Paeonol reduces microbial metabolite α-hydroxyisobutyric acid to alleviate the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in atherosclerosis mice  

作　　者：LIU Yarong WU Hongfei WANG Tian SHI Xiaoyan HE Hai HUANG Hanwen YANG Yulong DAI Min 

机构地区：[1]School of Pharmacy,Anhui University of Chinese Medicine,Hefei 230012,China [2]Anhui Province Key Laboratory of Research and Development of Chinese Medicine,Hefei 230012,China

出　　处：《Chinese Journal of Natural Medicines》2023年第10期759-774,共16页中国天然药物（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82104556 and 82174014);the Natural Science Foundation of Anhui Province,China(No.2108085-QH375);the National Project Cultivation Fund of Anhui University of Chinese Medicine(No.2021py01);the Talent Support Program of Anhui University of Chinese Medicine(No.2023rcyb027).

摘　　要：Gut microbiota dysbiosis is an avenue for the promotion of atherosclerosis(AS)and this effect is mediated partly via the circulating microbial metabolites.More microbial metabolites related to AS vascular inflammation,and the mechanisms involved need to be clarified urgently.Paeonol(Pae)is an active compound isolated from Paeonia suffruticoas Andr.with anti-As inflammation effect.However,considering the low oral bioavailability of Pae,it is worth exploring the mechanism by which Pae reduces the harmful metabolites of the gut microbiota to alleviate AS.In this study,ApoE--mice were fed a high-fat diet(HFD)to establish an AS model.AS mice were administrated with Pae(200 or 400 mg:kg')by oral gavage and fecal microbiota transplantation(FMT)was conducted.16S rDNA sequencing was performed to investigate the composition of the gut microbiota,while metabolomics analysis was used to identify the metabolites in serum and cecal contents.The results indicated that Pae significantly improved AS by regulating gut microbiota composition and microbiota metabolic profile in AS mice.We also identified a-hydroxyisobutyric acid(HIBA)as a harmful microbial metabolite reduced by Pae.HIBA supplementation in drinking water promoted AS inflammation in AS mice.Furthermore,vascular endothelial cells(VECs)were cultured and stimulated by HIBA.We verified that HIBA stimulation increased intracellular ROS levels,thereby inducing VEC inflammation via the TXNIP/NLRP3 pathway.In sum,Pae reduces the production of the microbial metabolite HIBA,thus alleviating the ROS/TXNIP/NLRP3 pathway-mediated endothelial inflammation in AS.Our study innovatively confirms the mechanism by which Pae reduces the harmful metabolites of gut microbiota to alleviate AS and proposes HIBA as a potential biomarker for AS clinical judgment.

关 键 词：ATHEROSCLEROSIS PAEONOL a-Hydroxyisobutyric acid Gut microbiota Vascular endothelial inflammation 

分 类 号：R965[医药卫生—药理学]