Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Mol Gastroenterol Hepatol. 2023;16(6):857-879. doi: 10.1016/j.jcmgh.2023.08.001. Epub 2023 Aug 11.
BACKGROUND＆AIMS: Gut bacteria translocate into the liver through a disrupted gut vascular barrier, which is an early and common event in the development of nonalcoholic fatty liver disease (NAFLD). Liver sinusoidal endothelial cells (LSECs) are directly exposed to translocated gut microbiota in portal vein blood. Escherichia coli, a commensal gut bacterium with flagella, is markedly enriched in the gut microbiota of patients with NAFLD. However, the impact of E coli on NAFLD progression and its underlying mechanisms remains unclear.
The abundance of E coli was analyzed by using 16S ribosomal RNA sequencing in a cohort of patients with NAFLD and healthy controls. The role of E coli was assessed in NAFLD mice after 16 weeks of administration, and the features of NAFLD were evaluated. Endothelial to mesenchymal transition (EndMT) in LSECs induced by E coli was analyzed through Western blotting and immunofluorescence.
The abundance of gut Enterobacteriaceae increased in NAFLD patients with severe fat deposition and fibrosis. Importantly, translocated E coli in the liver aggravated hepatic steatosis, inflammation, and fibrosis in NAFLD mice. Mechanistically, E coli induced EndMT in LSECs through the TLR5/MYD88/TWIST1 pathway during NAFLD development. The toll-like receptor 5 inhibitor attenuated E coli-induced EndMT in LSECs and liver injury in NAFLD mice. Interestingly, flagellin-deficient E coli promoted less EndMT in LSECs and liver injury in NAFLD mice.
E coli promoted the development of NAFLD and promoted EndMT in LSECs through toll-like receptor 5/nuclear factor kappa B-dependent activation of TWIST1 mediated by flagellin. Therapeutic interventions targeting E coli and/or flagellin may represent a promising candidate for NAFLD treatment.
肠道细菌通过受损的肠道血管屏障易位到肝脏，这是非酒精性脂肪性肝病（NAFLD）发展过程中的早期和常见事件。肝窦内皮细胞（LSEC）直接暴露于门静脉血液中易位的肠道微生物群。大肠杆菌是一种具有鞭毛的共生肠道细菌，在 NAFLD 患者的肠道微生物群中明显富集。然而，大肠杆菌对 NAFLD 进展的影响及其潜在机制尚不清楚。
使用 16S 核糖体 RNA 测序对 NAFLD 患者和健康对照者进行分析，评估大肠杆菌在 16 周给药后 NAFLD 小鼠中的作用，并评估 NAFLD 的特征。通过 Western blot 和免疫荧光分析大肠杆菌诱导的 LSEC 内皮到间充质转化（EndMT）。
严重脂肪沉积和纤维化的 NAFLD 患者肠道肠杆菌科的丰度增加。重要的是，肝脏易位的大肠杆菌加剧了 NAFLD 小鼠的肝脂肪变性、炎症和纤维化。在机制上，大肠杆菌通过 TLR5/MYD88/TWIST1 通路在 NAFLD 发展过程中诱导 LSEC 中的 EndMT。TLR5 抑制剂减弱了大肠杆菌诱导的 LSEC 和 NAFLD 小鼠肝脏损伤中的 EndMT。有趣的是，鞭毛缺陷型大肠杆菌在 NAFLD 小鼠中促进较少的 LSEC 和肝脏损伤中的 EndMT。
大肠杆菌通过鞭毛介导的 TLR5/核因子 kappa B 依赖性 TWIST1 激活促进 NAFLD 的发展，并促进 LSEC 中的 EndMT。针对大肠杆菌和/或鞭毛的治疗干预可能是治疗 NAFLD 的有前途的候选药物。
