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 devel-opment 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.16S rRNA 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 metabolite 3,4-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-dihydroxyphenylpropio-nic acid suppressed the macrophage pro-inflammatory response in vivo and in vitro.This metabolite in-hibits 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.

Rui Li;Li Xie;Lei Li;Xiaojiao Chen;Tong Yao;Yuanxin Tian;Qingping Li;Kai Wang;Chenyang Huang;Cui Li;Yifan Li;Hongwei Zhou;Neil Kaplowitz;Yong Jiang;Peng Chen

Department of Pathophysiology,Guangdong Provincial Key Laboratory of Proteomics,School of Basic Medical Sciences,Southern Medical University,Guangzhou 510515,China;Microbiome Medicine Center,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Science,Southern Medical University,Guangzhou 510515,China;Division of Hepatobiliopancreatic Surgery,Department of General Surgery,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;USC Research Center for Liver Disease,Department of Medicine,Keck School of Medicine of USC,Los Angeles,CA 90089,USA

药学学报（英文版）

[1]Rui Li;Li Xie;Lei Li;Xiaojiao Chen;Tong Yao;Yuanxin Tian;Qingping Li;Kai Wang;Chenyang Huang;Cui Li;Yifan Li;Hongwei Zhou;Neil Kaplowitz;Yong Jiang;Peng Chen-.The gut microbial metabolite,3,4-dihydroxyphenylpropionic acid,alleviates hepatic ischemia/reperfusion injury via mitigation of macrophage pro-inflammatory activity in mice)[J].药学学报（英文版）,2022(01):182-196

dihydroxyphenylpropionic,dihydroxyphenylpropio

gut,microbial,acid,alleviates,hepatic,ischemia,reperfusion,injury,mitigation,inflammatory,activity,mice,Hepatic,HIRI,serious,complication,that,occurs,following,shock,liver,surgery,Gut,microbiota,their,metabolites,key,upstream,modulators,devel,opment,Herein,investigated,potential,contribution,microbes,Ischemia,was,performed,establish,murine,model,16S,rRNA,gene,sequencing,metabolomics,were,used,analysis,Transcriptomics,proteomics,employed,study,host,cell,responses,Our,results,significantly,increased,when,occurred,evening,ZT12,compared,morning,ZT0,however,antibiotic,pretreatment,reduced,this,diurnal,variation,abundance,higher,compound,protected,against,Furthermore,suppressed,vivo,vitro,This,hibits,histone,deacetylase,by,reducing,phosphorylation,Histone,inhibition,activation,diminished,findings,revealed,novel,protective,underlying,mechanism,least,part,dependent,immune,regulation,HDAC,macrophages

0.530585