College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; Institute of Nutritional and Metabolic Disorders in Domestic Animals and Fowls, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China; MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
Sci Total Environ. 2022 Nov 25;849:157861. doi: 10.1016/j.scitotenv.2022.157861. Epub 2022 Aug 5.
Cadmium (Cd) is a widely prevalent environmental pollutant that accumulates in the liver and induces liver injury. The mechanism of Cd-induced liver injury remains elusive. Our study aimed to clarify the mechanism by which changes in the gut microbiota contribute to Cd-induced liver injury. Here, a murine model of liver injury induced by chronic Cd exposure was used. Liver injury was assessed by biochemistry and histopathology. Expression profiles of genes involved in bile acid (BA) homeostasis, inflammation and injury were assessed via Realtime-PCR and Western-blot. 16S rRNA gene sequencing and mass spectrometry-based metabolomics were used to investigate changes in the gut microbiota and its metabolites in the regulation of Cd-induced liver injury. Here, we showed that Cd exposure induced hepatic ductular proliferation, hepatocellular damage and inflammatory infiltration in mice. Cd exposure induced gut microbiota dysbiosis and reduced the fecal bile salt hydrolase activity leading to an increase of tauro-β-muricholic acid levels in the intestine. Cd exposure decreased intestine FXR/FGF-15 signaling and promoted hepatic BA synthesis. Furthermore, the mice receiving fecal microbiota transplantation from Cd-treated mice showed reduced intestinal FXR/FGF-15 signaling, increased hepatic BA synthesis, and liver injury. However, the depletion of the commensal microbiota by antibiotics failed to change these indices in Cd-treated mice. Finally, the administration of the intestine-restricted FXR agonist fexaramine attenuated the liver injury, improved the intestinal barrier, and decreased hepatic BA synthesis in the Cd-treated mice. Our study identified a new mechanism of Cd-induced liver injury. Cd-induced gut microbiota dysbiosis, decreased feces BSH activity, and increased intestinal T-βMCA levels led to an inhibition of intestinal FXR/FGF-15 signaling and an increase in hepatic BA synthesis, ultimately facilitating the development of hepatic ductular proliferation, inflammation, and injury in mice. This study expands our understanding of the health hazards caused by environmental Cd pollution.
镉 (Cd) 是一种广泛存在的环境污染物，会在肝脏中积累并导致肝损伤。镉诱导肝损伤的机制仍不清楚。我们的研究旨在阐明肠道微生物群的变化如何导致镉诱导的肝损伤。在这里，我们使用了慢性镉暴露诱导肝损伤的小鼠模型。通过生物化学和组织病理学评估肝损伤。通过 Realtime-PCR 和 Western-blot 评估参与胆汁酸 (BA) 稳态、炎症和损伤的基因的表达谱。16S rRNA 基因测序和基于质谱的代谢组学用于研究肠道微生物群及其代谢物在调节镉诱导的肝损伤中的变化。在这里，我们表明镉暴露诱导小鼠肝内胆管增生、肝细胞损伤和炎症浸润。镉暴露诱导肠道微生物群失调，降低粪便胆盐水解酶活性，导致肠道中牛磺-β-鼠胆酸水平升高。镉暴露降低了肠道 FXR/FGF-15 信号传导，促进了肝脏 BA 的合成。此外，从镉处理小鼠中接受粪便微生物群移植的小鼠表现出肠道 FXR/FGF-15 信号传导减少、肝脏 BA 合成增加和肝损伤。然而，抗生素耗尽共生菌群并不能改变镉处理小鼠的这些指标。最后，肠道受限的 FXR 激动剂 fexaramine 的给药减轻了镉处理小鼠的肝损伤，改善了肠道屏障，并减少了肝脏 BA 的合成。我们的研究确定了镉诱导肝损伤的新机制。镉诱导的肠道微生物群失调、粪便 BSH 活性降低和肠道 T-βMCA 水平升高导致肠道 FXR/FGF-15 信号传导抑制和肝脏 BA 合成增加，最终促进了小鼠肝内胆管增生、炎症和损伤的发展。这项研究扩展了我们对环境镉污染引起的健康危害的认识。
