Li Dongping, Wan Meijuan, Xue Lanfeng, Zhang Zhelin, Qiu Yifeng, Mei Fengyi, Tang Niexing, Yu Chunxiao, Yu Yao, Chen Tianqi, Ding Xing, Yang Qin, Liu Qiuyan, Gu Peng, Jia Wei, Chen Yu, Chen Peng
Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China.
Cell Host Microbe. 2024 Dec 11;32(12):2195-2211.e9. doi: 10.1016/j.chom.2024.11.002. Epub 2024 Nov 27.
Cholestatic liver disease (CLD) is a common liver disorder with limited treatment options. Here, we demonstrate that zinc (Zn) supplementation can alter the gut microbiome to mitigate cholestatic liver injury. Oral Zn altered the microbiota of mice and humans (this study was registered at clinicaltrials.gov [NCT05597137]), increasing the abundance of Blautia producta (B. producta) and promoting the generation of p-coumaric acid. Additionally, p-coumaric acid concentrations were negatively correlated with liver injury parameters in CLD patients. In mice, the protective effects of Zn were partially mediated by p-coumaric acid, which directly bound to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and suppressed the production of reactive oxygen species (ROS) in hepatocytes, thus preventing hepatocyte cell death and liver damage. Additionally, knocking out the histidine ammonia-lyase, which catalyzes the conversion of tyrosine to p-coumaric acid in B. producta, blunted the protective effects of Zn. These findings highlight a host-microbiota interaction that is stimulated by Zn supplementation, providing potential benefits for CLD.
胆汁淤积性肝病（CLD）是一种常见的肝脏疾病，治疗选择有限。在此，我们证明补充锌（Zn）可以改变肠道微生物群，减轻胆汁淤积性肝损伤。口服锌改变了小鼠和人类的微生物群（本研究已在ClinicalTrials.gov注册 [NCT05597137]），增加了普拉梭菌（B. producta）的丰度并促进了对香豆酸的生成。此外，对香豆酸浓度与CLD患者的肝损伤参数呈负相关。在小鼠中，锌的保护作用部分由对香豆酸介导，对香豆酸直接与烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶2（NOX2）结合并抑制肝细胞中活性氧（ROS）的产生，从而防止肝细胞死亡和肝损伤。此外，敲除催化普拉梭菌中酪氨酸转化为对香豆酸的组氨酸解氨酶，会减弱锌的保护作用。这些发现突出了补充锌所刺激的宿主-微生物群相互作用，为CLD带来潜在益处。
