Procyanidin C1 Modulates the Microbiome to Increase FOXO1 Signaling and Valeric Acid Levels to Protect the Mucosal Barrier in Inflammatory Bowel Disease  

作　　者：Xifan Wang Pengjie Wang Yixuan Li Huiyuan Guo Ran Wang Siyuan Liu Ju Qiu Xiaoyu Wang Yanling Hao Yunyi Zhao Haiping Liao Zhongju Zou Josephine Thinwa Rong Liu 

机构地区：[1]Department of Obstetrics and Gynecology,Columbia University,New York,NY 10032,USA [2]Food Laboratory of Zhongyuan,Luohe 462000,China [3]Department of Internal Medicine,Department of Microbiology,UT Southwestern Medical Center,Dallas 75390-9030,USA

出　　处：《Engineering》2024年第11期108-120,共13页工程（英文）

基　　金：supported by the 111 projects of the Education Ministry of China(B18053);the National Natural Science Foundation(32130081);the National Key Research and Development Program of China(2022YFF0710402);the Pinduoduo-China Agricultural University Research Fund(PC2023B01014).

摘　　要：Inflammatory bowel disease(IBD)refers to a pair of prevalent conditions(Crohn’s disease and ulcerative colitis)distinguished by persistent inflammation of the large intestine.Procyanidin C1(PCC1)is a natu-rally occurring substance derived from grape seeds that has demonstrated notable anti-inflammatory properties.This study examines the potential utility of PCC1 as a treatment for IBD and subsequently examines the host-cell-and microbiome-related mechanisms underlying the detected therapeutic bene-fits.Working with a classic dextran sodium sulfate(DSS)-induced mouse IBD model,we show that PCC1 protects the mucosal barrier and thereby confers strong protective effects against IBD.PCC1 pretreatment resulted in anti-inflammatory effects and protection against multiple pathological phenotypes in the IBD model mice,including reduced weight loss,lower disease activity index(DAI)totals,and enhanced colon size,as well as obviously beneficial effects on the mucosal barrier(e.g.,barrier thickness and activity of mucus-degrading enzymes).We also analyzed the autophagy marker microtubule-associated protein1 light chain 3(LC3)and found that the level of LC3 was significantly elevated in the intestinal epithelial cell samples of the PCC1-pretreatment group as compared with the non-model mice samples.PCC1 altered the fecal microbiome composition,which included elevating the abundance of Akkermansia muci-niphila and Christensenella minuta.Fecal microbiome transplant(FMT)experiments showed that deliver-ing a microbiome from PCC1-treated animals into PCC1-naïve animals conferred protection.Metabolic profiling revealed that both the PCC1-pretreatment and PCC1 FMT groups had elevated levels of the microbiota-derived metabolite valeric acid,and supplementation with this short-chain fatty acid(SCFA)also conferred strong protection against IBD.Finally,inhibitor experiments confirmed that the beneficial effects of valeric acid on the mucus layer are mediated by FOXO1 signaling in the goblet cells of the intestinal epithelium.Beyond s

关 键 词：Inflammatory bowel disease Mucosal Barrier AUTOPHAGY 

分 类 号：R574[医药卫生—消化系统] TS201.4[医药卫生—内科学]