附子理中汤治疗腹泻型肠易激综合征的临床与实验研究
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摘要
目的：
肠易激综合征(irritable bowel syndrome IBS)是临床常见的胃肠道功能紊乱性疾病,是一组包括腹痛、腹胀伴排便习惯改变,粪便性状异常等临床表现的症候群,持续存在或间歇发作,但无器质性损害疾病的证据。目前认为IBS是由多种因素共同作用的结果。在治疗上尚无理想的治疗方法,多为对症治疗。治疗IBS的药物包括解痉剂、导泻药、止泻剂、肠道动力感觉调节剂、微生态制剂和抗抑郁药等。
腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome, D-IBS)是中医治疗的特色优势病种之一。祖国医学采用辨证论治结合针灸、推拿等方法从整体治疗本病取得了较好的疗效。认为本病初期,为肝气郁结,肝失疏泄,肝气横逆乘脾；继则脾失健运,湿从中生；脾虚日久而致脾阳不足,肾阳受累。此病以湿为中心,湿为病理产物；以肝气郁结贯穿始终,气机失调为疾病之标,而脾肾阳虚为病之根本。肝郁、脾虚、肾阳不足为肠易激综合征主要病机。本研究以脾肾阳虚型D-IBS为对象,设计了附子理中汤组和得舒特组的临床对照研究,观察临床疗效及对患者生活质量的改善情况。同时为了探讨附子理中汤的起效机制,设计了动物实验,从炎症、内脏敏感性、TLR4及AQP8mRNA的表达情况等多角度来研究其可能的作用途径、环节和靶点。
方法：
临床部分：
将符合纳入标准的患者62分为治疗组32例,对照组30例。治疗组予附子理中方,对照组予得舒特,疗程为4周。观察两组治疗前后的中医证候、症状积分、总体有效率、生存质量的变化情况。
实验部分：
将50只SPF级大鼠随机分为正常对照组、模型组、得舒特组、附子理中汤低剂量组、附子理中汤高剂量组,每组10只。雌雄各半。采用束缚应激加大黄泻下法复制腹泻型大鼠模型。造模成功后,开始用药,正常组及模型组大鼠每日予生理盐水灌胃;其余3组分别灌服不同剂量的附子理中汤方及得舒特,共用药14天。疗程结束后观察大鼠体重变化、腹泻率、腹泻指数和肠组织形态变化；测定各组大鼠血清IL-8水平、血清5-HT水平的变化情况；测定各组大鼠结肠粘膜样本中TLR4、AQP8的mRNA表达水平。
结果
1临床研究结果
1.1临床治疗后,无论是中药组还是西药组,腹痛或腹部不适,大便次数,大便性状、排便紧迫感、黏液的症状积分均有降低,配对t检验示治疗前后症状总积分有明显差异。中药组治疗后症状总积分与西药组相比存在差异。
1.2治疗后,中药组和西药组在腹部不适、大便次数、大便性状、排便紧迫感、腹胀、黏液等症状积分均较治疗前有下降。中药组在大便性状、排便紧迫感、腹胀、黏液的改善情况较西药组对比有差异。
1.3治疗后,两组患者的生活质量均得到不同程度的改善：中药组在生理功能PF、生理职能RP、躯体疼痛BP、总体健康GH、活力YT、情感职能RE、心理健康MH方面的积分均有明显提高(P<0.05)；西药组仅在生理职能PF、躯体疼痛BP的积分有明显提高(P<0.05),中药组在改善生理职能RP、躯体疼痛BP、情感职能RE、心理健康MH方面优于西药组(P<0.05)。
1.4治疗后IBS-QOL各方面积分比较,中药组患者的焦虑不安DP、行为障碍IA、身体角色BI、健康担忧HW、饮食限制FA、社会反应SR方面积分均有不同程度改善(P<0.05),西药组在焦虑不安DP、健康担忧HW、饮食限制FA方面有不同程度改善(P<0.05)。中药组在焦虑不安DP、行为障碍IA、身体角色BI、健康担忧HW、饮食限制FA方面改善程度优于西药组。
2实验研究结果
2.1不同剂量附子理中汤组可使血清IL-8水平趋于正常；与得舒特组相比差异有统计学意义(P<0.05),附子理中汤高、低剂量组相比,差异无显著性(P>0.05)。
2.2本研究动物实验发现附子理中汤不同剂量组均能降低D-IBS模型大鼠血清5-HT含量,其疗效与得舒特相当(P>0.05)。
2.3模型组大鼠肠粘膜的TLR4的表达高于正常对照组,有统计学差异(P<0.01)。而附子理中汤的干预可使大鼠肠粘膜的TLR4的表达趋于正常,与得舒特组比较差异有统计学意义。不同剂量附子理中汤组比较无明显差异。
2.4模型组大鼠结肠组织中AQP8的表达下降(P<0.05),经附子理中汤干预后,AQP8的表达趋于正常,与得舒特组比较差异有统计学意义；附子理中汤不同剂量组相比无明显差异。
结论
本临床试验研究表明附子理中方对脾肾阳虚型D-IBS患者的临床症状、生存质量有良好的治疗作用；对照组也显示一定的治疗效果,附子理中汤方的临床总体疗效明显优于对照剂。
动物实验从炎症、内脏敏感性、免疫、水代谢等方面研究附子理中方治疗脾肾阳虚型D-IBS可能的作用机理,从而推断附子理中汤治疗脾肾阳虚型D-IBS的作用机理可能与其减轻炎症反应、降低内脏敏感性、减少免疫应答、恢复水液代谢等因素有关。
Objective:
Irritable bowel syndrome (IBS)is a common clinical gastrointestinal functional diseases, which including abdominal pain, abdominal distention associated with changes in bowel habits and abnormal stool, these clinical manifestations of the syndrome persistent or intermittent seizures, but found no evidence of organic disease of damage. IBS has become a global gastrointestinal functional diseases, serious impact on the patient's quality of life, and has caused tremendous economic and emotional burden to individuals, families and society. So far, the etiology and pathogenesis of IBS is not completely clear, most scholars believe that the psychological, diet, inflammation, genetic and other common causes of the disease, the known relevant factors including dysfunction of gastrointestinal motility and intestinal smooth muscle,abnormal psychological and visceral sensory abnormalities, gastrointestinal hormone secretion, brain-gut axis doctrine, stress, and intestinal infections, etc. IBS is considered to be the result of various factors. There is no ideal method of treatment in the treatment of more than symptomatic treatment. The treatment of IBS drugs including antispasmodic agents, conduct laxatives, antidiarrheal agents, intestinal motility sensory modulation, probiotics, and antidepressants. IBS is a disease of the characteristic advantages of Chinese medicine treatment. The TCM treatment withChinese herbal medicine and combined with acupuncture, massage and other methods to obtain a better efficacy overall treatment of the disease.
In this study, we chose deficiency of spleen and kidney syndrome D-IBS patients in recent years increasing as object, fuzilizhong decoction group and dicetel group controlled clinical study was designed to observe the clinical efficacy and situation to improve patients'quality of life. In order to investigate the onset mechanism of the Fuzi Lizhong Decoction, design the animal experiments, from inflammation, visceral sensitivity and expression of AOP8mRNA, TLR4and so many angles to study its possible mechanism, process and targets.
Methods:
The clinical part:
Divided62patients who meet the inclusion criteria into treatment group of32patients and in the control group of30cases. Fuzilizhong soup is taken by each patients in treatment group, dicetel is taken by each patients in control group. Both groups were treated for4weeks. TCM syndromes, symptom score, the overall efficiency, quality of life changes were observed before and after treatment,
Experimental part:
50of SPF rats were randomly divided into normal control group, model group, get the dicetel group, Lizhong Tang low-dose group, Lizhong Tang high-dose group (n=10). Half male and half female.
Using rhubarb laxation and ice water stimulation replication diarrhea type in rat model. The model was successful, start the medication, the normal group and model group rats daily to normal saline; the remaining three groups were fed with different doses of fuzilizhong soup side and get Dicetel, a total of medication for14days.
Observed changes in body weight of rats after treatment, the diarrhea rate diarrhea index and intestinal tissue morphological changes; determination of the serum levels of IL-8, serum5-the HT level changes; determination of each rat colonic mucosa samples of TLR4AQP8is the mRNA expression levels.
Results:
1Results of clinical studies
1.1After clinical treatment, whether it is traditional Chinese medicine group or western medicine group, abdominal pain or abdominal discomfort, stool frequency, stool consistency, bowel movement a sense of urgency, mucus symptom scores are lower, paired t-test show the before and after treatment the total symptom score were significantly different. Compared to the total symptom score after the treatment of traditional Chinese medicine group and western medicine group,there is differences (P=0.000).
1.2After treatment, the traditional Chinese medicine group and western medicine group in abdominal discomfort, stool frequency, stool consistency, bowel movement a sense of urgency, bloating, mucus and other symptoms points than before treatment have decreased. Chinese medicine group in the stool, bowel movement a sense of urgency, bloating, mucus improvement better than the western medicine group.
1.3After treatment, the quality of life of the two groups of patients were improved to varying degrees:the SF-36integral treatment group in the physiological function of the physiological functions, bodily pain, general health, vitality, role emotional, mental health integration were significantly higher (P<0.05); the control group only in the physiological functions, the integral of bodily pain improved significantly (P<0.05); treatment groups in the improvement of physiological functions, physical pain, emotional function and mental health were better than the control group (P<0.05).
1.4After treatment of IBS-QOL in all aspects, integration of patients in treatment group with anxiety, behavioral disorders, physical roles, health concerns, dietary restrictions, social response points were significantly improved (P<0.05), in the control group in anxiety, health concerns and dietary restrictions were significantly improved (P<0.05). treatment groups in the improvement of anxiety, behavioral disorders, physical character, health concerns, dietary restrictions were better than control group.
2The experimental results
2.1Lizhong Tang group, different doses allows serum IL-8levels tended to be normal; the Dicetel group of IL-8levels higher than the normal group (P <0.05), compared to model group declined slightly, but statistically the analysis showed no significant difference (P>0.05).
2.2The study of animal experiment found that Fuzilizhong Decoction of different dose group could decrease5-HT content in serum of D-IBS rat model, compared to Dicetel group, its efficacy had no significant difference (P>0.05).
2.3TLR4expression of the intestinal mucosa of the model group were higher than the normal control group were significantly different (P<0.01). Lizhong Tang intestinal mucosa of intervention allows the expression of TLR4is normal, but no significant difference with the normal group. Have Dicetel group compared to the normal group TLR4expression was increased significantly (P <0.01).
2.4The expression of AQP8in rat colon tissue of model group decreased (P <0.05),after the intervention by Lizhong Tang, the expression of AQP8is normal, no difference in the expression of AQP8in the Dicetel group intervention compared with the model group.
Conclusions:
The clinical trials show that fuziLizhong decoction for deficiency of spleen and kidney syndrome D-IBS patients has a good therapeutic effect in clinical symptoms, quality of life; control group also shows a certain therapeutic effect, fuziLizhong decoction clinical overall efficacy was significantly superiorin the control agent.
Animal experiments in terms of inflammation, visceral sensitivity, immunity, and water metabolism study Fuzi Lizhong decoction treatment of deficiency of spleen and kidney syndrome D-IBS possible mechanism, to infer the mechanism of Lizhong Tang treatment of deficiency of spleen and kidney syndrome D-IBS may be it can reduce the inflammatory response, reducing visceral sensitivity, and reduce the immune response, and recovery of water metabolism and other factors.
肠易激综合征(irritable bowel syndrome IBS)是临床常见的胃肠道功能紊乱性疾病,是一组包括腹痛、腹胀伴排便习惯改变,粪便性状异常等临床表现的症候群,持续存在或间歇发作,但无器质性损害疾病的证据。目前认为IBS是由多种因素共同作用的结果。在治疗上尚无理想的治疗方法,多为对症治疗。治疗IBS的药物包括解痉剂、导泻药、止泻剂、肠道动力感觉调节剂、微生态制剂和抗抑郁药等。
腹泻型肠易激综合征(diarrhea-predominant irritable bowel syndrome, D-IBS)是中医治疗的特色优势病种之一。祖国医学采用辨证论治结合针灸、推拿等方法从整体治疗本病取得了较好的疗效。认为本病初期,为肝气郁结,肝失疏泄,肝气横逆乘脾；继则脾失健运,湿从中生；脾虚日久而致脾阳不足,肾阳受累。此病以湿为中心,湿为病理产物；以肝气郁结贯穿始终,气机失调为疾病之标,而脾肾阳虚为病之根本。肝郁、脾虚、肾阳不足为肠易激综合征主要病机。本研究以脾肾阳虚型D-IBS为对象,设计了附子理中汤组和得舒特组的临床对照研究,观察临床疗效及对患者生活质量的改善情况。同时为了探讨附子理中汤的起效机制,设计了动物实验,从炎症、内脏敏感性、TLR4及AQP8mRNA的表达情况等多角度来研究其可能的作用途径、环节和靶点。
方法：
临床部分：
将符合纳入标准的患者62分为治疗组32例,对照组30例。治疗组予附子理中方,对照组予得舒特,疗程为4周。观察两组治疗前后的中医证候、症状积分、总体有效率、生存质量的变化情况。
实验部分：
将50只SPF级大鼠随机分为正常对照组、模型组、得舒特组、附子理中汤低剂量组、附子理中汤高剂量组,每组10只。雌雄各半。采用束缚应激加大黄泻下法复制腹泻型大鼠模型。造模成功后,开始用药,正常组及模型组大鼠每日予生理盐水灌胃;其余3组分别灌服不同剂量的附子理中汤方及得舒特,共用药14天。疗程结束后观察大鼠体重变化、腹泻率、腹泻指数和肠组织形态变化；测定各组大鼠血清IL-8水平、血清5-HT水平的变化情况；测定各组大鼠结肠粘膜样本中TLR4、AQP8的mRNA表达水平。
结果
1临床研究结果
1.1临床治疗后,无论是中药组还是西药组,腹痛或腹部不适,大便次数,大便性状、排便紧迫感、黏液的症状积分均有降低,配对t检验示治疗前后症状总积分有明显差异。中药组治疗后症状总积分与西药组相比存在差异。
1.2治疗后,中药组和西药组在腹部不适、大便次数、大便性状、排便紧迫感、腹胀、黏液等症状积分均较治疗前有下降。中药组在大便性状、排便紧迫感、腹胀、黏液的改善情况较西药组对比有差异。
1.3治疗后,两组患者的生活质量均得到不同程度的改善：中药组在生理功能PF、生理职能RP、躯体疼痛BP、总体健康GH、活力YT、情感职能RE、心理健康MH方面的积分均有明显提高(P<0.05)；西药组仅在生理职能PF、躯体疼痛BP的积分有明显提高(P<0.05),中药组在改善生理职能RP、躯体疼痛BP、情感职能RE、心理健康MH方面优于西药组(P<0.05)。
1.4治疗后IBS-QOL各方面积分比较,中药组患者的焦虑不安DP、行为障碍IA、身体角色BI、健康担忧HW、饮食限制FA、社会反应SR方面积分均有不同程度改善(P<0.05),西药组在焦虑不安DP、健康担忧HW、饮食限制FA方面有不同程度改善(P<0.05)。中药组在焦虑不安DP、行为障碍IA、身体角色BI、健康担忧HW、饮食限制FA方面改善程度优于西药组。
2实验研究结果
2.1不同剂量附子理中汤组可使血清IL-8水平趋于正常；与得舒特组相比差异有统计学意义(P<0.05),附子理中汤高、低剂量组相比,差异无显著性(P>0.05)。
2.2本研究动物实验发现附子理中汤不同剂量组均能降低D-IBS模型大鼠血清5-HT含量,其疗效与得舒特相当(P>0.05)。
2.3模型组大鼠肠粘膜的TLR4的表达高于正常对照组,有统计学差异(P<0.01)。而附子理中汤的干预可使大鼠肠粘膜的TLR4的表达趋于正常,与得舒特组比较差异有统计学意义。不同剂量附子理中汤组比较无明显差异。
2.4模型组大鼠结肠组织中AQP8的表达下降(P<0.05),经附子理中汤干预后,AQP8的表达趋于正常,与得舒特组比较差异有统计学意义；附子理中汤不同剂量组相比无明显差异。
结论
本临床试验研究表明附子理中方对脾肾阳虚型D-IBS患者的临床症状、生存质量有良好的治疗作用；对照组也显示一定的治疗效果,附子理中汤方的临床总体疗效明显优于对照剂。
动物实验从炎症、内脏敏感性、免疫、水代谢等方面研究附子理中方治疗脾肾阳虚型D-IBS可能的作用机理,从而推断附子理中汤治疗脾肾阳虚型D-IBS的作用机理可能与其减轻炎症反应、降低内脏敏感性、减少免疫应答、恢复水液代谢等因素有关。
Objective:
Irritable bowel syndrome (IBS)is a common clinical gastrointestinal functional diseases, which including abdominal pain, abdominal distention associated with changes in bowel habits and abnormal stool, these clinical manifestations of the syndrome persistent or intermittent seizures, but found no evidence of organic disease of damage. IBS has become a global gastrointestinal functional diseases, serious impact on the patient's quality of life, and has caused tremendous economic and emotional burden to individuals, families and society. So far, the etiology and pathogenesis of IBS is not completely clear, most scholars believe that the psychological, diet, inflammation, genetic and other common causes of the disease, the known relevant factors including dysfunction of gastrointestinal motility and intestinal smooth muscle,abnormal psychological and visceral sensory abnormalities, gastrointestinal hormone secretion, brain-gut axis doctrine, stress, and intestinal infections, etc. IBS is considered to be the result of various factors. There is no ideal method of treatment in the treatment of more than symptomatic treatment. The treatment of IBS drugs including antispasmodic agents, conduct laxatives, antidiarrheal agents, intestinal motility sensory modulation, probiotics, and antidepressants. IBS is a disease of the characteristic advantages of Chinese medicine treatment. The TCM treatment withChinese herbal medicine and combined with acupuncture, massage and other methods to obtain a better efficacy overall treatment of the disease.
In this study, we chose deficiency of spleen and kidney syndrome D-IBS patients in recent years increasing as object, fuzilizhong decoction group and dicetel group controlled clinical study was designed to observe the clinical efficacy and situation to improve patients'quality of life. In order to investigate the onset mechanism of the Fuzi Lizhong Decoction, design the animal experiments, from inflammation, visceral sensitivity and expression of AOP8mRNA, TLR4and so many angles to study its possible mechanism, process and targets.
Methods:
The clinical part:
Divided62patients who meet the inclusion criteria into treatment group of32patients and in the control group of30cases. Fuzilizhong soup is taken by each patients in treatment group, dicetel is taken by each patients in control group. Both groups were treated for4weeks. TCM syndromes, symptom score, the overall efficiency, quality of life changes were observed before and after treatment,
Experimental part:
50of SPF rats were randomly divided into normal control group, model group, get the dicetel group, Lizhong Tang low-dose group, Lizhong Tang high-dose group (n=10). Half male and half female.
Using rhubarb laxation and ice water stimulation replication diarrhea type in rat model. The model was successful, start the medication, the normal group and model group rats daily to normal saline; the remaining three groups were fed with different doses of fuzilizhong soup side and get Dicetel, a total of medication for14days.
Observed changes in body weight of rats after treatment, the diarrhea rate diarrhea index and intestinal tissue morphological changes; determination of the serum levels of IL-8, serum5-the HT level changes; determination of each rat colonic mucosa samples of TLR4AQP8is the mRNA expression levels.
Results:
1Results of clinical studies
1.1After clinical treatment, whether it is traditional Chinese medicine group or western medicine group, abdominal pain or abdominal discomfort, stool frequency, stool consistency, bowel movement a sense of urgency, mucus symptom scores are lower, paired t-test show the before and after treatment the total symptom score were significantly different. Compared to the total symptom score after the treatment of traditional Chinese medicine group and western medicine group,there is differences (P=0.000).
1.2After treatment, the traditional Chinese medicine group and western medicine group in abdominal discomfort, stool frequency, stool consistency, bowel movement a sense of urgency, bloating, mucus and other symptoms points than before treatment have decreased. Chinese medicine group in the stool, bowel movement a sense of urgency, bloating, mucus improvement better than the western medicine group.
1.3After treatment, the quality of life of the two groups of patients were improved to varying degrees:the SF-36integral treatment group in the physiological function of the physiological functions, bodily pain, general health, vitality, role emotional, mental health integration were significantly higher (P<0.05); the control group only in the physiological functions, the integral of bodily pain improved significantly (P<0.05); treatment groups in the improvement of physiological functions, physical pain, emotional function and mental health were better than the control group (P<0.05).
1.4After treatment of IBS-QOL in all aspects, integration of patients in treatment group with anxiety, behavioral disorders, physical roles, health concerns, dietary restrictions, social response points were significantly improved (P<0.05), in the control group in anxiety, health concerns and dietary restrictions were significantly improved (P<0.05). treatment groups in the improvement of anxiety, behavioral disorders, physical character, health concerns, dietary restrictions were better than control group.
2The experimental results
2.1Lizhong Tang group, different doses allows serum IL-8levels tended to be normal; the Dicetel group of IL-8levels higher than the normal group (P <0.05), compared to model group declined slightly, but statistically the analysis showed no significant difference (P>0.05).
2.2The study of animal experiment found that Fuzilizhong Decoction of different dose group could decrease5-HT content in serum of D-IBS rat model, compared to Dicetel group, its efficacy had no significant difference (P>0.05).
2.3TLR4expression of the intestinal mucosa of the model group were higher than the normal control group were significantly different (P<0.01). Lizhong Tang intestinal mucosa of intervention allows the expression of TLR4is normal, but no significant difference with the normal group. Have Dicetel group compared to the normal group TLR4expression was increased significantly (P <0.01).
2.4The expression of AQP8in rat colon tissue of model group decreased (P <0.05),after the intervention by Lizhong Tang, the expression of AQP8is normal, no difference in the expression of AQP8in the Dicetel group intervention compared with the model group.
Conclusions:
The clinical trials show that fuziLizhong decoction for deficiency of spleen and kidney syndrome D-IBS patients has a good therapeutic effect in clinical symptoms, quality of life; control group also shows a certain therapeutic effect, fuziLizhong decoction clinical overall efficacy was significantly superiorin the control agent.
Animal experiments in terms of inflammation, visceral sensitivity, immunity, and water metabolism study Fuzi Lizhong decoction treatment of deficiency of spleen and kidney syndrome D-IBS possible mechanism, to infer the mechanism of Lizhong Tang treatment of deficiency of spleen and kidney syndrome D-IBS may be it can reduce the inflammatory response, reducing visceral sensitivity, and reduce the immune response, and recovery of water metabolism and other factors.
引文
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