Gut Microbiome-Generated Phenylacetylglutamine from Dietary Protein is Associated with Crohn’s Disease and Exacerbates Colitis in Mouse Model Possibly via Platelet Activation

结肠炎 离体 血小板活化 血小板 肠道菌群 免疫学 炎症性肠病 丁酸盐 内科学 医学 生物 体内 疾病 生物化学 发酵 生物技术
作者
Rui Feng,Zhenyi Tian,Ren Mao,Wei Wang,Wanrong Luo,Min Zhao,Xiaozhi Li,Yunchong Liu,Kan Huang,Liyuan Xiang,Xiaojun Zhuang,Bitao Huo,Tiantian Yu,Sifan Chen,Minhu Chen,Yijun Zhu
出处
期刊:Journal of Crohn's and Colitis [Oxford University Press]
卷期号:17 (11): 1833-1846 被引量:9
标识
DOI:10.1093/ecco-jcc/jjad098
摘要

Abstract Objectives Our aims were to better understand the interplay of diet and gut microbiota in Crohn’s disease [CD], taking advantage of a new-onset treatment-naïve CD cohort. We focus on phenylacetylglutamine [PAGln], a diet-derived meta-organismal prothrombotic metabolite. Design We collected faecal and serum samples from a CD cohort [n = 136] and healthy controls [n = 126] prior to treatment, and quantified serum PAGln using LC-MS/MS. Diet was assessed using food-frequency questionnaires. Mice [C57BL/6] were fed high/low-protein diets and administered dextran sodium sulphate [DSS] to examine plasma PAGly, thrombosis potential, and colitis severity. PAGly or saline was administered to DSS-induced colitis mice, and colitis severity and colonic tissue gene expression were examined. P-selectin and CD40L expression were determined in human platelet-rich plasma [n = 5–6] after exposure to platelet agonists following PAGln priming. Bioinformatic analysis and bacterial culturing identified the main contributor of PAGln in CD. Results PAGln, a meta-organismal prothrombotic metabolite, is associated with CD. Administration of PAGly exacerbated colitis in a mouse model and upregulated coagulation-related biological processes. Antiplatelet medicine, dipyridamole, attenuated PAGly-enhanced colitis susceptibility. PAGln enhanced platelet activation and CD40L expression in platelet-rich plasma ex vivo. Further study revealed that high dietary protein intake and increased abundance of phenylacetic acid [PAA]-producing Proteobacteria mediated by phenylpyruvate decarboxylase act in concert to cause the elevated PAGln levels in CD patients. Conclusion Taken together, ppdc-carrying Proteobacteria-generated PAGln from dietary protein is associated with CD and exacerbates colitis possibly via platelet-induced coagulation and inflammation These results suggest that PAGln is a potential early diagnostic marker and therapeutic target of CD.
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