WO2020020342A1 - 白芍总苷用于预防或治疗糖尿病的用途 - Google Patents

白芍总苷用于预防或治疗糖尿病的用途 Download PDF

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WO2020020342A1
WO2020020342A1 PCT/CN2019/097897 CN2019097897W WO2020020342A1 WO 2020020342 A1 WO2020020342 A1 WO 2020020342A1 CN 2019097897 W CN2019097897 W CN 2019097897W WO 2020020342 A1 WO2020020342 A1 WO 2020020342A1
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intestinal flora
paeony
total glucosides
paeoniflorin
stress
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PCT/CN2019/097897
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French (fr)
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张作光
田晖
李克峰
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张作光
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • the invention belongs to the field of medicine, and relates to the use of total glucosides of paeony to improve intestinal flora balance through anti-stress to prevent or treat diabetes, and particularly relates to total glucosides of paeony, paeoniflorin and paeoniflorin through anti-stress, recovery and Improve the intestinal flora balance and increase the abundance of probiotics such as Akk bacteria, bifidobacteria, and lactic acid bacteria that are beneficial to glucose metabolism to prevent or treat diabetes.
  • probiotics such as Akk bacteria, bifidobacteria, and lactic acid bacteria that are beneficial to glucose metabolism to prevent or treat diabetes.
  • Sustained stress response not only affects the body's glucose metabolism through neuroendocrine-related hormones, causing insulin resistance, but also disrupts the intestinal flora balance and further exacerbates glucose metabolism disorders. Disturbance of the intestinal flora and insulin resistance caused by stress are one of the important causes of diabetes. Stress causes hyperfunction of the HPA axis, which increases the secretion of adrenaline, norepinephrine, glucocorticoids and glucagon. These factors directly affect the body's glucose-lipid metabolism, increase blood sugar, and increase insulin resistance. Therefore, in the prevention and treatment of diabetes, in addition to the use of hypoglycemic drugs, it is necessary to fully understand the stress, especially the negative effects of social and psychological stress factors on the occurrence and treatment of diabetes.
  • Intestinal microorganisms are the largest and most important micro-ecosystem 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 and the host cell form a symbiotic relationship, in a dynamic and balanced ecology.
  • the role of intestinal flora and its impact on human health have attracted much attention from the medical community.
  • the metabolic activity of the human intestinal flora is an important environmental factor that affects diabetes. More and more studies have shown that the intestinal flora is closely related to the occurrence of metabolic diseases such as diabetes. Many major metabolisms related to the intestinal flora Substances and their potential biological functions have been discovered, see Table 1 below.
  • Akk bacteria have mucin-degrading properties, which can promote mucus production, thicken mucus, and improve metabolic disorders caused by high-fat diets, such as increased body fat, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance.
  • Intervention treatment for intestinal flora, prevention and control of diabetes by regulating intestinal flora has become a focus of research in recent years.
  • the current approach is usually to supplement the exogenous probiotics, such as bifidobacteria, lactic acid bacteria, Akk bacteria, etc., to improve the host intestinal flora structure and alleviate the symptoms of diabetes; or to supplement bile acids and other substances to improve the intestinal bacteria Group metabolic environment to resist the occurrence of diabetes.
  • the purpose of the present invention is to provide the use of total glucosides of paeony and its main functional components, paeoniflorin and paeoniflorin, in the preparation of a medicament for preventing or treating diabetes.
  • the inventors have discovered that total glucosides of paeony and its main functional components paeoniflorin and paeoniflorin can improve intestinal flora balance through anti-stress and anti-inflammatory, and can be used to prevent or treat diabetes.
  • the total paeony glycosides, paeoniflorin, and paeoniflorin of the present invention as a natural product for rapid anti-stress, anti-depression, and anti-inflammatory, improve the function of the intestinal flora system, can increase the intestine by adjusting the intestinal flora balance
  • the abundance of microorganisms such as Akk bacteria, lactic acid bacteria, and bifidobacteria can improve glucose-lipid metabolism in the body and prevent diabetes.
  • the present invention finds that chronic unpredictable stress (CUMS) is not only in the process of studying the main functional components of paeony
  • CUMS chronic unpredictable stress
  • the metabolic balance of the intestinal flora of the model rats was disrupted, and the glucose metabolism was disturbed and the blood glucose was increased.
  • Paeoniflorin can quickly restore the intestinal flora balance, reduce blood sugar, and prevent diabetes through anti-stress, anti-depression, and anti-inflammatory.
  • metabolomics and 16SrDNA metagenome tests on rat stool samples and found that paeoniflorin can significantly improve the composition and metabolic characteristics of intestinal flora in stress (depression) rats, making them normal. Rat intestinal flora pattern approached.
  • probiotics such as Akk bacteria, lactic acid bacteria, and bifidobacteria in the intestinal flora of stress (depression) rats was significantly reduced, especially the Akk bacteria in the intestine of CUMS model rats. Almost 0, and taking peony lactone glycosides can increase the abundance of probiotics such as Akk bacteria, lactic acid bacteria, and bifidobacteria in the intestine of CUMS rats.
  • the present invention provides the use of total glucosides of paeony in the preparation of a medicament for preventing or treating diabetes; wherein the total glucosides of paeony is used to prevent or treat diabetes by improving the balance of intestinal flora;
  • the total glucosides of paeony regulate intestinal flora function through anti-stress, anti-depression and anti-inflammatory.
  • the total glucosides of paeony comprises paeoniflorin and paeoniflorin.
  • the function of improving the intestinal flora balance is to increase the content of probiotic bacteria such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium longum in the intestine.
  • probiotic bacteria such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium longum in the intestine.
  • the present invention provides a method for treating diabetes, the method comprising administering a therapeutically effective amount of total paeony glucosides in a diabetic patient; wherein the paeony total glycosides are prevented or treated by improving intestinal flora balance diabetes;
  • the total glucosides of paeony regulate intestinal flora function through anti-stress, anti-depression and anti-inflammatory.
  • the total glucosides of paeony comprises paeoniflorin and paeoniflorin.
  • the function of improving the intestinal flora balance is to increase the content of probiotic bacteria such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium in the intestine.
  • probiotic bacteria such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium in the intestine.
  • the present invention provides the use of a total glucoside of paeony for improving the glucose metabolism of the human body; wherein the total glucoside of paeony improves the glucose metabolism of the human body by improving the intestinal flora balance;
  • the total glucosides of paeony regulate intestinal flora function through anti-stress, anti-depression and anti-inflammatory.
  • the total glucosides of paeony comprises paeoniflorin and paeoniflorin.
  • the product is a medicine, a health product, a nutritional supplement or a food additive.
  • the function of improving the intestinal flora balance is to increase the abundance of probiotics such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium in the intestine.
  • probiotics such as Akk bacteria, rumen cocci, lactic acid bacteria, bifidobacteria, and bifidobacterium in the intestine.
  • the invention discloses total glucosides of paeony and its main functional components paeoniflorin and paeoniflorin, which can increase the content of bile acids, amino acids and vitamins in the intestine of diabetic patients through anti-stress, anti-depression and anti-inflammatory, and improve the intestinal flora. Metabolism, so that normal intestinal flora function is restored. This improvement in the function of the intestinal flora is manifested in the restoration of probiotics such as firmicutes, in particular, the content of microorganisms such as Akk bacteria, lactic acid bacteria, and bifidobacteria in the intestinal flora is increased. Improving human glucose-lipid metabolism provides a good intestinal flora environment and has a significant synergistic effect on the treatment of glucose-lowering drugs such as metformin.
  • the present invention provides the use of total glucosides of paeony and its main functional components, paeoniflorin and paeoniflorin, to improve the glucose metabolism of the human body through anti-stress, anti-depression, and anti-inflammatory regulation of intestinal flora function;
  • the present invention has the functions of anti-stress, anti-depression, anti-inflammatory and restoration of intestinal flora disorder, and is suitable for the conditioning of diabetic patients with depression or inflammation, and is used to improve the overall body Glucose metabolism
  • the present invention is suitable for people who are under stress in daily life, psychological stress, emotional stress, and stress in a busy and busy environment, and can be used for conditioning, which can effectively balance the state of psychological survival and prevent the occurrence of diabetes.
  • the invention for improving the glucose metabolism of the human body through anti-stress, anti-depression, anti-inflammatory and regulating the function of the intestinal flora can be used as a medicine for preventing diabetes, a health product, a nutritional supplement or a food additive.
  • the present invention provides an anti-stress, anti-depression, and anti-inflammatory to improve the intestinal flora balance, increase Akk bacteria, lactic acid bacteria, bifidobacteria and other microorganisms in the intestine, comprehensively regulate sugar-lipid metabolism and prevent diabetes Methods.
  • the present invention provides a method for improving intestinal flora balance through anti-stress, anti-depression, and anti-inflammatory, and comprehensively regulating glucose-lipid metabolism for the prevention and treatment of diabetes.
  • This method is particularly suitable for treating stress-type diabetes or associated diseases. Patients with diabetes or depression.
  • the present invention has the following advantages:
  • the invention increases the content of bile acid, vitamins and amino acids in the intestinal flora through anti-stress, anti-depression, and anti-inflammatory, restores and improves the metabolic balance of the intestinal flora, and increases the Akk bacteria, lactic acid bacteria, Abundance of probiotics such as Bifidobacterium.
  • the experiment proves that the total glucosides of paeony, paeoniflorin, and paeoniflorin of the present invention can quickly improve various stresses (including depression, diabetes, diabetes syndrome, and other stress-induced diseases) within one week after administration. ) Caused by intestinal flora disturbance.
  • the present invention is to improve the living environment of endogenous intestinal flora and increase the abundance of probiotics such as Akk bacteria, lactic acid bacteria and bifidobacteria through anti-stress, anti-depression, anti-inflammatory, improving the living environment of intestinal flora, Improve the function of the intestinal flora, which directly promotes the growth of endogenous probiotics in the human intestine.
  • probiotics such as Akk bacteria, lactic acid bacteria and bifidobacteria
  • anti-stress such as Akk bacteria, lactic acid bacteria and bifidobacteria
  • anti-depression anti-inflammatory
  • Antidepressants such as fluoxetine and SSRIs can aggravate the intestinal flora of patients after taking it, which may have a negative impact on the treatment of diabetes.
  • Paeony total glycosides, paeoniflorin, and paeoniflorin can simultaneously improve the intestinal flora balance while antidepressant, restore and enhance the expression of probiotics such as Akk bacteria, lactic acid bacteria, and bifidobacteria. Therefore, the present invention More suitable for the treatment of diabetes with depression.
  • Figure 3 Structural analysis of intestinal flora of high-throughput sequencing stress rat model group (depression group) and blank group (Control: blank group; CUMS: stress rat model).
  • Figure 4 Cluster analysis of intestinal population structure of high-throughput metagenomic sequencing after administration of paeoniflorin.
  • Control blank group; Alb: peiolide group, CUMS: rat model.
  • FIG. 6 PLS-DA shows that the fluoxetine group increased the intestinal flora of the model group rats.
  • peony lactone glycosides and total peony glycosides containing peony lactone glycosides can rapidly improve the intestinal flora disorder in rats and restore Normal function of the intestinal flora.
  • Example 1 "Sub-healthy" state of internal and external environmental stress causes disturbance of intestinal flora
  • Example 2 Paeonolide administration for 7 days can quickly restore the structure and function of intestinal flora of slow stress rats
  • the overall metabolism of the intestinal flora was significantly increased compared with the depression group after 7 days of paeoniflorin administration.
  • the main manifestations were increased bile acid content and increased amino acid and vitamin content, see Figure 4 below.
  • Figure 5 is a cluster analysis diagram of the intestinal flora structure correlation.
  • the structure of the peony lactone administration group (Alb) is similar to that of the normal group (Control), and they are clustered together without statistical difference (P> 0.05).
  • the beneficial bacteria Firmicutes, especially lactic acid bacteria have increased significantly.
  • Example 3 Administration of fluoxetine for 7 days exacerbates intestinal flora disturbance in stressed rats
  • the positive drug fluoxetine was administered continuously for 7 days at a dose of 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 the rat intestinal flora to deviate more. Normal state, indicating that SSRI-type antidepressants further exacerbated the intestinal flora, see Figure 6.
  • Bacteroides and pachybacteria are the main components of the intestinal flora of rats, and the change in the ratio of Bacteroides / thick-wall bacteria (B / F) is a key indicator of the ecological imbalance of the intestinal flora.
  • B / F the change in the ratio of Bacteroides / thick-wall bacteria
  • paeoniflorin and paeoniflorin containing paeoniflorin and paeoniflorin can rapidly regulate and improve the intestinal flora of CUMS rats. Function, can increase the abundance of probiotics such as Akk bacteria, lactic acid bacteria, bifidobacteria in the intestinal flora, and the increase and recovery of these probiotics can improve the balance of glucose metabolism, lower blood sugar and reduce insulin resistance.
  • probiotics such as Akk bacteria, lactic acid bacteria, bifidobacteria in the intestinal flora
  • mice 40 male db / db mice (6-8 weeks of age) were randomly divided into 4 groups, 10 in each group: model group, metformin hydrochloride group (140mg / kg), and peiolide group (14mg / kg) kg), total glucoside group (100 mg / kg).
  • Ten male C57 / BL mice of the same week age were used as the blank control group.
  • Each group was administered orally once a day with an intragastric volume of 0.1ml / 10g for 4 weeks.
  • the blank control group and the model group were intragastrically administered with a volume of 0.1ml / 10g of drinking water.
  • the food and water consumption of the mice in each group were measured daily, and the fasting blood glucose and serum insulin levels were measured.
  • Paeoniflorin, paeoniflorin, paeoniflorin, or paeony extract can be used to prepare medicines, health foods, food additives, and nutritional supplements that can quickly improve the intestinal flora disturbance, increase the content of probiotics in the intestine, and prevent diabetes.

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Abstract

白芍总苷用于制备预防或治疗糖尿病的药物的用途；其中，所述白芍总苷通过改善肠道菌群平衡以预防或治疗糖尿病。其中所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的含量。一种治疗糖尿病的方法，所述方法包括给予糖尿病患者治疗有效量的白芍总苷；其中，所述白芍总苷通过改善肠道菌群平衡以预防或治疗糖尿病。白芍总苷用于改善人体糖代谢的产品的用途；其中，所述白芍总苷通过改善肠道菌群平衡以改善人体糖代谢。

Description

白芍总苷用于预防或治疗糖尿病的用途 技术领域
本发明属于医药领域，涉及白芍总苷通过抗应激改善肠道菌群平衡以预防或治疗糖尿病的用途，具体涉及白芍总苷、芍药内酯苷和芍药苷通过抗应激，恢复和改善肠道菌群平衡，增加肠道有利于糖代谢的Akk菌、双歧杆菌、乳酸菌等益生菌丰度以预防或治疗糖尿病。
背景技术
持续应激反应，不仅通过神经内分泌相关激素影响人体糖代谢，引起胰岛素抵抗，而且会破坏肠道菌群平衡，进一步加剧糖代谢紊乱。应激造成的肠道菌群紊乱和胰岛素抵抗，是发生糖尿病的重要原因之一。应激引起HPA轴功能亢进，促使肾上腺素、去甲肾上腺素、糖皮质激素和胰高血糖素的分泌增高，这些因素直接影响人体糖-脂代谢，升高血糖，加重胰岛素抵抗。因此，在糖尿病的防治中，除了使用降糖药外，还需要充分认识到应激，特别是社会心理应激因素对糖尿病发生与治疗的负面影响，在沿袭传统应用降血糖药物的同时亦需进行抗应激、抗抑郁、抗炎的治疗。应激对糖尿病的影响，也表现在对肠道菌群平衡的破坏上，通过抗应激、抗抑郁、抗炎，恢复肠道菌群的平衡，在防治糖尿病中十分重要。
肠道微生物是人体最庞大、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中。肠道菌群的作用和其对人体健康的影响，已备受医药界关注。人体肠道菌群的代谢活动是影响糖尿病的一个重要环境因素，越来越多的研究表明，肠道菌群与糖尿病等代谢性疾病的发生关系密切，很多与肠道菌群相关的主要代谢物及其潜在生物学功能已被发现，见下表1。
表1与肠道菌群相关的代谢产物及其功能表
Figure PCTCN2019097897-appb-000001
以肠道菌群为切入点探讨糖尿病的发病机制，寻找防治糖尿病的新方法和新的药物、保健食品，已成为当下学界研究的新热点：
1、研究发现，某些肠道细菌，如产生丁酸盐的双歧杆菌和乳酸菌，协同改善肠道通透性和内毒血症，提高机体葡萄糖耐受量，进而降低胰岛素抵抗和降糖。
2、研究发现，在人体中，肠道菌群Akk菌丰度与Ⅰ型糖尿病呈负相关，提示Akk菌在Ⅰ型糖尿病中起保护作用。Akk菌具有粘蛋白降解特性，可促进黏液产生，使黏液增厚，改善高脂饮食引起的代谢紊乱，如体脂增加、代谢性内毒素血症、脂肪组织炎症以及胰岛素抵抗。
3、Ⅱ型糖尿病患者肠道中以丁酸盐为产物的菌种比较低，而以非丁酸盐为产物的菌种比例较高，增加肠道双歧杆菌和乳酸菌等益生菌的丰度，有助于Ⅱ型糖尿病的治疗。
4、临床研究发现，糖尿病患者与健康人相比，肠道菌群的结构发生改变，似杆菌属和普氏菌属数量增加，而厚壁菌门和梭状孢杆菌数量减少。
动物实验与临床证据表明，肠道菌群直接影响机体胰岛素敏感度，其结构改变，与胰岛素抵抗和血糖升高密切相关，现已证实肠道菌群参与了糖尿 病的发病。
针对肠道菌群进行干预治疗，通过调控肠道菌群防治糖尿病，成为近年来研究的重点课题。当前的做法，通常是通过补充外源性益生菌，例如补充双歧杆菌、乳酸菌、Akk菌等，改善宿主肠道菌群结构，缓解糖尿病症状；或是通过补充胆汁酸等物质改善肠道菌群代谢环境，抵御糖尿病的发生。
发明内容
本发明的目的在于提供一种白芍总苷及其主要功效成分芍药内酯苷(Albiflorin)、芍药苷(Paeoniflorin)用于制备预防或治疗糖尿病的药物中的用途。发明人发现，白芍总苷及其主要功效成分芍药内酯苷、芍药苷通过抗应激、抗炎改善肠道菌群平衡，可以用于预防或治疗糖尿病。
本发明白芍总苷、芍药内酯苷、芍药苷，作为一种快速抗应激、抗抑郁、抗炎改善肠道菌群系统功能的天然产物，能够通过调节肠道菌群平衡，增加肠道Akk菌、乳酸菌、双歧杆菌等微生物的丰度，改善体内糖-脂代谢，防治糖尿病。
本发明是在利用靶向代谢组学方法研究白芍总苷主要功效成分芍药内酯苷、芍药苷通过调节肠脑轴抗应激治疗抑郁症过程中，发现慢性不可预知应激(CUMS)不仅破坏了模型大鼠肠道菌群代谢平衡，而且造成糖代谢紊乱，升高血糖。芍药内酯苷可以通过抗应激，抗抑郁，抗炎，快速恢复肠道菌群平衡，降低血糖，防治糖尿病。继而，我们又对大鼠粪便样品进行了代谢组学和16SrDNA宏基因组检测，发现芍药内酯苷可以显著改善应激(抑郁症)大鼠肠道菌群的组成和代谢特征，使其向正常大鼠肠道菌群模式趋近。其中，尤为重要的是，我们发现应激(抑郁症)大鼠肠道菌群中的Akk菌、乳酸菌、双歧杆菌等益生菌的丰度明显减少，特别是CUMS模型鼠肠道中的Akk菌近乎为0，而服用芍药内酯苷，可以增加CUMS大鼠肠道中的Akk菌、乳酸菌、双歧杆菌等益生菌丰度。
基于以上，本发明的目的是通过以下技术方案实现的：
一方面，本发明提供了白芍总苷用于制备预防或治疗糖尿病的药物的用途；其中，所述白芍总苷通过改善肠道菌群平衡以预防或治疗糖尿病；
优选地，所述白芍总苷通过抗应激、抗抑郁、抗炎调节肠道菌群功能。
优选地，所述白芍总苷包含芍药内酯苷和芍药苷。
根据本发明所述的用途，所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的含量。
另一方面，本发明提供了一种治疗糖尿病的方法，所述方法包括给予糖尿病患者治疗有效量的白芍总苷；其中，所述白芍总苷通过改善肠道菌群平 衡以预防或治疗糖尿病；
优选地，所述白芍总苷通过抗应激、抗抑郁、抗炎调节肠道菌群功能。
优选地，所述白芍总苷包含芍药内酯苷和芍药苷。
根据本发明所述的方法，所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的含量。
再一方面，本发明提供了白芍总苷用于改善人体糖代谢的产品的用途；其中，所述白芍总苷通过改善肠道菌群平衡以改善人体糖代谢；
优选地，所述白芍总苷通过抗应激、抗抑郁、抗炎调节肠道菌群功能。
优选地，所述白芍总苷包含芍药内酯苷和芍药苷。
优选地，所述产品为药物、保健品、营养补充剂或是食品添加剂。
根据本发明所述的用途，所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的丰度。本发明研究结果表明：
1、联合使用抗应激(抗抑郁)、改善肠道菌群平衡、降血糖三种方法，可以实现对糖尿病标本兼治，有助于Ⅱ型糖尿病患者病情的平稳转归。
2、白芍总苷及其主要功效成分芍药内酯苷、芍药苷，作为一种快速抗应激、抗抑郁的天然产物，能够通过调节肠道菌群平衡，增加肠道Akk菌、乳酸菌、双歧杆菌等微生物的丰度，改善人体糖-脂代谢，协助降血糖和降低胰岛素抵抗作用。
3、与抑郁症共病的糖尿病患者，大多会出现肠道菌群紊乱，肠道中的Akk菌、乳酸菌、双歧杆菌等益生菌的丰度明显减少，因此，在使用口服降糖药时，需要同时进行抗应激、抗抑郁治疗，而且一定要选择那些能够调节和恢复肠道菌群平衡的抗应激、抗抑郁、抗炎药物治疗，通过改善肠道菌群平衡，升高肠道菌群中的Akk菌、乳酸菌、双歧杆菌等益生菌的丰度，减轻胰岛素抵抗，促进胰岛素分泌。
本发明披露了白芍总苷及其主要功效成分芍药内酯苷、芍药苷，通过抗应激、抗抑郁、抗炎增加糖尿病患者肠道内胆汁酸、氨基酸和维生素含量，改善肠道菌群的代谢，使得正常的肠道菌群功能得到恢复。这种肠道菌群功能的改善，表现为厚壁菌门(firmicutes)等益生菌的恢复，其中特别是增加了肠道菌群中的Akk菌、乳酸菌、双歧杆菌等微生物的含量，为改善人体糖-脂代谢提供了一个良好的肠道菌群环境，对二甲双胍等降糖药物的治疗有明显的增效作用。
一方面，本发明提供了白芍总苷及其主要功效成分芍药内酯苷、芍药苷，通过抗应激、抗抑郁、抗炎调节肠道菌群功能改善人体糖代谢的用途；
优选地，本发明具有抗应激、抗抑郁、抗炎和恢复肠道菌群紊乱的功能， 适于作为伴发抑郁症或是炎症的糖尿病患者进行调理性服用，用于全方位整体改善机体糖代谢功能；
优选地，本发明适用于生活应激、心理应激、情感应激和处于紧张忙碌环境应激的人群进行调理性服用，可以有效平衡心理生存状态，防治糖尿病的发生。
所述通过抗应激、抗抑郁、抗炎和调节肠道菌群功能改善人体糖代谢改善的本发明，可以作为防治糖尿病的药物、保健品、营养补充剂或是食品添加剂。
另一方面，本发明提供了一种通过抗应激、抗抑郁、抗炎改善肠道菌群平衡，增加肠道中的Akk菌、乳酸菌、双歧杆菌等微生物，综合调理糖-脂代谢防治糖尿病的方法。
优选地，本发明提供了一种通过抗应激、抗抑郁、抗炎改善肠道菌群平衡，综合调理糖-脂代谢防治糖尿病的方法，这种方法尤其适用于治疗应激型糖尿病或伴生抑郁症、抑郁障碍的糖尿病患者。
与现有技术相比，本发明具有以下优点：
本发明通过抗应激、抗抑郁、抗炎提升肠道菌群代谢物胆酸、维生素及氨基酸的含量，恢复和改善肠道菌群代谢平衡，增加肠道菌群中的Akk菌、乳酸菌、双歧杆菌等益生菌的丰度。实验证明，本发明白芍总苷、芍药内酯苷、芍药苷在给药一周内，即可快速改善各种应激(包括抑郁症、糖尿病、糖尿病综合症及癌症等疾病产生的应激作用)所造成的肠道菌群紊乱。
2、本发明是通过抗应激、抗抑郁、抗炎、改善肠道菌群生存环境，恢复人体内源性肠道菌群平衡，增加Akk菌、乳酸菌、双歧杆菌等益生菌丰度，改善肠道菌群功能，这种直接促进人体肠道内源性益生菌生长，与间接补充外源性益生菌的现有技术相比，在保持益生菌的活性、稳定性、丰富性、功能完整性方面更有优势；同时人体抗应激能力的提高，有助于糖尿病患者病情的转归。此外，促进人体肠道内源性益生菌生长，与补充外源性益生菌的现有技术相比，具有明显的性价比优势。
3、氟西汀等SSRIs等抗抑郁药物，服用后会加剧患者肠道菌群紊乱，可能对糖尿病的治疗产生负面影响。白芍总苷、芍药内酯苷、芍药苷，在抗抑郁同时，可以快速改善肠道菌群平衡，恢复和提升肠道Akk菌、乳酸菌、双歧杆菌等益生菌的表达，因此，本发明更适宜治疗与抑郁症共生的糖尿病。
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 酯苷具有快速恢复和改善调节肠道菌群的功能。
附图1、靶向代谢组学多重比较分析(PLS-DA)。
附图2、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、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、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、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、PLS-DA表明，氟西汀组加大了模型组大鼠肠道菌群紊乱。
附图7、科(Family)水平上物种相对丰度柱状图
附图8、芍药内酯苷组与CUMS组粪便中似杆菌/厚壁菌比率(B/F比率)
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，通过整合靶向代谢组学和高通量测序技术，发现芍药内酯苷及含有芍药内酯苷的白芍总苷，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)。运用靶向代谢组学方法，对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)，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成分构成，各种菌群丰度和平衡的破坏，功能的紊乱，均与内外环境的应激类型和程度有着密切的联系。
实施例2：芍药内酯苷给药7天可快速恢复慢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，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)，发现芍药内酯苷给药后，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)与正常组(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，表明SSRI类型的抗抑郁药物进一步加剧了肠道菌群的紊乱，见附图6。
实施例4：芍药内酯苷对慢应激大鼠粪便菌群16SrDNA表达的影响
实验结果
1、OTU分析和物种注释
科(Family)水平上最大丰度排名前10物种及Akk菌的相对丰度(％)表
Figure PCTCN2019097897-appb-000002
根据附图7和附表所显示的科水平上最大丰度Top10物种及Akk菌的数据，可以发现CUMS模型大鼠肠道Akk菌、乳酸菌、双歧杆菌等微生物明显减少，其中肠道Akk菌近乎为0；芍药内酯苷给药组，服用7天，可以逆转CUMS造成的肠道菌群体系紊乱，增加Akk菌、乳酸菌、双歧杆菌、等益生菌的丰度，而这些物种菌群表达的提升和恢复，可以改善糖代谢平衡，降低胰岛素抵抗。
2、芍药内酯苷组和CUMS组粪便中似杆菌与厚壁菌的比率
似杆菌与厚壁菌是大鼠肠道菌群的主要成分，似杆菌/厚壁菌的比例(B/F)变化是肠道菌群生态失调的关键标志。与正常组比较，CUMS组粪便中似杆菌丰度和B/F比率(附图8，P<0，05)，说明CUMS破坏了肠道菌群的平衡状态。给予芍药内酯苷，7天之后，B/F比率较CUMS下降，表明芍药内酯苷缓解CUMS引发的大鼠肠道菌群紊乱。见附图8。
综上所述，代谢组学和16sRNA高通量测序的整合研究表明，芍药内酯苷和含有芍药内酯苷、芍药苷的白芍皂苷，具有快速调节和改善CUMS大鼠肠道菌群的功能，能够增加肠道菌群中Akk菌、乳酸菌、双歧杆菌等益生菌的丰度，而这些益生菌丰度的增加和恢复，可以改善糖代谢平衡，降血糖和降低胰岛素抵抗。
实施例5：芍药内酯苷对db/db小鼠空腹血糖的影响
实验方法：40只雄性db/db小鼠(6～8周龄)，随机分为4组，每组10只：模型组、盐酸二甲双胍组(140mg/kg)、芍药内酯苷组(14mg/kg)、白芍总苷组(100mg/kg)。10只同周龄的雄性C57/BL小鼠为空白对照组。各组灌胃给药，每日1次，灌胃体积0.1ml/10g，连续给药4周，其中空白对照组和模型组每天灌胃体积0.1ml/10g的饮用水。每天测定各组小鼠的食量、饮水量，检测空腹血糖量和血清胰岛素水平。
实验结果：分组时db/db小鼠各组血糖不存在差异，持续喂养4周，与正常对照组比较，db/db小鼠血糖显著升高，盐酸二甲双胍组、芍药内酯苷组、白芍总苷组与模型组比较，空腹血糖显著降低，有统计学差异，见下表。
Figure PCTCN2019097897-appb-000003
*P<0.05，与正常对照组比较#P<0.05，与模型组比较
实施例6：对db/db小鼠胰岛素抵抗指数的影响
实验方法：同实施案例5。
实验结果：与正常对照组比较，db/db小鼠模型组胰岛素抵抗指数(MOMA-IR)显著增高。与db/db小鼠模型组比较，芍药内酯苷、白芍总苷组及盐酸二甲双胍组，胰岛素抵抗指数(MOMA-IR)显著下降，表明芍药内酯苷、白芍总苷、盐酸二甲双胍均可显著改善胰岛素抵抗作用，见下表。
芍药内酯苷、白芍总苷组及二甲双胍对db/db小鼠胰岛素抵抗指数的影响
Figure PCTCN2019097897-appb-000004
*,P<0.05，与正常对照组比较；#，P<0.05，与模型组比较。
可用芍药内酯苷、芍药苷、白芍皂苷或是白芍提取物，制备快速改善肠道菌群紊乱，增加肠道益生菌含量，防治糖尿病的药物、保健食品、食品添加剂、营养补充剂。
由于这些产品安全、性价比高，可以长期服用进行调理性治疗，因此，具有较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. 白芍总苷用于制备预防或治疗糖尿病的药物的用途；其中，所述白芍总苷系通过改善肠道菌群平衡预防或治疗糖尿病。
  2. 根据权利要求1所述的用途，其中，所述白芍总苷通过抗应激、抗抑郁、抗炎调节肠道菌群功能。
  3. 根据权利要求1所述的用途，其中，所述白芍总苷包含芍药内酯苷和芍药苷。
  4. 根据权利要求1至3中任一项所述的用途，其中所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的丰度。
  5. 一种治疗糖尿病的方法，所述方法包括给予糖尿病患者治疗有效量的白芍总苷；其中，所述白芍总苷通过改善肠道菌群平衡以预防或治疗糖尿病。
  6. 根据权利要求5所述的方法，其中，所述白芍总苷通过抗应激、抗抑郁、抗炎调节肠道菌群功能。
  7. 根据权利要求5所述的方法，其中，所述白芍总苷包含芍药内酯苷和芍药苷。
  8. 根据权利要求1至3中任一项所述的方法，其中所述改善肠道菌群平衡功能为增加肠道中的Akk菌、瘤胃球菌、乳酸菌、双歧杆菌、长双歧杆菌等益生菌的含量。
  9. 白芍总苷用于改善人体糖代谢的产品的用途；其中，所述白芍总苷通过改善肠道菌群平衡以改善人体糖代谢。
  10. 根据权利要求9所述的用途，其中，所述产品为药物、保健品、营养补充剂或是食品添加剂。
PCT/CN2019/097897 2018-07-26 2019-07-26 白芍总苷用于预防或治疗糖尿病的用途 WO2020020342A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101628926A (zh) * 2009-08-11 2010-01-20 张守力 芍药苷提取工艺
CN102824423A (zh) * 2012-09-18 2012-12-19 宁波立华制药有限公司 一种含白芍苷和牛蒡苷的药物组合物及应用
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
CN107397752A (zh) * 2016-10-11 2017-11-28 张作光 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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101628926A (zh) * 2009-08-11 2010-01-20 张守力 芍药苷提取工艺
CN102824423A (zh) * 2012-09-18 2012-12-19 宁波立华制药有限公司 一种含白芍苷和牛蒡苷的药物组合物及应用
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
CN107397752A (zh) * 2016-10-11 2017-11-28 张作光 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

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
WANG, QIAO ET AL: "HPLC Determination of Albiflorin, Paeoniflorin, and Benzoylpaeoniflorinin Total Glucoside of Paeony Capsule", HINESE HERBAL MEDICINES, vol. 36, no. 11, 30 November 2005 (2005-11-30), pages 1630 - 1632 *
YUAN, LIANG ET AL: "Effect of Total Glucosides of Paeony on the Expression of Intercellular Adhesion Molecule-1 andTransforming Growth Factorl Protein in the Kidney in Experimental Diabetes", CHINESE PHARMACOLOGICAL BULLETIN, vol. 23, no. 6, 30 June 2007 (2007-06-30), pages 821 - 826, XP055681123 *
ZENG XIAO-YI ET AL: "Screening for the efficacy on lipid accumulation in 3T3- L1 cells is an effective tool for the identification of new anti-diabetic compounds", BIOCHEMICAL PHARMACOLOGY, vol. 84, no. 6, 20 July 2012 (2012-07-20), pages 830 - 837, XP055080668 *

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