State Key Laboratory for Diagnosis, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang Universitygrid.13402.34, Hangzhou, China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
Microbiol Spectr. 2022 Feb 23;10(1):e0159621. doi: 10.1128/spectrum.01596-21. Epub 2022 Feb 2.
The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.
肠道微生物群驱动个体对过量对乙酰氨基酚（APAP）介导的肝毒性的敏感性。据报道，阿克曼氏菌（Akkermansia muciniphila）通过肝肠轴保护宿主免受肝病的影响，但它对药物性肝损伤的治疗潜力尚不清楚。在本研究中，我们旨在研究阿克曼氏菌对 APAP 诱导的肝损伤的影响及其潜在机制。阿克曼氏菌的给药有效地缓解了 APAP 诱导的肝毒性，并降低了血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）的水平。阿克曼氏菌显著减轻了 APAP 诱导的氧化应激和炎症反应，表现为还原型谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）平衡的恢复、超氧化物歧化酶（SOD）活性的增强、促炎细胞因子产生的减少以及巨噬细胞和中性粒细胞浸润的减轻。此外，阿克曼氏菌维持了肠道屏障功能，重塑了失调的微生物群落，并促进了短链脂肪酸（SCFA）的分泌。阿克曼氏菌的有益作用伴随着转录水平上的肝基因表达改变和磷脂酰肌醇 3-激酶（PI3K）/Akt 信号通路的激活。我们的结果表明，阿克曼氏菌可能是 APAP 诱导的肝损伤的一种潜在预处理方法。我们的工作表明，阿克曼氏菌通过减轻肝脏中的氧化应激和炎症来减轻 APAP 诱导的肝损伤，其肝保护作用伴随着 PI3K/Akt 通路的激活，并通过调节肠道微生物群落的组成和代谢功能来介导。这一发现表明，微生物群落对药物代谢有不可忽视的影响，益生菌的给药可能是药物性肝损伤的一种潜在治疗方法。
