刘窈玉;穆芳园;王一程;王曼宇;王春国;闫兴丽;
LIU Yao-yu;MU Fang-yuan;WANG Yi-cheng;WANG Man-yu;WANG Chun-guo;YAN Xing-li;College of Chinese Traditional Medicine, Beijing University of Chinese Medicine;Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine;

• 1:北京中医药大学中医学院
• 2:北京中医药大学北京中医药研究院

摘要(Abstract)：

该文研究蜘蛛香提取物对母婴分离联合3种应激所致腹泻型肠易激综合征(IBS-D)模型大鼠的药效作用和干预后粪便中内源性代谢产物的变化,以寻找潜在的生物标志物及相关代谢通路。采用母婴分离联合束缚、冰泳、夹尾3种应激等复制腹泻型IBS动物模型,通过对大鼠的腹部回撤反射压力阈值、粪便含水量、强迫游泳实验不动时长等药效评价指标来考察蜘蛛香提取物各剂量组的治疗作用。在此基础上,收集大鼠粪便,运用UPLC-LTQ-Orbitrap MS平台检测小分子代谢物的代谢轮廓,通过PCA与OPLS-DA等多元统计分析方法寻找差异代谢生物标志物。结果显示,与正常组相比,模型组大鼠腹部回撤反射压力阈值降低、粪便含水量增加、强迫游泳实验的不动时长延长,而经蜘蛛香提取物干预后能使各药效指标显著回调。粪便代谢组学研究结果表明,模型动物经蜘蛛香高剂量组干预后,39个代谢物呈现下调,37个代谢物呈现上调,且均具有显著性差异,进一步分析发现,这些差异代谢物与胆汁酸代谢、不饱和脂肪酸代谢、氨基酸代谢、神经酰胺神经类物质代谢等多种代谢途径相关。该研究证明了蜘蛛香提取物对IBS-D模型大鼠具有明确的药效作用,并从粪便代谢组学的角度探讨了蜘蛛香提取物治疗IBS-D模型大鼠的药效机制。
The purpose of this study was to understand the pharmacodynamic effect of Valeriana jatamansi extract in diarrhea predominant irritable bowel syndrome(IBS-D) rat model induced by maternal separation combined with three kinds of stress, and observe the changes of endogenous metabolites in feces after intervention to find potential biomarkers and related metabolic pathways. The animal model of IBS-D was established by maternal separation combined with restraint, ice swimming and tail clamping. The therapeutic effect of each dose group of V. jatamansi extract was evaluated in terms of abdominal withdrawal reflex pressure threshold, fecal water content and immobility time of forced swimming test. In addition, rat feces were collected for detection of metabolic profiles of small molecular metabolites with UPLC-LTQ-Orbitrap MS platform, so as to find the biomarkers of differential metabolism with multivariate statistical analysis methods such as principal component analysis(PCA) and orthogon partial least squares discrimination analysis(OPLS-DA). The results showed that as compared with the normal group, the threshold of abdominal withdrawal reflex pressure was decreased, the fecal water content was increased, and the immobility time of forced swimming test was prolonged in the model group. The results of fecal metabonomics showed that the levels of 39 metabolites were down-regulated and those of 37 metabolites were up-re-gulated. Further analysis showed that these metabolites were related to bile acid metabolism, unsaturated fatty acid metabolism, amino acid metabolism, ceramide metabolism and other metabolic pathways. This study proved that the extract of V. jatamansi had definite pharmacodynamic effect on IBS-D model rats, and the mechanism was discussed from the perspective of fecal metabonomics.

关键词(KeyWords)： 腹泻型肠易激综合征;代谢组学;蜘蛛香提取物;母婴分离
diarrheal irritable bowel syndrome(IBS-D);metabolomics;extract of Valeriana jatamansi;maternal infant separation

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81374044)

作者(Author): 刘窈玉;穆芳园;王一程;王曼宇;王春国;闫兴丽;
LIU Yao-yu;MU Fang-yuan;WANG Yi-cheng;WANG Man-yu;WANG Chun-guo;YAN Xing-li;College of Chinese Traditional Medicine, Beijing University of Chinese Medicine;Beijing Institute of Traditional Chinese Medicine, Beijing University of Chinese Medicine;

Email:

DOI: 10.19540/j.cnki.cjcmm.20201119.201

参考文献(References)：

• [1] SPERBER A D,DUMITRASCU D,FUKUDO S,et al.The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies:a Rome Foundation working team literature review [J].Gut,2017,66(6):1075.
• [2] 姚欣,杨云生,赵卡冰,等.罗马Ⅲ标准研究肠易激综合征临床特点及亚型[J].世界华人消化杂志,2008,16(5):563.
• [3] GUAGNOZZI D,ARIAS á,LUCENDO A J.Systematic review with Meta-analysis:diagnostic overlap of microscopic colitis and functional bowel disorders[J].Aliment Pharmacol Therap,2016,43(8):851.
• [4] 赵鑫鑫,黄文龙,钱海,等.肠易激综合征治疗药物的研究进展[J].中国药科大学学报,2011,42(2):182.
• [5] 国家药典委员会.中华人民共和国药典.一部[S].北京:中国医药科技出版社,2015:368.
• [6] 王国强.全国中草药汇编[M].北京:人民卫生出版社,2014.
• [7] 吴家荣.中草药蜘蛛香(印度缬草)的鉴定研究[J].新医药通讯,1976(1):73.
• [8] 闫兴丽.蜘蛛香环烯醚萜对肠易激综合征的治疗作用及机理探讨[D].北京:北京中医药大学,2009.
• [9] 王娟,史瑞瑞,闫兴丽,等.蜘蛛香环烯醚萜类成分ZXX对肠易激综合征模型大鼠的治疗作用和胃肠激素的影响[J].长春中医药大学学报,2014,30(3):396.
• [10] 王娟,张婷,闫兴丽,等.蜘蛛香环烯醚萜类成分ZXX止泻作用实验研究[J].辽宁中医药大学学报,2014,16(11):30.
• [11] 史瑞瑞,王娟,王晶,等.蜘蛛香环烯醚萜类成分对肠易激综合征大鼠的作用机制研究[J].北京中医药大学学报,2014,37(5):304.
• [12] 肖丛瑞,陶丝雨,王晶,等.蜘蛛香成分11-ethoxyviburtinal对肠易激综合征大鼠肠嗜铬细胞及肥大细胞表达的影响[J].北京中医药大学学报,2016,39(1):21.
• [13] 陶丝雨,肖丛瑞,闫兴丽,等.缬草醛对肠易激综合征模型大鼠结肠CRF,TPH1 mRNA及5-HT表达的影响[J].中国中药杂志,2017,42(2):347.
• [14] CHNKARA D K,RAWAT D J,TALLEY N J.The epidemiology of childhood recurrent abdominal pain in Western countries:a systematic review [J].Am J Gastroenterol,2005,100(8):1868.
• [15] 王一程,穆芳园,闫兴丽,等.母婴分离联合3种应激致腹泻型肠易激综合征大鼠模型的建立和评价[J].中华中医药杂志,2018,33(6):2314.
• [16] 李攀,孙凤霞,李晓玲,等.胆汁酸代谢异常与肠易激综合征相关性研究[J].胃肠病学和肝病学杂志,2017,26(1):110.
• [17] DUBOC H,RAINTEAU D,RAJCA S,et al.Increase in fecal primary bile acids and dysbiosis in patients with diarrhea-predo-minant irritable bowel syndrome[J].Neurogastroenterol Motil,2012,24(6):513.
• [18] 徐沙丽,李中明,李哈妮,等.缬草提取物对胆汁酸代谢及肝损伤影响的实验研究[J].医药导报,2011,30(3):298.
• [19] 叶建明,王钰,汪晓珍,等.缬草波春对大鼠非炎症性结肠致敏模型的影响[J].世界华人消化杂志,2009,17(25):2616.
• [20] 孙翔宇,高贵田,段爱莉,等.多不饱和脂肪酸的研究进展[J].食品工业科技,2012,33(7):418.
• [21] 乔立君,郑征,马文慧,等.多不饱和脂肪酸对大鼠肠道菌群及脂肪代谢相关基因的影响[J].食品科学,2014,35(17):231.
• [22] 舒劲,李花,武正权.腹泻型肠易激综合征伴焦虑抑郁状态的中西医诊治进展[J].西部中医药,2019,32(9):147.
• [23] 杜红丽.知母百合协同抗抑郁的代谢组学研究[D].上海:第二军医大学,2016.
• [24] 李雷,王恒林,郭颖,等.神经类固醇激素与焦虑症及抑郁症等精神疾病关系的研究进展[J].国际药学研究杂志,2017,44(3):236.
• [25] RUDOLPH U,M?HLER H.GABAA receptor subtypes:therapeutic potential in down syndrome,affective disorders,schizophrenia,and autism[J].Annu Rev Pharmacol Toxicol,2014,54(1):483.