Deng Shenghe, Cao Huan, Li Tongxi, Wang Xueling, Meng Junpeng, Zeng Teng, Zhang Di, Zhang Shuhua, Wang Guoliang, Liu Ran, Zou Tianhao, Cai Mao, Lang Ren, Lu Di, Gu Jinyang
Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of General Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Gut Microbes. 2025 Dec;17(1):2460543. doi: 10.1080/19490976.2025.2460543. Epub 2025 Jan 30.
Ischemia-reperfusion injury (IRI) is a major obstacle in liver transplantation, especially with steatotic donor livers. Dysbiosis of the gut microbiota has been implicated in modulating IRI, and plays a pivotal role in regulating host inflammatory and immune responses, but its specific role in liver transplantation IRI remains unclear. This study explores whether can mitigate IRI and its underlying mechanisms. We found (.) abundance was significantly reduced in rats with liver cirrhosis. .-treated rats exhibited improved intestinal permeability, reduced IRI severity in both normal and steatotic donor livers, and decreased levels of neutrophil and macrophage infiltration, and inflammatory cytokines. Multi-omics analysis revealed elevated pyruvate levels in transplanted livers after . treatment, alongside reduced Alox15 and Foxo3 expression. Mechanistically, .-derived pyruvate inhibited Alox15 expression and reduced ferroptosis in normal and steatotic donor livers. Furthermore, reduced nuclear translocation of Foxo3 further suppressed Alox15 expression, alleviating IRI, especially in steatotic donor livers. Clinical samples confirmed reduced donor livers IRI in cirrhotic recipients with high . abundance after liver transplantation. In conclusion, . alleviates IRI in steatotic donor liver transplantation by inhibiting ferroptosis via the Foxo3-Alox15 axis, providing a potential therapeutic strategy to modulate gut microbiota to alleviate IRI following liver transplantation.
缺血再灌注损伤（IRI）是肝移植中的一个主要障碍，尤其是对于脂肪变性的供体肝脏。肠道微生物群的失调与调节IRI有关，并且在调节宿主炎症和免疫反应中起关键作用，但其在肝移植IRI中的具体作用仍不清楚。本研究探讨了[具体物质]是否可以减轻IRI及其潜在机制。我们发现肝硬化大鼠中[具体物质]的丰度显著降低。用[具体物质]处理的大鼠表现出肠道通透性改善、正常和脂肪变性供体肝脏的IRI严重程度降低、中性粒细胞和巨噬细胞浸润水平以及炎性细胞因子水平降低。多组学分析显示，[具体物质]处理后移植肝脏中的丙酮酸水平升高，同时Alox15和Foxo3表达降低。从机制上讲，[具体物质]衍生的丙酮酸抑制正常和脂肪变性供体肝脏中的Alox15表达并减少铁死亡。此外，Foxo3核转位减少进一步抑制了Alox15表达，减轻了IRI，尤其是在脂肪变性供体肝脏中。临床样本证实，肝移植后[具体物质]丰度高的肝硬化受者的供体肝脏IRI降低。总之，[具体物质]通过Foxo3 - Alox15轴抑制铁死亡来减轻脂肪变性供体肝移植中的IRI，为调节肠道微生物群以减轻肝移植后IRI提供了一种潜在的治疗策略。
