本文選題：功能性消化不良　切入點：代謝組學(xué)　出處：《北京中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：研究背景功能性消化不良(functional dyspepsia, FD)屬于臨床常見功能性胃腸病,具有病程漫長、病情易反復(fù)等臨床特點,約有15%-20%的FD患者相關(guān)臨床癥狀難以緩解。然而,傳統(tǒng)治療方法,包括生活方式調(diào)整、抑酸藥、促動力藥、抗焦慮抑郁藥及幽門螺旋桿菌的根除等,臨床療效有限。約達50%的患者有尋求其他療法,如補充替代醫(yī)學(xué)(complementary and alternative medicine, CAM)的幫助。中藥(Chinese herbal medicine, CHM)治療FD在緩解癥狀、改善患者生活質(zhì)量等方面具有一定優(yōu)勢。魏瑋教授基于20多年臨證經(jīng)驗,遵循辛開苦降法,創(chuàng)立中藥胃康寧,經(jīng)臨床試驗證實具有良好療效。同時基于動物實驗、體外分子實驗及蛋白質(zhì)組學(xué)等研究,證實中藥胃康寧具有促進胃腸運動、調(diào)節(jié)內(nèi)臟高敏感、調(diào)節(jié)胃壁肌電活動與自主神經(jīng)功能以及改善抗氧化能力、能量代謝及線粒體的功能等作用。系統(tǒng)評價(system review, SR)是循證醫(yī)學(xué)的重要研究方法及最佳證據(jù)來源,而薈萃分析(meta analysis)作為系統(tǒng)評價的研究類型之一,為臨床研究及實踐提供高等級證據(jù)支持,已為臨床醫(yī)學(xué)各專業(yè)廣泛使用。代謝組學(xué)(metabonomics)作為系統(tǒng)生物學(xué)領(lǐng)域內(nèi)研究生物體在不同因素影響下整體功能狀態(tài)變化的一門科學(xué),其所特有的整體觀、動態(tài)觀與中醫(yī)復(fù)方研究中的指導(dǎo)思想,如整體觀念、系統(tǒng)生物學(xué)的思考模式、復(fù)雜性科學(xué)等觀念相契合,為應(yīng)用現(xiàn)代科學(xué)技術(shù)手段研究傳統(tǒng)中醫(yī)藥物質(zhì)基礎(chǔ)及作用機制提供了新的技術(shù),逐漸成為中藥復(fù)方研究領(lǐng)域內(nèi)的新熱點。研究目的基于1HNMR代謝組學(xué)技術(shù)研究夾尾刺激FD模型大鼠血清及尿液中內(nèi)源性代謝物的變化,初步探索辛開苦降法代表方胃康寧干預(yù)FD的作用機制。研究方法1.文獻綜述及系統(tǒng)評價通過國內(nèi)外文獻分析,綜述FD中西醫(yī)臨床論治及代謝組學(xué)在中藥復(fù)方領(lǐng)域內(nèi)研究的最新進展。同時采用薈萃分析對中藥復(fù)方治療FD的臨床療效及安全性進行評價。具體方法：檢索Web of Science, PubMed, EMBASE, Cochrane Library,以及中國知網(wǎng)、中國生物醫(yī)學(xué)文獻數(shù)據(jù)庫、維普數(shù)據(jù)庫中文科技期刊數(shù)據(jù)庫、萬方數(shù)據(jù)資源系統(tǒng)等數(shù)據(jù)庫中口服中藥復(fù)方干預(yù)FD的隨機、雙盲、安慰劑對照試驗,對納入文獻采用Cochrane風(fēng)險偏倚評估工具評價質(zhì)量,并使用Review Manager V.5.2.7軟件進行Meta分析。2.代謝組學(xué)研究30只Wistar雄性大鼠隨機分為正常組10只、模型組20只,對模型組大鼠采用夾尾刺激法進行FD模型復(fù)制,連續(xù)7天。模型成功后,隨機抽取模型組中半數(shù)大鼠構(gòu)成胃康寧中藥組,參照臨床劑量給予藥物干預(yù)：胃康寧中藥組給予胃康寧中藥溶液灌胃14天,正常組、模型組給予蒸餾水灌胃14天。分別在造模第0、4、7天及灌胃第4、7、11、14天經(jīng)代謝籠留取大鼠尿液,在造模14天后經(jīng)腹主動脈取血留取大鼠血清。采用VARIAN 600MHz核磁共振波譜儀分別對大鼠尿液、血清樣品進行檢測,MestReNova7.1.0軟件對核磁圖譜進行處理,SIMCA-P+12.0軟件進行多變量統(tǒng)計分析。選用主成分分析、偏最小二乘判別分析以及正交偏最小二成判別分析等分析方法進行數(shù)據(jù)處理,同時聯(lián)合使用變量權(quán)重重要性排序值、相關(guān)系數(shù)進行差異代謝物的篩選。研究結(jié)果1.文獻綜述及系統(tǒng)評價FD西醫(yī)治療以對癥治療為主,遵循個體化治療原則,其中以生活方式調(diào)整、抑酸劑、促動力藥為一線治療,以抗焦慮抑郁藥、CAM為二線治療,對于幽門螺旋桿菌感染者建議行根除治療；中醫(yī)藥物治療則主要從經(jīng)典方劑、自擬效方、辨證施治、中西藥結(jié)合等方面論治；代謝組學(xué)在中藥復(fù)方領(lǐng)域內(nèi)的研究主要集中基于中醫(yī)證型、西醫(yī)病癥、病證結(jié)合研究以及針對藥效機制、配伍規(guī)律、毒性評價、煎煮方法等研究。共納入14篇文獻(1424例患者),進行合并處理后,總計10篇研究納入薈萃分析。(1)療效評價總體癥狀緩解率中藥高于安慰劑對照(RR 1.45,95% CI[1.31-1.60];Z= 7.29,P0.00001)、中藥對于中醫(yī)證候的總體改善優(yōu)于安慰劑(RR 1.36,95%CI[1.23-1.50];Z=6.17,P0.00001)、中藥較安慰劑能更好改善FD患者生活質(zhì)量(SMD 0.30, 95%CI[0.15-0.45];Z=3.80,P=0.0001);(2)安全性評價不良反應(yīng)事件的發(fā)生率在中藥治療組與安慰劑對照組間無明顯差異(RR 1.06,95%CI[0.66-1.70];Z=0.23,P=0.82)。2.代謝組學(xué)研究尿液代謝分析發(fā)現(xiàn)：在夾尾刺激FD大鼠模型復(fù)制過程中,模型組與正常組尿液代謝輪廓相較,上調(diào)的差異代謝物有亮氨酸、乳酸、丙氨酸、二甲胺、苯乙酰甘氨酸、馬尿酸、尿囊素、胞啶、酪氨酸、咪唑及苯丙氨酸,下調(diào)的差異代謝物有乙酸、乙酰谷氨酸、琥珀酸、α-酮戊二酸、檸檬酸及三甲胺。在中藥胃康寧干預(yù)FD的過程中,中藥胃康寧組與模型組尿液代謝信息相較,上調(diào)的差異代謝物有乙酰谷氨酸、葡萄糖、肌酸、馬尿酸、葫蘆巴堿及甲酸,下調(diào)的生物標(biāo)志物有α-羥基戊酸、亮氨酸、丙氨酸、己二酸、甘氨酸、順烏頭酸及苯丙氨酸。血清代謝分析發(fā)現(xiàn)：在夾尾刺激FD大鼠模型復(fù)制過程中,模型組與正常組尿液代謝輪廓相較,上調(diào)的差異代謝物有異亮氨酸、亮氨酸、脯氨酸及甲醇,下調(diào)的差異代謝物有葡萄糖。在中藥胃康寧干預(yù)FD的過程中,中藥胃康寧組與模型組尿液代謝信息相較,上調(diào)的差異代謝物有葡萄糖,下調(diào)的差異代謝物有脯氨酸、谷氨酸、β-羥丁酸、檸檬酸、蛋氨酸、甘油、1-甲基組氨酸、苯丙氨酸及甲酸。在應(yīng)激FD模型復(fù)制過程中,內(nèi)源性代謝信息的擾動主要影響的代謝通路涉及：苯丙氨酸、酪氨酸和色氨酸生物合成,檸檬酸循環(huán),苯丙氨酸代謝,纈氨酸、亮氨酸和異亮氨酸生物合成,乙醛酸和二羧酸代謝以及酪氨酸代謝。在中藥胃康寧干預(yù)FD過程中,內(nèi)源性代謝信息網(wǎng)絡(luò)變化涉及的代謝通路有：乙醛酸和二羧酸代謝,苯丙氨酸、酪氨酸和色氨酸生物合成,甘氨酸、絲氨酸和蘇氨酸代謝,苯丙氨酸代謝,纈氨酸、亮氨酸和異亮氨酸生物合成以及甘油酯代謝。研究結(jié)論1.通過文獻綜述、系統(tǒng)評價,認(rèn)為FD有效藥物治療需整合中醫(yī)、西醫(yī)及循證醫(yī)學(xué)證據(jù)等,實現(xiàn)中西醫(yī)結(jié)合優(yōu)勢互補以有效改善FD,同時代謝組學(xué)在中藥復(fù)方研究領(lǐng)域內(nèi)應(yīng)用前景廣泛。2.夾尾刺激FD模型大鼠的血清及尿液代謝信息與正常大鼠相較,主要發(fā)生能量代謝、應(yīng)激相關(guān)代謝及腸道菌群等方面的代謝信息改變；經(jīng)辛開苦降法代表方胃康寧干預(yù)后,夾尾刺激FD模型大鼠被擾動的代謝信息向正常狀態(tài)發(fā)生轉(zhuǎn)歸,提示中藥胃康寧對FD的作用機制可能是通過影響能量代謝、應(yīng)激相關(guān)代謝及腸道菌群等多個代謝通路,調(diào)節(jié)代謝紊亂,從而起到對于FD的治療作用。
[Abstract]:The research background of functional dyspepsia (functional dyspepsia FD) is a common clinical functional gastrointestinal disease, has a long course and clinical features of repeated relapses, about FD of patients with clinical symptoms of 15%-20% is difficult to solve. However, the traditional treatment methods, including lifestyle changes, acid suppression drugs, prokinetic drugs, anti anxiety antidepressant drugs and Helicobacter pylori eradication therapy, clinical curative effect is limited. Approximately 50% of the patients had to seek other therapies, such as complementary and alternative medicine (complementary and alternative medicine, CAM) with the help of traditional Chinese medicine. (Chinese herbal medicine, CHM) in the treatment of FD is to alleviate the symptoms, improve the quality of life of patients has certain advantages such as Wei Wei. At 20 years of clinical experience based on the following xinkaikujiang method, founded Corelle herbal medicine, proved by clinical experiments has good curative effect. At the same time, based on animal experiments, in vitro experiments and protein molecules Group research, Corelle has confirmed herbal medicine to promote gastrointestinal motility, regulate visceral hypersensitivity, regulating gastric myoelectrical activity and autonomic nerve function and improve the antioxidant capacity, energy metabolism and mitochondrial function. The evaluation system (system review SR) is an important research method of evidence-based medicine and the best source of evidence, and meta analysis (meta analysis) as one of the types of research evaluation system, provides a high level of evidence to support clinical research and practice, has been widely used for clinical medical professional. Metabonomics (metabonomics) as a science within the field of systems biology of organisms under the influence of different factors overall functional changes, the overall view of the the unique, dynamic view and guiding ideology of Chinese medicine research, such as the overall concept, systems biology thinking, complexity science ideas fit for The application of modern scientific and technical means of the traditional Chinese medicine material basis and mechanism provides a new technology, gradually become a new focus of research in traditional Chinese medicine in the field of 1HNMR. Changes of metabonomics technique stimulate tail FD model of endogenous metabolites in serum and urine in rats based on the purpose of the study, a preliminary exploration of xinkaikujiang mechanism on behalf of Corelle square stomach intervention of FD. 1. analysis methods of literature review and evaluation system at home and abroad through the literature review, the FD in western medicine clinical treatment and the new research progress of metabonomics in medicine field. The meta analysis of clinical efficacy and safety of traditional Chinese Medicine in the treatment of FD was evaluated at the same time. Specific methods: Web Science PubMed, of search, EMBASE, Cochrane, Library, and China HowNet, China biomedical literature database, VIP database Chinese according to the number of scientific journals Library, Wanfang Data Resource Database in the oral administration of traditional Chinese medicine intervention FD randomized, double-blind, placebo-controlled trial, the meta-analysis using Cochrane tool for assessing the risk of bias of quality evaluation, and the Meta analysis of the.2. metabolomics study of 30 male Wistar rats were randomly divided into normal group 10 using Review Manager V.5.2.7 software, model group 20, model group of rats by tail clamp stimulus method established FD model for 7 consecutive days. After the success of the model, half of the rats in the model group were randomly selected to form gastric Corelle Chinese medicine group, according to clinical dose of drug intervention: Corelle gastric medicine group were given gastric gavage for 14 Corelle herbal solution day, the normal group, model group were given distilled water for 14 days respectively in the model. The first 0,4,7 days and 4,7,11,14 days after intragastric administration of the metabolic cages to collect urine from rats at 14 days after modeling abdominal aortic blood specimens from rat serum by VA. RIAN 600MHz nuclear magnetic resonance spectroscopy of rat urine and serum samples were detected on the NMR spectra of the MestReNova7.1.0 software, SIMCA-P+12.0 software in multivariate statistical analysis. Using principal component analysis, partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis method to carry on the data processing, and combined use of variable weights of importance the value of screening, correlation coefficient of different metabolites. 1. the results of literature review and evaluation system of FD medicine treatment for symptomatic treatment, follow the principle of individualized treatment, including lifestyle changes, antacids, prokinetic drugs as first-line treatment with anti anxiety depression drug CAM as second-line treatment for eradication therapy Helicobacter pylori infection; Chinese medicine treatment mainly from classical prescriptions, with side effects, traditional Chinese medicine and Western medicine combined with syndrome differentiation, etc. Surface treatment; metabonomics in compound Chinese medicine in the field of research mainly based on TCM, western medicine disease, and for evaluation of drug mechanism, combining disease with syndrome of regularity of compatibility, toxicity, study on Decoction methods. A total of 14 articles were included (1424 patients), by combining treatment, a total of 10 studies included in the meta-analysis. (1) the curative effect evaluation of the overall remission rate of Chinese medicine was higher than that of placebo (RR 1.45,95% CI[1.31-1.60] Z=; 7.29, P0.00001), traditional Chinese medicine for general syndromes of traditional Chinese medicine is better than placebo (RR 1.36,95%CI[1.23-1.50]; Z=6.17, P0.00001), traditional Chinese medicine can better improve the quality of life in patients with FD than placebo (SMD 0.30, 95%CI[0.15-0.45]; Z=3.80, P=0.0001); (2) adverse events occurred in safety evaluation of Chinese medicine treatment group and placebo groups had no obvious difference (RR 1.06,95%CI[0.66-1.70]; Z=0.23, P=0.82).2. metabonomics Study on metabolism of urine analysis found: in the stimulate tail FD rats in model group and normal group urinary metabolic profile in different metabolites have increased leucine, lactic acid, alanine, two methylamine, phenylacetylglycine, hippuric acid, allantoin, cytidine, tyrosine, phenylalanine and imidazole, metabolites that are down regulated. Acetic acid, acetyl Glutamic acid, succinic acid, ketoglutaric acid, citric acid and trimethylamine. In the process of Chinese medicine intervention in gastric Corelle FD, Corelle herbal medicine group and model group compared with the urine metabolic information, increase the differences of metabolites have acetyl glutamic acid, glucose, creatine, hippuric acid, formic acid and trigonelline, down regulated biological markers of alpha hydroxy acid, leucine, alanine, glycine, adipic acid, CIS aconitic acid and phenylalanine. The serum metabolic analysis found: in the stimulate tail FD rats in model group, and positive Often group urinary metabolic profile by upregulation of different metabolites have isoleucine, leucine, proline and methanol, lowered the difference. In the process of Chinese medicine glucose metabolites have stomach Corelle intervention FD, Corelle herbal medicine group and model group compared the difference of urine metabolic information, increased glucose metabolites, downregulation of different metabolites have proline. Glutamic acid, beta hydroxybutyric acid, citric acid, methionine, glycerol, 1- methyl histidine, phenylalanine and formic acid. The stress model of FD replication process, endogenous metabolic information disturbance mainly affect the metabolic pathways involved: phenylalanine, tyrosine and tryptophan biosynthesis, the citric acid cycle, phenylalanine metabolism, valine, leucine and isoleucine biosynthesis. Glyoxylic acid and two carboxylic acid metabolism and tyrosine metabolism. In the traditional Chinese medicine intervention of gastric Corelle FD process, involving endogenous metabolic changes in Information Network The metabolic pathway: glyoxylic acid and two carboxylic acid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, glycine, serine and threonine metabolism, phenylalanine metabolism, valine, leucine and isoleucine biosynthesis and glyceride metabolism. Conclusion: 1. through literature review, evaluation system, FD effective drug therapy should be integrated Chinese medicine, western medicine and evidence-based medical evidence, to realize the combination of complementary advantages to improve the FD of traditional Chinese medicine and Western medicine, and metabonomics widely used.2. tail clamp stimulation of FD model rats serum and urine metabolic information compared with normal rats in the study of Chinese herbal compound in the field, mainly in energy metabolism, the metabolic information related to stress metabolism and intestinal microflora the change of xinkaikujiang method; the representative prescription of Weikang Ninggan prognosis, metabolic information stimulate tail FD model rats by disturbance to the normal state change It suggests that the action mechanism of Corelle on FD is probably to regulate the metabolic disorder through metabolic pathways such as energy metabolism, stress related metabolism and intestinal flora, thereby playing a role in the treatment of FD.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R259
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本文編號：1716165