State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Collaborative Innocation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, 250000, China.
Free Radic Biol Med. 2023 Jul;203:11-23. doi: 10.1016/j.freeradbiomed.2023.03.026. Epub 2023 Mar 30.
Acetaminophen (APAP) overdose is the most common driver of drug-induced liver injury (DILI) worldwide, and the gut microbiome plays a crucial role in this process. In this study, we estimated the effect of Bifidobacterium longum R0175 on APAP-induced liver injury in mice and discovered that B. longum R0175 alleviated liver injury by diminishing inflammation, reducing oxidative stress levels, inhibiting hepatocyte death and improving APAP-induced microbiome dysbiosis. Further studies revealed that the antioxidative effects of B. longum R0175 were primarily due to activation of the Nrf2 pathway, which was supported by the Nrf2 pathway inhibitor ML385 counteracting these ameliorative effects. B. longum R0175 modified intestinal metabolites, especially the key metabolite sedanolide, which could activate the Nrf2 pathway and contribute to the protective effects against APAP-induced liver injury. Moreover, we found that sedanolide exhibited close interrelationships with specific microbial taxa, indicating that this factor may be derived from gut microbes. In conclusion, our work demonstrated that B. longum R0175 could reduce oxidative damage, inflammation and hepatocyte death by activating the Nrf2 pathway. Importantly, we identified the microbiota-derived metabolite sedanolide, which was first discovered in the mouse intestine, as a key agonist of the Nrf2 pathway and primary effector of B. longum R0175 in APAP challenge. These findings provide new perspectives for APAP overdose therapy and demonstrate the enormous potential of B. longum R0175 in alleviating acute liver injury.
对乙酰氨基酚（APAP）过量是全球范围内导致药物性肝损伤（DILI）的最常见原因，而肠道微生物组在这一过程中起着至关重要的作用。在这项研究中，我们评估了长双歧杆菌 R0175 对 APAP 诱导的小鼠肝损伤的影响，发现长双歧杆菌 R0175 通过减少炎症、降低氧化应激水平、抑制肝细胞死亡和改善 APAP 诱导的微生物组失调来缓解肝损伤。进一步的研究表明，长双歧杆菌 R0175 的抗氧化作用主要归因于 Nrf2 通路的激活，这一结论得到了 Nrf2 通路抑制剂 ML385 拮抗这些改善作用的支持。长双歧杆菌 R0175 改变了肠道代谢物，特别是关键代谢物 sedanolide，它可以激活 Nrf2 通路，有助于对 APAP 诱导的肝损伤发挥保护作用。此外，我们发现 sedanolide 与特定的微生物类群密切相关，表明这一因素可能来源于肠道微生物。总之，我们的工作表明，长双歧杆菌 R0175 通过激活 Nrf2 通路可以减少氧化损伤、炎症和肝细胞死亡。重要的是，我们确定了微生物衍生的代谢物 sedanolide，这是首次在小鼠肠道中发现的，它是 Nrf2 通路的关键激动剂，也是长双歧杆菌 R0175 在 APAP 挑战中发挥作用的主要效应物。这些发现为 APAP 过量治疗提供了新的视角，并展示了长双歧杆菌 R0175 在缓解急性肝损伤方面的巨大潜力。
