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The gut microbial metabolite, 3,4-dihydroxyphenylpropionic acid, alleviates hepatic ischemia/reperfusion injury via mitigation of macrophage pro-inflammatory activity in mice

查看全文 作　　者：Rui [1]Li;Li [1]Xie;Lei [1]Li;Xiaojiao [5]Chen;Tong [1]Yao;Yuanxin [2]Tian;Qingping [3]Li;Kai [3]Wang;Chenyang [1]Huang;Cui [1]Li;Yifan [1]Li;Hongwei [5]Zhou;Neil [4]Kaplowitz;Yong [1]Jiang;Peng [1,5]Chen 高影响力作者 机构地区：[1]Department of Pathophysiology,Guangdong Provincial Key Laboratory of Proteomics,School of Basic Medical Sciences,Southern Medical University,Guangzhou 510515,China;[2]Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Science,Southern Medical University,Guangzhou 510515,China;[3]Division of Hepatobiliopancreatic Surgery,Department of General Surgery,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;[4]USC Research Center for Liver Disease,Department of Medicine,Keck School of Medicine of USC,Los Angeles,CA 90089,USA;[5]Microbiome Medicine Center,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China高影响力机构 出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第1期,共15页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China(81873926,32071124);Natural Science Funds for Distinguished Young Scholar of Guangdong province grant(2016A030306043,China)to Peng Chen;Grants from the NSFCGuangdong Joint Foundation of China(U1601225);Natural Science Foundation of China(81971895);Special Support Plan for Outstanding Talents of Guangdong Province(2019JC05Y340,China)to Yong Jiang。 摘　　要：Hepatic ischemia/reperfusion injury(HIRI) is a serious complication that occurs following shock and/or liver surgery. Gut microbiota and their metabolites are key upstream modulators of development of liver injury. Herein, we investigated the potential contribution of gut microbes to HIRI.Ischemia/reperfusion surgery was performed to establish a murine model of HIRI. 16 S r RNA gene sequencing and metabolomics were used for microbial analysis. Transcriptomics and proteomics analysis were employed to study the host cell responses. Our results establish HIRI was significantly increased when surgery occurred in the evening(ZT12, 20:00) when compared with the morning(ZT0, 08:00);however, antibiotic pretreatment reduced this diurnal variation. The abundance of a microbial metabolite3,4-dihydroxyphenylpropionic acid was significantly higher in ZT0 when compared with ZT12 in the gut and this compound significantly protected mice against HIRI. Furthermore, 3,4-dihydroxyphenylpropionic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro. This metabolite inhibits histone deacetylase activity by reducing its phosphorylation. Histone deacetylase inhibition suppressed macrophage pro-inflammatory activation and diminished the diurnal variation of HIRI. Our findings revealed a novel protective microbial metabolite against HIRI in mice. The potential underlying mechanism was at least in part, via 3,4-dihydroxyphenylpropionic acid-dependent immune regulation and histone deacetylase(HDAC) inhibition in macrophages. 关 键 词：Hepatic ischemia/reperfusion injury Diurnal variation 3,4-Dihydroxy phenylpropionic acid Gut microbiota
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