群体的减少和肝细胞和 HSCs 中细菌 DNA 的明显富集。在没有 Vsig4+巨噬细胞的情况下，肠道 mEVs 的易位导致细菌 DNA 在肝细胞和 HSCs 中积累，导致肝细胞炎症和 HSC 纤维生成激活增加。相比之下，在瘦 WT 小鼠中，Vsig4+巨噬细胞通过 C3 依赖性调理机制将肠道 mEVs 从血液中清除，并防止肠道 mEVs 渗透到肝细胞中。此外，Vsig4 小鼠在西方饮食喂养后比 WT 小鼠更快地发展出显著的肝脂肪变性和纤维化。体外用 NASH mEVs 处理会引发肝细胞炎症和 HSC 纤维生成激活。微生物 DNA 是肠道 mEVs 作用的关键载体，通过激活 cGAS/STING。
微生物 DNA 的积累为 NAFLD/NASH 相关肝异常的发展提供了动力。
