Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department of Gastroenterology and Hepatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
BMC Microbiol. 2024 Feb 28;24(1):69. doi: 10.1186/s12866-024-03195-7.
Liver steatosis is the most frequent liver disorder and its advanced stage, non-alcoholic steatohepatitis (NASH), will soon become the main reason for liver fibrosis and cirrhosis. The "multiple hits hypothesis" suggests that progression from simple steatosis to NASH is triggered by multiple factors including the gut microbiota composition. The Epstein Barr virus induced gene 2 (EBI2) is a receptor for the oxysterol 7a, 25-dihydroxycholesterol synthesized by the enzymes CH25H and CYP7B1. EBI2 and its ligand control activation of immune cells in secondary lymphoid organs and the gut. Here we show a concurrent study of the microbial dysregulation and perturbation of the EBI2 axis in a mice model of NASH.We used mice with wildtype, or littermates with CH25H, EBI2, or CYP7B1 genotypes fed with a high-fat diet (HFD) containing high amounts of fat, cholesterol, and fructose for 20 weeks to induce liver steatosis and NASH. Fecal and small intestinal microbiota samples were collected, and microbiota signatures were compared according to genotype and NASH disease state.We found pronounced differences in microbiota composition of mice with HFD developing NASH compared to mice did not developing NASH. In mice with NASH, we identified significantly increased 33 taxa mainly belonging to the Clostridiales order and/ or the family, and significantly decreased 17 taxa. Using an Elastic Net algorithm, we suggest a microbiota signature that predicts NASH in animals with a HFD from the microbiota composition with moderate accuracy (area under the receiver operator characteristics curve = 0.64). In contrast, no microbiota differences regarding the studied genotypes (wildtype vs knock-out CH25H, EBI2, or CYP7B1) were observed.In conclusion, our data confirm previous studies identifying the intestinal microbiota composition as a relevant marker for NASH pathogenesis. Further, no link of the EBI2 - oxysterol axis to the intestinal microbiota was detectable in the current study.
肝脏脂肪变性是最常见的肝脏疾病，其晚期阶段——非酒精性脂肪性肝炎（NASH），将很快成为肝纤维化和肝硬化的主要原因。“多次打击假说”表明，从单纯脂肪变性到 NASH 的进展是由多种因素触发的，包括肠道微生物群落组成。Epstein Barr 病毒诱导基因 2（EBI2）是由酶 CH25H 和 CYP7B1 合成的氧化固醇 7α、25-二羟胆固醇的受体。EBI2 和其配体控制次级淋巴器官和肠道中免疫细胞的激活。在这里，我们在 NASH 小鼠模型中同时研究了微生物失调和 EBI2 轴的扰动。我们使用野生型小鼠或具有 CH25H、EBI2 或 CYP7B1 基因型的同窝仔鼠，用高脂肪饮食（HFD）喂养 20 周，其中含有大量脂肪、胆固醇和果糖，以诱导肝脏脂肪变性和 NASH。收集粪便和小肠微生物样本，并根据基因型和 NASH 疾病状态比较微生物特征。我们发现，与未发生 NASH 的小鼠相比，发生 NASH 的 HFD 喂养小鼠的微生物组成有明显差异。在发生 NASH 的小鼠中，我们鉴定出显著增加的 33 个分类群，主要属于梭菌目和/或科，以及显著减少的 17 个分类群。使用弹性网络算法，我们提出了一个基于微生物组成的预测动物 NASH 的微生物特征，具有中等准确性（接收器操作特征曲线下面积 = 0.64）。相比之下，未观察到研究基因型（野生型与敲除 CH25H、EBI2 或 CYP7B1）的微生物差异。总之，我们的数据证实了先前的研究，即肠道微生物组成是 NASH 发病机制的一个相关标志物。此外，在本研究中，未检测到 EBI2-氧化固醇轴与肠道微生物之间的联系。
