Objective: The gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury. Design: Fecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5∆hep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice over-expressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor. Results: The composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5∆hep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice. Conclusion: Gut dysbiosis can remedy liver injury in Atg5∆hep mice through the FXR-FGF15 signaling. Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gut-liver axis.

中文翻译：

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肠道营养不良通过FXR-FGF15反馈信号转导保护自噬缺陷小鼠的肝损伤

目的：肠道菌群（GM）与体内许多器官的功能之间可能具有复杂且常常不确定的相互作用。GM在多种肝病中都有变化，但是这种变化对肝病的意义仍不清楚。肝自噬不足会导致肝损伤并伴有胆汁淤积。在这里，我们研究了这种肝脏变化对转基因的影响，以及肠道营养不良对肝损伤的影响。设计：通过16S测序分析了具有肝脏特异性自噬相关基因5（Atg5）缺失的小鼠（Atg5Δhep小鼠）的粪便微生物群。抗生素（ABX）用于调节小鼠的GM。胆甾胺被用于降低肠肝胆汁酸（BA）水平。在过表达FGF15基因的小鼠中或给予成纤维细胞生长因子受体4（FGFR4）抑制剂的小鼠中检查了成纤维细胞生长因子15（FGF15）和回肠法呢素X受体（FXR）的功能作用。结果：在Atg5Δhep小鼠中，GM的组成发生了显着变化，其中BA代谢细菌显着增加，导致肠道内tauro结合BA的比例降低，而未结合BA的比例更高，从而显着激活了回肠FXR FGF15表达增加。ABX或消胆胺治疗可加重自噬缺陷小鼠的肝损伤和导管反应，并降低FGF15表达，而调节FGF15信号改变了肝脏表型。结论：肠道营养不良可以通过FXR-FGF15信号传导修复Atg5Δhep小鼠的肝损伤。