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WO2018068566A1 - 芍药内酯苷在制备改善肠道菌群系统功能的产品中的用途 - Google Patents

芍药内酯苷在制备改善肠道菌群系统功能的产品中的用途 Download PDF

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WO2018068566A1
WO2018068566A1 PCT/CN2017/095986 CN2017095986W WO2018068566A1 WO 2018068566 A1 WO2018068566 A1 WO 2018068566A1 CN 2017095986 W CN2017095986 W CN 2017095986W WO 2018068566 A1 WO2018068566 A1 WO 2018068566A1
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intestinal flora
intestinal
function
improving
paeoniflorin
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张作光
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the field of medicine, relates to the use of paeoniflorin (Albiflorin), and more particularly to the use of paeoniflorin in the preparation of products for improving the function of intestinal flora system and increasing the content of intestinal probiotics, especially lactic acid bacteria, including It is used in the preparation of a medicament, a food, a health supplement, a food additive or a nutritional regulator or the like for preventing and/or treating a sub-health state and/or disease caused by a disorder of the intestinal flora.
  • paeoniflorin Albiflorin
  • paeoniflorin paeoniflorin in the preparation of products for improving the function of intestinal flora system and increasing the content of intestinal probiotics, especially lactic acid bacteria, including It is used in the preparation of a medicament, a food, a health supplement, a food additive or a nutritional regulator or the like for preventing and/or treating a sub-health state and/or disease caused by a disorder of the intestinal flor
  • the intestinal micro-ecological system is the largest and most important micro-ecological system of the human body.
  • the total weight of intestinal bacteria in a healthy adult can reach 1-1.5kg.
  • the intestinal flora in the human body forms a symbiotic relationship with the host cells and is in a dynamic and balanced ecological environment.
  • the role of intestinal bacteria and its impact on human health has attracted the attention of the medical community.
  • the intestinal flora and the host cells continuously exchange information, evolve with the host, regulate various metabolic pathways of the host, affect the immune-anti-inflammatory axis, and closely relate to the physiological and biochemical activities of the host, thereby maintaining the health of the host.
  • Have an impact. More and more studies have shown that the intestinal flora structure disorders and dysfunction and heart disease, liver cancer, Parkinson's disease, depression Alzheimer's disease, irritable bowel syndrome, kidney infection, obesity and diabetes, etc. Have a close relationship.
  • intestinal flora plays an important role in the pathogenesis of depression and anxiety. Some intestinal flora can promote the onset of depression and anxiety by interfering with the metabolism of amino acids and carbohydrates in the host organism. Regulating the ecology of the intestinal flora to treat mental disorders such as depression and anxiety is an important topic in the current medical research. Intestinal flora disorder is one of the important reasons for the promotion of irritable bowel syndrome, colitis and colon cancer.
  • White peony is one of the 101 traditional Chinese medicines that can be used for health products announced by the National Health and Family Planning Commission.
  • Albiflorin is the main active ingredient in the white peony.
  • Modern pharmacological studies have shown that paeoniflorin has analgesic, sedative, anticonvulsant effects, effects on the immune system, effects on smooth muscle, and liver protection. It is mainly used for anti-epilepsy, sedation, vertigo and treatment of the elderly.
  • Sexual disease The function of rapidly regulating and improving the balance of intestinal flora in paeoniflorin and its use have not been disclosed so far.
  • the object of the present invention is to provide a new use of bismuth lactone (Albiflorin) as a new product for improving the function of the intestinal flora system, which can significantly regulate the balance of intestinal flora, in view of the deficiencies of the prior art. It increases the intestinal probiotics, particularly the lactic acid bacteria content, and thus can be used for preventing and/or treating sub-health states and/or diseases caused by intestinal flora disorders.
  • bismuth lactone Albiflorin
  • the present invention proves that the paeoniflorin system improves the function of the intestinal flora system by regulating the endogenous cannabinoid system, while the endocannabinoid system and the intestinal flora and irritable bowel syndrome (IBS), depression Anxiety disorders are closely related.
  • IBS irritable bowel syndrome
  • cannabinoid receptor CB2 agonists can reduce intestinal inflammation and can reduce the incidence of cancer or inhibit the growth of cancer by inhibiting inflammatory reactions, because inflammatory bowel disease (IBD) has an inseparable link with cancer (2016) January, World Journal of Digestion of the World: "Cannabinoid receptor 2 and several digestive diseases”).
  • IBD inflammatory bowel disease
  • paeoniflorin is a cannabinoid receptor CB2 agonist, which can increase the expression of cannabinoid receptor CB2 in intestinal epithelial cells by increasing intestinal lactic acid bacteria, increase intestinal pain threshold, relieve IBS, and treat inflammation.
  • IBD Intestinal disease
  • prevention and treatment of colon cancer IBD
  • the present invention also provides a method of improving the function of the intestinal flora system in a living organism.
  • the paeoniflorin of the present invention as a product for improving the function of the intestinal flora system, can be used for preparing a medicament for preventing and/or treating a sub-health state, a disease caused by a disorder of the intestinal flora, a food, a health supplement, a food additive or Nutritional regulators.
  • the sub-health state caused by the disorder of the intestinal flora is selected from a dysfunction of the intestinal system and/or an affective disorder; the disease is selected from one of irritable bowel syndrome, depression, anxiety, colitis and colon cancer or A variety.
  • Albiflorin is a monoterpenoid compound with a molecular formula of C 23 H 28 O 11 and a molecular weight of 480.46.
  • the molecular structure is as shown in the following formula. It is a natural active substance derived from the genus Ranunculaceae ( Paeonia lactiflora Pall) or the root of Paeonia veitchii Lynch, the root of P. suffrsticosa Andrz.
  • the pharmaceutically acceptable salt of the compound of the formula (I) may be selected from the group consisting of citrate, hydrochloride, sulfate, malate, tartrate, citrate and phosphoric acid. One or more of the salts.
  • the present invention discloses a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, which can be used for the preparation of a product for improving the function of the intestinal flora system;
  • An extract of paeoniflorin or a pharmaceutically acceptable salt thereof, or a paeoniflorin or a pharmaceutically acceptable salt thereof can increase bile acid, amino acid, vitamins and beneficial substances in the intestinal tract of the test rat by increasing the intestinal metabolite
  • the firmicutes, especially the content of various lactic acid bacteria in the intestine rapidly improve and adjust the intestinal flora disorder, improve and treat the sub-health state and disease caused by the intestinal flora disorder.
  • the sub-health state is selected from a gastrointestinal dysfunction and/or an affective disorder; the disease is selected from one or more of irritable bowel syndrome, depression, anxiety, colitis, and colon cancer.
  • the present invention provides a paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof, in the manufacture of a product for improving the function of the intestinal flora system use.
  • the product that improves the function of the gut flora system is provided in the form of a drug, food, health supplement, food additive or nutritional modulator.
  • the function of improving the intestinal flora system is to prevent and/or treat a sub-health state and/or disease caused by a disorder of the intestinal flora, particularly a significant decrease in the content of intestinal probiotics and lactic acid bacteria;
  • the sub-health state is selected from, but not limited to, intestinal system dysfunction and/or affective disorder; more preferably, the sub-health state is selected from a probiotic, preferably a lactic acid bacteria, caused by a decrease in lactic acid bacteria content Intestinal system dysfunction and/or affective disorder;
  • the disease is selected from one or more of irritable bowel syndrome, depression, anxiety, colitis, and colon cancer, but is not limited to these symptoms.
  • the invention provides a method for improving the function of a gut flora system, the method comprising administering to a subject an effective amount of a paeoniflorin or a pharmaceutically acceptable salt thereof, or comprising hydrazine An extract of a drug lactone or a pharmaceutically acceptable salt thereof;
  • the function of improving the intestinal flora system is to improve the intestinal flora disorder and increase the intestinal probiotics, particularly the lactic acid bacteria content.
  • the function of improving the intestinal flora system is to prevent and/or treat a sub-health state and/or disease caused by a disorder of the intestinal flora, particularly a significant decrease in the content of intestinal probiotics and lactic acid bacteria;
  • the sub-health state is selected from, but not limited to, intestinal system dysfunction and/or affective disorder; more preferably, the sub-health state is selected from a probiotic, preferably a lactic acid bacteria, caused by a decrease in lactic acid bacteria content Intestinal system dysfunction and/or affective disorder;
  • the disease is selected from one or more of the group consisting of irritable bowel syndrome, depression, anxiety, colitis and colon cancer, but is not limited to these symptoms.
  • the present invention provides a composition for improving the function of an intestinal flora system comprising a paeoniflorin or a pharmaceutically acceptable salt thereof, or a paeoniflorin or a pharmaceutically acceptable Extract of salt;
  • the function of improving the intestinal flora system is to improve the intestinal flora disorder and increase the intestinal probiotics, particularly the lactic acid bacteria content.
  • the composition for improving the function of the intestinal flora system is a medicine, a food, a health supplement, a food additive or a nutritional regulator.
  • the function of improving the intestinal flora system is to prevent and/or treat a sub-health state and/or disease caused by a disorder of the intestinal flora, particularly a significant decrease in the content of intestinal probiotics and lactic acid bacteria;
  • the sub-health state is selected from, but not limited to, intestinal system dysfunction and/or affective disorder; more preferably, the sub-health state is selected from a probiotic, preferably a lactic acid bacteria, caused by a decrease in lactic acid bacteria content Intestinal system dysfunction and/or affective disorder;
  • the disease is selected from one or more of the group consisting of irritable bowel syndrome, depression, anxiety, colitis and colon cancer, but is not limited to these symptoms.
  • the present invention provides a paeoniflorin or a pharmaceutically acceptable salt thereof for improving the function of the intestinal flora system, or an extract comprising the paeoniflorin or a pharmaceutically acceptable salt thereof ;
  • the function of improving the intestinal flora system is to improve the intestinal flora disorder and increase the intestinal probiotics, particularly the lactic acid bacteria content.
  • the function of improving the intestinal flora system is to prevent and/or treat a sub-health state and/or disease caused by a disorder of the intestinal flora, particularly a significant decrease in the content of intestinal probiotics and lactic acid bacteria;
  • the sub-health state is selected from, but not limited to, intestinal system dysfunction and/or affective disorder; more preferably, the sub-health state is selected from a probiotic, preferably a lactic acid bacteria, caused by a decrease in lactic acid bacteria content Intestinal system dysfunction and/or affective disorder;
  • the disease is selected from the group consisting of irritable bowel syndrome, depression, anxiety, colitis and colon One or more of cancers, but are not limited to these symptoms.
  • the present invention rapidly regulates and improves human intestinal bacteria by administering an effective amount of paeoniflorin or a pharmaceutically acceptable salt thereof, or an extract comprising paeoniflorin or a pharmaceutically acceptable salt thereof.
  • Disorders increase the intestinal probiotics, especially the lactic acid bacteria. It is used to control the sub-health status and diseases caused by the intestinal flora disorder, especially the intestinal probiotics and lactic acid bacteria.
  • the present invention has the following advantages:
  • the invention restores and improves the function of the intestinal system by increasing the content of bile acid, vitamins and amino acids in the intestinal flora metabolites, and experiments prove that the paeoniflorin can quickly recover and improve each within one week of administration.
  • the present invention improves the intestinal flora function by promoting the growth of human endogenous probiotics, especially by increasing the growth of lactic acid bacteria, which directly promotes the growth of endogenous lactic acid bacteria and supplements exogenous lactic acid bacteria. Compared with the technology, it is much stronger in maintaining the activity, stability and abundance of lactic acid bacteria, especially the types of lactic acid bacteria which are exogenous lactic acid bacteria functional foods and beverage supplements, and the invention increases the intestinal lactic acid bacteria, restores and enhances It is the overall function of the intestinal lactic acid flora.
  • First-line antidepressant preparations such as fluoxetine and other SSRIs make the metabolism of rat intestinal flora deviate from the normal state after administration, and the metabolism of intestinal flora in rats moves toward the normal group after administration of paeoniflorin. It almost completely overlaps with the normal group, indicating that the paeoniflorin helps the metabolism of the intestinal flora of the stressed rats to return to normal. Therefore, the paeoniflorin not only has no common intestinal adverse reactions of fluoxetine, but also rapidly recovers. The balance of the intestinal flora.
  • the figure is intended to illustrate that integration of a new generation of metabolomics and high-throughput metagenomic sequencing has shown that paeoniflorin has a rapidly improving function of regulating the intestinal flora.
  • Figure 1 is a targeted metabolomics multiple comparative analysis (PLS-DA);
  • Figure 2 is a VIP analysis of intestinal flora metabolism in the depression model group and the blank group (Top 20 metabolites, VIP>1.5 is significantly different)
  • Figure 3 is a structural analysis of the intestinal flora of a high-throughput sequencing stress rat model group (depression group) and a blank group.
  • Control blank group;
  • CUMS stress rat model;
  • Figure 4 is a cluster analysis of high-throughput metagenomic sequencing intestine population structure after administration of paeoniflorin.
  • Control blank group; Alb: paeoniflorin group, CUMS: rat model.
  • Figure 5 is a diagram showing the disorder of intestinal microbial metabolism in the model group of the paeoniflorin group (metalogous product with significant changes after Top25 administration).
  • Figure 6 shows that PLS-DA showed that the fluoxetine group increased the intestinal flora disorder in the model group.
  • Example 1 The "sub-health" state of internal and external environmental stress in Example 1 leads to disturbance of intestinal flora
  • the intestinal flora metabolism of the depression group was significantly lower than that of the blank group.
  • 16 (80%) metabolites were significantly reduced in the depression model (VIP > 1.5), see Figure 2.
  • the reduced metabolites are mainly amino acids and vitamins and their derivatives, see Figure 2.
  • Example 2 Administration of Paeoniflorin for 7 days can quickly restore the structure and function of intestinal flora in stressed rats
  • Figure 5 is a graph showing the cluster analysis of intestinal flora structure correlation.
  • the paeoniflorin administration group (Alb) was similar to the blank group (Control), and was clustered together, and there was no statistical difference (P>0.05).
  • the beneficial bacteria were compared.
  • the positive drug fluoxetine was administered continuously for 7 days, each dose was 10 mg/kg/d, multivariate PLS-DA Analysis showed that the effect of fluoxetine was opposite to that of paeoniflorin, which caused the metabolism of rat intestinal flora to deviate from the normal state, see Figure 6.
  • paeoniflorin has the function of rapidly regulating and improving the intestinal flora, and can be used with paeoniflorin or paeoniflorin.
  • White peony extract and functional composition are used to prepare foods, food additives, health foods, or medicines that rapidly improve intestinal flora imbalance, increase intestinal lactic acid bacteria content, and have high application value and huge market potential.

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Abstract

芍药内酯苷或其药学上可接受的盐在制备调节和改善人体肠道菌群平衡的产品中的用途。芍药内酯苷或其药学上可接受的盐作为改善肠道菌群系统功能的调节剂，可用于制备改善和治疗由肠道菌群紊乱引起的亚健康状态和/或疾病的药物、保健品、食品、食品添加剂或营养补充剂；这些亚健康状态选自肠道系统功能紊乱和/或情感障碍；这些疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。

Description

芍药内酯苷在制备改善肠道菌群系统功能的产品中的用途 技术领域
本发明属于医药领域，涉及芍药内酯苷(Albiflorin)的用途，更具体涉及芍药内酯苷在制备改善肠道菌群系统功能，增加肠道益生菌特别是乳酸菌含量的产品中的用途，包含其在制备用于预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病的药物、食品、保健品、食品添加剂或营养调节剂等中的用途。
背景技术
肠道微生态系统是人体最庞大、最重要的的微生态系统。一个健康成人的肠道细菌总重量可以达到1-1.5kg。正常情况下，人体中的肠道菌群与宿主细胞形成共生的关系，处于动态平衡的生态环境中。肠道菌的作用和其对人体健康的影响，已备受医药界关注。肠道菌群与宿主细胞之间不断地进行信息交流，与宿主一同进化，调控宿主的多种代谢路径，影响免疫-抗炎轴，与宿主的生理、生化活动关系密切，从而对宿主的健康产生影响。越来越来的研究表明，肠道菌群结构的失调和功能紊乱与心脏疾病、肝癌、帕金森症、抑郁症阿尔茨海默症、肠易激综合征、肾脏感染、肥胖和糖尿病等都有密切关系。
近期研究发现，肠道菌群在抑郁症、焦虑症发病中发挥了重要作用，某些肠道菌群，能够通过干扰宿主机体氨基酸和碳水化合物的代谢来促进抑郁症、焦虑症的发病，通过调节肠道菌群生态来治疗抑郁症、焦虑症等精神疾患是当前医药界研究的重要课题。肠道菌群紊乱又是促使肠易激综合症、结肠炎、结肠癌发病的重要原因之一，但是，通过调节肠道菌群紊乱缓解肠易激综合症、防治结肠炎、结肠癌的产品，目前技术仅停留在补充外源性益生菌或是乳酸菌这类饮料和保健食品层面上，它们究竟是否具有调节肠道菌群的作用和这种作用的机制均尚不十分清楚。
开发调节恢复肠道菌群平衡的药物和保健品，已经成为当前药物和功能食品研发的重要课题。2016年9月初，由中国人民解放军总医院、中国健康促进基金会主办多家三甲医院在北京就肠道微生物检测技术和干预课题进行研讨，提出合理补充膳食纤维对于良好的肠道菌群构建有着十分重要意义。会上重点推介了博奥颐和公司研制开发的九叶堂益生菌固体饮料，据研发人员讲述该产品可以用于调理和改善不同肠道菌群失调。
中药，是中医治疗疾病和强身健体的主要形式，同时也是食品和保健品开发的重要资源，素有“药食同源”之说。许多中药本身即是药物，又是食物，可以药食兼用。中药对于肠道菌群调节作用的研究刚刚起步，2016年有研究表明，人参中的多糖能够增强乳酸菌和拟杆菌这两种人参皂苷主要代谢细菌的生长速率，进而提高人参皂苷的吸收，增加药效。
白芍是国家卫计委公布的可用于保健品的101种中药之一。芍药内酯苷(Albiflorin)是白芍中的主要有效成分。现代药理学研究表明芍药内酯苷具有镇痛、镇静、抗惊厥作用，对免疫系统的作用、对平滑肌的作用、护肝作用等，临床上主要用于抗癫痫，镇静，止眩晕和治疗老年性疾病。有关芍药内酯苷快速调节和改善肠道菌群平衡的功能及其用途至今未见披露。
发明内容
本发明的目的在于针对现有技术的不足，提供一种芍药内酯苷(Albiflorin)的新用途，其作为一种新的改善肠道菌群系统功能的产品，能够明显调节肠道菌群平衡，增加肠道益生菌特别是乳酸菌含量，因此，可以用于预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病。
本发明研究证明，芍药内酯苷系通过调节内源性大麻素系统改善肠道菌群系统功能，而内源性大麻素系统与肠道菌群和肠易激综合症(IBS)、抑郁症、焦虑症关系密切。
研究证明，大麻素受体CB2激动剂，可以减轻肠道炎症，可以通过抑制炎症反应进而减少癌症的发生或抑制癌症的生长，因为炎症性肠病(IBD)与癌症有着难以分开的联系(2016年1月《世界华人消化杂志》：“大麻素受体2与几种消化系统疾病”)。
本发明研究证明，芍药内酯苷是大麻素受体CB2激动剂，可以通过增加肠道乳酸菌上调肠道上皮细胞中大麻素受体CB2的表达，提高肠道的疼痛阈值，缓解IBS，治疗炎症性肠病(IBD)和防治结肠癌。
本发明还提供了一种改善生物体内的肠道菌群系统功能的方法。
本发明芍药内酯苷作为改善肠道菌群系统功能的产品，可以用于制备预防和/或治疗由肠道菌群紊乱引起的亚健康状态、疾病的药物、食品、保健品、食品添加剂或营养调节剂。这些因肠道菌群紊乱引起的亚健康状态选自肠道系统功能紊乱和/或情感障碍；疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。
芍药内酯苷(Albiflorin)为单萜类化合物，其分子式为C23H28O11，分子量为480.46，分子结构如下式所示，是一种天然活性物质，来源于毛莨科植 物白芍(Paeonia lactiflora Pall)或川赤芍(Paeonia veitchii Lynch)的根、牡丹(P.suffrsticosa Andrz)的根。
Figure PCTCN2017095986-appb-000001
根据本发明提供的用途，其中，式(I)所示化合物的药学上可接受的盐可以选自枸橼酸盐、盐酸盐、硫酸盐、苹果酸盐、酒石酸盐、柠檬酸盐和磷酸盐中的一种或多种。
本发明披露了芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物可以用于制备改善肠道菌群系统功能的产品；本发明的芍药内酯苷或其药学上可接受的盐，或者包含芍药内酯苷或其药学上可接受的盐的提取物可以通过增加受试大鼠肠道内代谢物胆酸、氨基酸、维生素及有益菌厚壁菌门(firmicutes)，其中特别是增加肠道各种乳酸菌的含量，快速改善和调整肠道菌群紊乱，改善和治疗由肠道菌群紊乱引起引起的亚健康状态、疾病，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍；所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。
一方面，本发明提供了芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物在制备改善肠道菌群系统功能的产品中的用途。
优选地，所述改善肠道菌群系统功能的产品以选自药物、食品、保健品、食品添加剂或营养调节剂的形式提供。
优选地，所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱，特别是肠道益生菌及乳酸菌含量明显减少引起的亚健康状态和/或疾病；
优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍，但不限于这些症状；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种，但不限于这些症状。
另一方面，本发明提供了一种用于改善肠道菌群系统功能的方法，所述方法包括给予对象有效量的芍药内酯苷或其药学上可接受的盐、或者包含芍 药内酯苷或其药学上可接受的盐的提取物；
优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌特别是乳酸菌含量。
优选地，所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱，特别是肠道益生菌及乳酸菌含量明显减少引起的亚健康状态和/或疾病；
优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍，但不限于这些症状；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中中的一种或多种，但不限于这些症状。
再一方面，本发明提供了一种用于改善肠道菌群系统功能的组合物，其包含芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；
优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌特别是乳酸菌含量。
优选地，所述用于改善肠道菌群系统功能的组合物为药物、食品、保健品、食品添加剂或营养调节剂。
优选地，所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱，特别是肠道益生菌及乳酸菌含量明显减少引起的亚健康状态和/或疾病；
优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍，但不限于这些症状；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中中的一种或多种，但不限于这些症状。
再另一方面，本发明还提供了用于改善肠道菌群系统功能的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；
优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌特别是乳酸菌含量。
优选地，所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱，特别是肠道益生菌及乳酸菌含量明显减少引起的亚健康状态和/或疾病；
优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍，但不限于这些症状；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠 癌中的一种或多种，但不限于这些症状。
本发明通过给予对象有效量的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物，多靶点快速调节和改善人体肠道菌群紊乱，增加肠道益生菌特别是乳酸菌含量。用于防治因肠道菌群系统紊乱，特别是肠道益生菌及乳酸菌含量明显减少引起的人体亚健康状态和疾病。
与现有技术相比，本发明具有以下优点：
1、本发明系通过提升肠道菌群代谢物中胆酸、维生素及氨基酸的含量恢复和改善肠道系统功能，实验证明，芍药内酯苷在给药一周之内即可快速恢复和改善各种应激所致的肠道菌群紊乱。
2、本发明系通过促进人体内源性益生菌生长，尤其是是通过增加乳酸菌的生长来改善肠道菌群功能，这种直接促进内源性乳酸菌的生长与补充外源性乳酸菌的现有技术相比，在保持乳酸菌的活性、稳定性和丰富性方面要强很多，特别是外源性乳酸菌功能食品、饮料补充的乳酸菌种类有限，而本发明增加的是肠道各种乳酸菌，恢复和增强的是肠道乳酸菌群的整体功能。
3、氟西汀等SSRIs等一线抗抑郁制剂在给药后使得大鼠肠道菌群的代谢更偏离正常状态，而芍药内酯苷给药后大鼠肠道菌群代谢朝向正常组方向移动，几乎完全与正常组重叠，说明芍药内酯苷有助于应激大鼠肠道菌群代谢恢复正常，因此，芍药内酯苷不仅没有氟西汀常见的肠道不良反应，而且会快速恢复肠道菌群的平衡。
附图的简要说明
附图用于说明整合新一代代谢组学和高通量宏基因组测序表明芍药内酯苷具有快速改善调节肠道菌群的功能。
附图1为靶向代谢组学多重比较分析(PLS-DA)；
附图2为抑郁症模型组和空白组大鼠肠道菌群代谢VIP分析(Top20代谢物，VIP＞1.5为有显著性差异)
附图3为高通量测序应激大鼠模型组(抑郁症组)与空白组肠道菌群结构分析。Control：空白组；CUMS：应激大鼠模型；
附图4为芍药内酯苷给药后高通量宏基因组测序肠道种群结构聚类分析。Control：空白组；Alb：芍药内酯苷组，CUMS：大鼠模型。
附图5为芍药内酯苷组纠正模型组大鼠肠道微生物代谢的紊乱(Top25给药后有显著变化的代谢产物)。
附图6为PLS-DA表明，氟西汀组加大了模型组大鼠肠道菌群紊乱。
实施发明的最佳方式
下面结合具体实施案例，进一步阐释本发明。但下述实施案例仅限于说明本发明，而不是用于限制本发明的范围。
我们在前期的研究中，通过整合新一代代谢组学和高通量测序技术发现，芍药内酯苷能够快速改善大鼠肠道菌群紊乱，恢复肠道菌群的正常功能。
实施例1内外环境应激的“亚健康”状态导致肠道菌群的紊乱
我们建立了慢性不可预见性温和应激大鼠模型(chronic unpredictable mild stress,CUMS)。运用新一代靶向代谢组学方法，对于应激大鼠肠道菌群的代谢功能进行了研究，PLS-DA多变量分析表明抑郁症模型组(抑郁症组)大鼠的肠道菌群代谢与空白组之间具有显著性差异，见附图1。
通过VIP分析，抑郁症组大鼠肠道菌群代谢与空白组相比，显著降低。在两组具有显著性的Top20代谢产物中，16个(80％)代谢产物在抑郁症模型中显著降低(VIP＞1.5)，见附图2。降低的代谢物主要是氨基酸和维生素类及其衍生物，见附图2。
高通量16sRNA测序表明，应激大鼠模型的肠道菌群结构和肠道菌群种类与空白组相比发生了显著的变化，见附图3。
研究证明肠道菌群的结构和功能紊乱与内外环境的刺激有密切联系。
实施例2芍药内酯苷给药7天可快速恢复应激大鼠肠道菌群结构和功能
我们进一步给予应激模型大鼠芍药内酯苷治疗，连续给药7，每次治疗剂量为7mg/kg/d。7天后，我们运用代谢组学和16sDNA高通量宏基因组测序技术对大鼠肠道菌群的功能和结构进行再评估。通过对代谢组学数据的多重比较分析(PLS-DA)表明，芍药内酯苷给药后，大鼠肠道菌群代谢，朝向正常组方向移动，几乎完全与正常组重叠，说明芍药内酯苷有助于应激大鼠肠道菌群代谢恢复正常，见附图1。这与菌群结构分析的结果相吻合。
VIP分析，芍药内酯苷给药7天后，肠道菌群整体代谢与抑郁症组相比，显著提高，主要表现为胆酸含量增加，氨基酸和维生素的含量增加，见附图4。
附图5是肠道菌群结构相关性聚类分析图。芍药内酯苷给药组(Alb)与空白组(Control)菌群结构相近，被聚类到一起，且无统计学差异(P＞0.05)，与应激大鼠模型组相比，有益菌厚壁菌门(firmicutes)，特别是其中的乳酸菌含量显著增加。
实施例3氟西汀给药7天加剧了应激大鼠肠道菌群紊乱
阳性药氟西汀连续给药7天，每次剂量为10mg/kg/d，多变量PLS-DA 分析表明氟西汀作用与芍药内酯苷相反，使得大鼠肠道菌群的代谢更偏离正常状态，见附图6。
综上所述，代谢组学和16sRNA高通量测序的整合研究表明，芍药内酯苷具有快速调节和改善肠道菌群的功能，可以用芍药内酯苷、或是含有芍药内酯苷的白芍提取物、功能组合物制备快速改善肠道菌群紊乱、增加肠道乳酸菌含量的食品、食品添加剂、保健食品，或是药品，这些产品具有极高的应用价值和巨大的市场潜力。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (10)

  1. 芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物在制备改善肠道菌群系统功能的产品中的用途。
  2. 根据权利要求1所述的用途，其中所述改善肠道菌群系统功能的产品以选自药物、保健品、食品、食品添加剂或营养补充剂的形式提供。
  3. 根据权利要求1或2所述的用途，其中所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病；
    优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
    优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。
  4. 一种用于改善肠道菌群系统功能的方法，所述方法包括给予对象有效量的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；
    优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌，优选地乳酸菌的含量。
  5. 根据权利要求4所述的方法，其中所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病；
    优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
    优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。
  6. 一种用于改善肠道菌群系统功能的组合物，其包含芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；
    优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌，优选地乳酸菌的含量。
  7. 根据权利要求6所述的组合物，其中所述用于改善肠道菌群系统功能的组合物为药物、食品、保健品、食品添加剂或营养调节剂。
  8. 根据权利要求6或7所述的组合物，其中所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病；
    优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
    优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中的一种或多种。
  9. 用于改善肠道菌群系统功能的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物；
    优选地，所述改善肠道菌群系统功能为改善肠道菌群紊乱，增加肠道益生菌，优选地乳酸菌的含量。
  10. 根据权利要求9所述的芍药内酯苷或其药学上可接受的盐、或者包含芍药内酯苷或其药学上可接受的盐的提取物，其中所述改善肠道菌群系统功能为预防和/或治疗由肠道菌群紊乱引起的亚健康状态和/或疾病；
    优选地，所述亚健康状态选自肠道系统功能紊乱和/或情感障碍；更优选地，所述亚健康状态选自由于肠道益生菌，优选地乳酸菌含量减少引起的肠道系统功能紊乱和/或情感障碍；
    优选地，所述疾病选自肠易激综合症、抑郁症、焦虑症、结肠炎和结肠癌中中的一种或多种。
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CN108451949B (zh) * 2018-06-20 2021-03-19 山东省分析测试中心 芍药苷代谢素i在制备治疗结肠炎药物中的应用
WO2020020342A1 (zh) * 2018-07-26 2020-01-30 张作光 白芍总苷用于预防或治疗糖尿病的用途
WO2020020343A1 (zh) * 2018-07-26 2020-01-30 张作光 白芍总苷作为治疗肿瘤的免疫检查点抑制剂的增效剂的用途
WO2020168760A1 (zh) * 2019-02-21 2020-08-27 张作光 芍药内酯苷在制备快速治疗抑郁症的药物中的用途
CN111658694A (zh) * 2019-03-08 2020-09-15 珠海岐微生物科技有限公司 白芍在调节肠道微生物中的用途
CN112791076A (zh) * 2021-01-25 2021-05-14 深圳大学 肠道菌落调节剂及其应用
CN116650510A (zh) * 2023-06-28 2023-08-29 天津农学院 芍药苷作为纳米氧化锌致肠道菌群紊乱调节剂方面的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010133015A1 (zh) * 2009-05-21 2010-11-25 陈婷 治疗抑郁症的药物组合物、制备方法及用途
WO2011003226A1 (zh) * 2009-07-10 2011-01-13 陈婷 治疗抑郁症的药物组合物、制备方法及用途
WO2011047576A1 (zh) * 2009-10-20 2011-04-28 Zhang Zuoguang 芍药内酯苷的抗抑郁用途
WO2012068958A1 (zh) * 2010-11-25 2012-05-31 Zhang Zuoguang 芍药内酯苷或其代谢物的抗焦虑及改善睡眠障碍的用途
CN103417561A (zh) * 2012-05-15 2013-12-04 北京京朋汇药业研究发展有限公司 芍药苷类化合物在制备抗肿瘤药物中的用途
WO2016134563A1 (zh) * 2015-02-26 2016-09-01 张作光 芍药内酯苷或其药学上可接受的盐预防和/或治疗肠易激综合征的用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101623366B (zh) * 2009-07-18 2012-09-05 南京师范大学 治疗胃肠功能紊乱的组合物、其制备方法及其在制备治疗胃肠功能紊乱药物中的应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010133015A1 (zh) * 2009-05-21 2010-11-25 陈婷 治疗抑郁症的药物组合物、制备方法及用途
WO2011003226A1 (zh) * 2009-07-10 2011-01-13 陈婷 治疗抑郁症的药物组合物、制备方法及用途
WO2011047576A1 (zh) * 2009-10-20 2011-04-28 Zhang Zuoguang 芍药内酯苷的抗抑郁用途
WO2012068958A1 (zh) * 2010-11-25 2012-05-31 Zhang Zuoguang 芍药内酯苷或其代谢物的抗焦虑及改善睡眠障碍的用途
CN103417561A (zh) * 2012-05-15 2013-12-04 北京京朋汇药业研究发展有限公司 芍药苷类化合物在制备抗肿瘤药物中的用途
WO2016134563A1 (zh) * 2015-02-26 2016-09-01 张作光 芍药内酯苷或其药学上可接受的盐预防和/或治疗肠易激综合征的用途

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