WO2020093237A1 - 粪肠球菌的用途 - Google Patents

粪肠球菌的用途 Download PDF

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WO2020093237A1
WO2020093237A1 PCT/CN2018/114132 CN2018114132W WO2020093237A1 WO 2020093237 A1 WO2020093237 A1 WO 2020093237A1 CN 2018114132 W CN2018114132 W CN 2018114132W WO 2020093237 A1 WO2020093237 A1 WO 2020093237A1
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disease
enterococcus faecalis
diabetic
cfu
metabolic syndrome
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PCT/CN2018/114132
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English (en)
French (fr)
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金万洙
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中国科学院动物研究所
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Priority to CN201880099068.6A priority Critical patent/CN113164530A/zh
Priority to PCT/CN2018/114132 priority patent/WO2020093237A1/zh
Publication of WO2020093237A1 publication Critical patent/WO2020093237A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

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  • the invention belongs to the field of biomedicine. Specifically, the present invention relates to the use of a probiotic in the preparation of a product for preventing or treating metabolic syndrome or for improving energy metabolism in the body. More specifically, the present invention relates to the use of an enteric microorganism, Enterococcus faecalis, in the preparation of products for preventing or treating metabolic syndrome or for improving energy metabolism in the body.
  • Obesity occurs when the body's energy intake exceeds energy expenditure. Obesity first causes insulin resistance, which in turn leads to a series of metabolic disorders such as diabetes, hypertension, hyperlipidemia, atherosclerosis, and cardiovascular and cerebrovascular diseases.
  • obesity has shown an explosive epidemic all over the world. Although hundreds of billions of yuan are spent on diet control and physical improvement, its incidence rate continues to rise. It is estimated that 400 million people are obese worldwide. The prevalence of obesity in China has also been on the rise in recent years. According to statistics, China currently has at least 270 million overweight people and at least 96 million obese people. In recent years, China's investment in the prevention and treatment of obesity and related diseases has skyrocketed. Not only that, the rapid development of obesity, especially childhood obesity, will inevitably have an inestimable adverse impact on the physical fitness of the whole people and the harmonious development of the entire society. In the long run, it will inevitably endanger our country ’s national security.
  • Orlistat is the first weight loss prescription drug approved by the US Food and Drug Administration (FDA). It can specifically inhibit the enzymes responsible for digesting fats in the human gastrointestinal tract, prevent the absorption of fats in the digestive tract, thereby reducing calorie intake and thereby controlling body weight.
  • FDA US Food and Drug Administration
  • undigested fat moves along the gastrointestinal tract while causing side effects such as diarrhea and steatorrhea. These side effects can cause patients to wear adult diapers, making it difficult for normal social life.
  • liraglutide can regulate insulin secretion, suppress appetite, delay gastric emptying, and increase satiety.
  • side effects such as pancreatitis, nausea, and vomiting, and is especially prohibited for patients with medullary thyroid cancer and type 2 multiple endocrine adenoma. Therefore, in view of the fact that existing obesity treatment agents usually have toxic and side effects, it is urgent to find a safe and effective method to control the spread of obesity.
  • Enterococcus faecalis also known as Enterococcus faecalis, is a type of enterococci that has a streptococcus or spherical shape. Enterococcus faecalis is a facultative anaerobic lactic acid bacteria. It is not only a normal bacterial species common in human and animal intestines, but also used to improve the quality of food and feed. Enterococcus faecalis is the preferred strain for easy production and use of Bifidobacterium and Lactobacillus, which are strictly anaerobic and have strict culture and storage conditions. In 1989, the US FDA announced that it is one of the strains that can be directly used in animals.
  • the object of the present invention is to provide a new use of Enterococcus faecalis.
  • Enterococcus faecalis can activate the hyperthermia-induced thermogenic activity of brown fat (BAT) in HFD mice, thereby consuming excess energy of the body, which can effectively improve the high Fat-induced obesity, fatty liver and obesity-related diseases in HFD mice. Therefore, in view of the defects of the drugs currently used to treat obesity, the present invention provides a new product for preventing and / or treating metabolic syndrome by improving energy metabolism in the body, especially for treating obesity, etc. And / or treat a metabolic syndrome, such as obesity, and open up a new way.
  • BAT brown fat
  • the present invention provides the use of Enterococcus faecalis in the preparation of a product for preventing or treating metabolic syndrome or for improving energy metabolism of the body, the product being a medicine, food, health care product or food additive.
  • the metabolic syndrome is selected from metabolic diseases, cardiovascular diseases or neurological damage diseases.
  • the metabolic disease is diabetes, obesity, fatty liver, diabetic kidney injury, diabetic macroangiopathy, diabetic microvascular injury, diabetic retinopathy, glucagonemia, necrotizing erythema or Glucagonoma;
  • the cardiovascular disease is coronary heart disease, hypertensive heart disease, valvular heart disease, alcoholic cardiomyopathy, or diabetic cardiovascular complications;
  • the nerve-damaging disease is Alzheimer's disease or Par Jinsen's disease.
  • the metabolic syndrome is selected from obesity, fatty liver or type II diabetes.
  • the invention also provides the use of Enterococcus faecalis in the preparation of products for improving energy metabolism of the body, the products being selected from medicines, foods, health care products or food additives.
  • the product of the present invention further includes other components for preventing and / or treating metabolic syndrome, such as drug extracts or other probiotics.
  • the probiotics are food-borne probiotics, further preferably other strains of the Enterococcus family include but are not limited to E. faecalis, E. faecium, E. avium (E.avium), E. casseliflavus, E. durans, E. galinarum, E. mundii, E. odorii maladoratum), E. hirae, E. solitarius, E. raffinosus, E. pseudoavium, E. faecalis faecalisvar).
  • the product includes an effective amount of Enterococcus faecalis and an auxiliary material acceptable in medicine, food, health care products or food additives.
  • the acceptable excipient is starch and / or nanoparticles for promoting absorption or slow release.
  • the auxiliary materials commonly used in the field of formulations can be used to prepare the medicines, foods, health products or food additives by conventional methods.
  • the medicine, food, health care product or food additive of the present invention can be prepared by mixing an effective amount of Enterococcus faecalis with an acceptable excipient.
  • the Enterococcus faecalis is commercially available or can be prepared by a method known in the art.
  • the product is a tablet, granule, powder, capsule or functional drink.
  • the content of the live bacteria of Enterococcus faecalis is not less than 10 7 CFU / g or 10 7 CFU / mL; more preferably, the enterococcus faecalis content of viable bacteria of not less than 10 8 CFU / g or 10 8 CFU / mL; more preferably, the Enterococcus faecalis (Enterococcus faecalis) content of live cells is not less than 10 9 CFU / g or 10 9 CFU / mL Most preferably, the content of the live bacteria of Enterococcus faecalis is not less than 10 10 CFU / g or 10 10 CFU / mL.
  • the present invention also provides a method for preventing or treating metabolic syndrome or for improving energy metabolism of the body, the method comprising administering an effective amount of Enterococcus faecalis to a subject;
  • the content of live bacteria of Enterococcus faecalis is not less than 10 7 CFU / g or 10 7 CFU / mL; more preferably, the content of live bacteria of Enterococcus faecalis (Enterococcus faecalis) is not less than 10 8 CFU / g or 10 8 CFU / mL; further preferably, the content of the enterococcus faecalis (Enterococcus faecalis) live bacteria is not less than 10 9 CFU / g or 10 9 CFU / mL; most preferably, the enterococcus faecalis (Enterococcus faecalis) The content of live bacteria is not less than 10 10 CFU / g or 10 10 CFU / mL.
  • the metabolic syndrome is selected from metabolic diseases, cardiovascular diseases or neurological damage diseases.
  • the metabolic disease is diabetes, obesity, fatty liver, diabetic kidney injury, diabetic macroangiopathy, diabetic microvascular injury, diabetic retinopathy, glucagonemia, necrotizing erythema or Glucagonoma;
  • the cardiovascular disease is coronary heart disease, hypertensive heart disease, valvular heart disease, alcoholic cardiomyopathy, or diabetic cardiovascular complications;
  • the nerve-damaging disease is Alzheimer's disease or Par Jinsen's disease.
  • the metabolic syndrome is selected from obesity, fatty liver or type II diabetes.
  • the method further comprises the combination of other components for preventing and / or treating metabolic syndrome, such as drug extracts or other probiotics.
  • the probiotics are food-borne probiotics, further preferably other strains of the Enterococcus family include but are not limited to E. faecalis, E. faecium, E. avium (E.avium), E. casseliflavus, E. durans, E. galinarum, E. mundii, E. odorii maladoratum), E. hirae, E. solitarius, E. raffinosus, E. pseudoavium, E. faecalis faecalisvar).
  • the present invention also provides Enterococcus faecalis for preventing or treating metabolic syndrome or for improving energy metabolism of the body.
  • the content of live bacteria of Enterococcus faecalis is not less than 10 7 CFU / g or 10 7 CFU / mL; more preferably, the content of live bacteria of Enterococcus faecalis (Enterococcus faecalis) is not less than 10 8 CFU / g or 10 8 CFU / mL; further preferably, the content of the enterococcus faecalis (Enterococcus faecalis) live bacteria is not less than 10 9 CFU / g or 10 9 CFU / mL; most preferably, the enterococcus faecalis (Enterococcus faecalis) The content of live bacteria is not less than 10 10 CFU / g or 10 10 CFU / mL.
  • the metabolic syndrome is selected from metabolic diseases, cardiovascular diseases or neurological damage diseases.
  • the metabolic disease is diabetes, obesity, fatty liver, diabetic kidney injury, diabetic macroangiopathy, diabetic microvascular injury, diabetic retinopathy, glucagonemia, necrotizing erythema or Glucagonoma;
  • the cardiovascular disease is coronary heart disease, hypertensive heart disease, valvular heart disease, alcoholic cardiomyopathy, or diabetic cardiovascular complications;
  • the nerve-damaging disease is Alzheimer's disease or Par Jinsen's disease.
  • the metabolic syndrome is selected from obesity, fatty liver or type II diabetes.
  • the E. faecalis can also be combined with other components for preventing and / or treating metabolic syndrome, such as drug extracts or other probiotics.
  • the probiotics are food-borne probiotics, further preferably other strains of the Enterococcus family include but are not limited to E. faecalis, E. faecium, E. avium ( E.avium), E. casseliflavus, E. durans, E. galinarum, E. mundii, E. maladoratum ), E.hirae, E.solitarius, E.raffinosus, E.pseudoavium, E.faecalis var).
  • the present invention has the following beneficial effects:
  • Enterococcus faecalis usually produces lactic acid, vitamins, enzymes and bacteriostatic substances. When used as food, medicine or health products, it can not only promote the flavor of the product, increase appetite; but also improve immunity, make Digestive and respiratory diseases are reduced, disease prevention and disease resistance are improved, and the amount of antibiotics and enzymes can be greatly reduced;
  • Enterococcus faecalis as a probiotic when used as food, medicine or health products, can improve the environment of intestinal flora and improve endocrine disorders. This has a more significant effect on patients with metabolic syndrome selected from obesity, fatty liver or type 2 diabetes;
  • the inventors of the present invention have found that when Enterococcus faecalis is used to treat or improve obesity caused by a high-fat diet, it can significantly improve body weight without affecting appetite and without side effects such as diarrhea, and is more suitable as an obesity treatment agent.
  • HFD high-fat induced HFD mice fed with equal volume of drinking water
  • HFD + Enterococcus faecalis 1 ⁇ 10
  • a group of high-fat induced HFD mice was fed with a dose of 10 CFU / pc / day to Enterococcus faecalis.
  • Figure 1 shows the detection results of body weight changes in the HFD group and the HFD + Enterococcus faecalis group.
  • Figure 2 shows the results of the average daily food intake of mice in the HFD group and HFD + Enterococcus faecalis group.
  • Figure 3a is a graph of changes in anal body temperature of the two groups of mice in the HFD group and the HFD + Enterococcus faecalis group under normal temperature and cold stimulation.
  • Fig. 3b is a diagram of observation of body surface temperature with infrared camera under cold stimulation in HFD group and HFD + Enterococcus faecalis group.
  • Fig. 4 is a graph showing the detection results of oxygen consumption in the HFD group and the HFD + Enterococcus faecalis group.
  • Fig. 5 shows the results of measuring the fat mass and lean mass of the HFD group and the HFD + Enterococcus faecalis group by the magnetic resonance imaging device (MRI).
  • MRI magnetic resonance imaging device
  • Figure 6 shows the results of liver samples collected from the eighth week of mice in the HFD group and the HFD + Enterococcus faecalis group.
  • mice used in the following examples were purchased from the Institute of Model Animals of Nanjing University.
  • the reagents used are all analytical grade reagents, and are commercially available from regular channels.
  • the used Enterococcus faecalis was purchased from Beina Chuanglian Biotechnology Co., Ltd. (production number BNCC102668).
  • the HFD group and the HFD + Enterococcus faecalis group are statistically analyzed, and P ⁇ 0.05 indicates that the difference between the groups is statistically significant.
  • mice Twenty male C57BL / 6 male mice aged 4 weeks were purchased and randomly divided into two groups of 10 mice, each given 60% H10060 high-fat diet (Hua Fukang) for 8 weeks to induce an obese mouse model.
  • the "HFD group” means a group of high-fat induced HFD mice fed with equal volume of drinking water
  • the "HFD + Enterococcus faecalis group” means that the enterococcus faecalis was fed at a dose of 1 ⁇ 10 10 CFU / pc / day ( Enterococcus faecalis) high fat induced HFD mouse group.
  • Figure 1 and Table 1 show the weekly body weight changes of the HFD group and HFD + Enterococcus faecalis group. This result shows that high-fat-induced HFD mice fed with Enterococcus faecalis daily can effectively suppress weight gain. There is a significant difference in body weight from the third week of feeding, and the difference in body weight by week 8 is 3.82 grams (see Figure 1 , Where week 3-4 is "*", week 5 is "**”, week 6 is "***”, and week 7-8 is "**", which means p ⁇ 0.05, p ⁇ 0.01 and p ⁇ 0.001)
  • Figure 2 shows the average daily food intake of mice in the HFD group and HFD + Enterococcus faecalis group. This result indicated that there was no significant difference in food intake when feeding Enterococcus faecalis. This result indicates that Enterococcus faecalis does not affect appetite, and the weight loss is not a phenomenon caused by decreased appetite.
  • Figure 3 is a graph showing the analysis of heat production and body temperature of two groups of mice in the HFD group and HFD + Enterococcus faecalis group under normal temperature and cold stimulation.
  • body temperature anal temperature
  • infrared thermal imager to detect body temperature showed that the HFD mice induced by high fat fed Enterococcus faecalis significantly increased Body temperature under cold conditions (see Figure 3a, where "***" means p ⁇ 0.001).
  • FIG. 4 is a graph showing the oxygen consumption indexes of the HFD group and the HFD + Enterococcus faecalis group, which are the results of detecting the energy metabolism of mice using an energy metabolism instrument. This result indicated that after feeding Enterococcus faecalis, the energy consumption of HFD mice induced by high fat was significantly increased (see FIG. 4, where "*" indicates p ⁇ 0.05).
  • Fig. 5 is a result of measuring the fat mass and lean mass of the HFD group and the HFD + Enterococcus faecalis group by a magnetic resonance imaging device (MRI). The results showed that Enterococcus faecalis treatment significantly reduced the fat mass of HFD-induced HFD mice (see Figure 5, where "***" indicates p ⁇ 0.001).
  • Figure 6 shows the results of liver samples collected in the eighth week of mice in the HFD group and HFD + Enterococcus faecalis group. The results show that Enterococcus faecalis has the effect of improving fatty liver
  • Figure 1-6 shows that the intestinal microorganism-Enterococcus faecalis effectively improves the body's energy metabolism, thereby improving the obesity of HFD mice induced by high fat.

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Abstract

提供了粪肠球菌在制备用于预防或治疗代谢综合征或用于改善机体能量的产品中的用途，所述产品为药物、食品、保健品或食品添加剂。还提供了所述粪肠球菌用于预防或治疗代谢综合征或用于改善机体能量的方法。

Description

粪肠球菌的用途 技术领域
本发明属于生物医药领域。具体而言，本发明涉及一种益生菌在制备用于预防或治疗代谢综合征或用于改善机体能量代谢的产品中的用途。更具体地，本发明涉及一种肠道微生物-粪肠球菌(Enterococcus faecalis)在制备用于预防或治疗代谢综合征或用于改善机体能量代谢的产品中的用途。
背景技术
肥胖是当机体能量摄入超过能量消耗时发生的。肥胖首先引起胰岛素抵抗，进而导致糖尿病、高血压、高脂血症、动脉粥样硬化、心脑血管疾病等一系列代谢紊乱症状的发生。近年来，肥胖在世界范围内均呈现出爆发性流行，尽管上千亿人民币花费在饮食控制和体质改善上，但其发生率仍呈持续上升的趋势。据估计，全世界有4.0亿人肥胖。我国的肥胖症患病率近年来也呈上升趋势。据统计，我国目前拥有超重者至少2.7亿，肥胖者至少9.6千万。近年来，中国投入到肥胖及其相关疾病的防治费用飞速上涨。不仅如此，肥胖尤其是儿童型肥胖的迅猛发展也必然会对全民的身体素质和整个社会的和谐发展产生无法估量的不利影响，长此以往也必然会危及我国的国家安全。
目前临床上用作肥胖治疗剂的处方药主要是用来控制食欲和抑制营养吸收，但它们均具有一些毒副作用。例如，奥利司他是获美国食品药品管理局(FDA)批准的第一个减肥处方药。它能够特异性抑制人体胃肠道中负责消化脂肪的酶，阻止脂肪在消化道的吸收，从而减少热量摄入，进而控制体重。但是，未消化的脂肪沿着胃肠道移动的同时会引发腹泻、脂肪泻等副作用。这些副作用会导致患者需穿着成人纸尿裤，难以进行正常社会生活。此外，作为GLP-1受体的激动剂，利拉鲁肽能够调节胰岛素分泌、抑制食欲、延缓胃排空、增加饱胀感。但是它同时会引发胰腺炎、恶心、呕吐等副作用，并且尤其对髓样甲状腺癌和2型多发内分泌腺瘤患者禁用。因此，鉴于现有的肥胖治疗剂通常具有毒副作用，寻找一种安全有效的方法控制肥胖的蔓延已迫在眉睫。
粪肠球菌又叫粪链球菌(Enterococcus faecalis)，属于肠球菌中的一 种，其菌体形态为链球或球状。粪肠球菌是兼性厌氧的乳酸菌，它不仅是人和动物肠道中常见的正常菌种，还用于改善食品、饲料的质量。粪肠球菌相对于严格厌氧、培养保存条件苛刻的双歧杆菌、乳杆菌来说，它是便于生产和使用的首选菌种。1989年美国FDA就公布它为可直接用于动物的菌种之一。大量实验证明，由粪肠球菌组成的益生素可提高幼年畜禽个体增重，改善饲料报酬，减少腹泻率，降低死亡率。另外，粪肠球菌代谢产生有机酸、双乙酰、过氧化氢、细菌素等物质，这些物质具有抑制病原菌和腐败菌、提高免疫力、改善畜产品品质等生理功效。
但是，现有技术中对粪肠球菌的研究多集中于其作为饲料添加剂或益生菌的用途，对于其进一步的生物医药学的用途缺乏深入的研究。
发明内容
针对现有技术的不足，本发明的目的是提供一种粪肠球菌的新用途。具体地，本申请人意外地发现，粪肠球菌(Enterococcus faecalis)可以激活高脂诱导的HFD小鼠的棕色脂肪(BAT)的产热活性，从而消耗机体多余的能量，进而可以有效地改善高脂诱导的HFD小鼠的肥胖、脂肪肝以及肥胖相关疾病。因此，本发明针对目前用于治疗肥胖症的药物的缺陷，提供了一种通过改善机体能量代谢而用于预防和/或治疗代谢综合征，特别是治疗肥胖症等的新型产品，从而为预防和/或治疗代谢综合征，例如肥胖症等开辟一条新的途径。
一方面，本发明提供了粪肠球菌在制备用于预防或治疗代谢综合征或用于改善机体能量代谢的产品中的用途，所述产品为药物、食品、保健品或食品添加剂。
优选地，所述代谢综合征选自代谢性疾病，心血管病或神经损伤性疾病。
更优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；所述神经损伤性疾病为阿尔兹海默症或帕金森症。
进一步优选地，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
本发明还提供了粪肠球菌在制备用于改善机体能量代谢的产品中的用途，所述产品选自药物、食品、保健品或食品添加剂。
优选地，本发明所述的产品还包括用于预防和/或治疗代谢综合征的其他组分，例如药物提取物或其他的益生菌等。更优选地，所述益生菌为食源性益生菌，进一步优选地为肠球菌科的其它菌株包括但不限于粪肠球菌(E.faecalis)、屎肠球菌(E.faecium)、鸟肠球菌(E.avium)、酪黄肠球菌(E.casseliflavus)、坚忍肠球菌(E.durans)、鸡肠球菌(E.galinarum)、芒地肠球菌(E.mundii)、恶臭肠球菌(E.maladoratum)、希拉肠球菌(E.hirae)、孤立肠球菌(E.solitarius)、棉子糖肠球菌(E.raffinosus)、假鸟肠球菌(E.pseudoavium)、粪肠球变异株(E.faecalis var)。
优选地，所述产品包括有效量的粪肠球菌和药物、食品、保健品或食品添加剂中可接受的辅料。更优选地，所述可接受的辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒。可以使用制剂领域常用辅料，采用常规方法来制备所述药物、食品、保健品或食品添加剂。例如，本发明的药物、食品、保健品或食品添加剂可通过将有效量的粪肠球菌(Enterococcus faecalis)与可接受的辅料混合来制备。
优选地，所述的粪肠球菌可以市售得到，也可以采用本领域已知的方法制备得到。
优选地，所述产品为片剂、颗粒剂、散剂、胶囊或功能性饮品。
优选地，在所述产品中，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 7CFU/g或10 7CFU/mL；更优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 8CFU/g或10 8CFU/mL；进一步优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 9CFU/g或10 9CFU/mL；最优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 10CFU/g或10 10CFU/mL。
另一方面，本发明还提供了用于预防或治疗代谢综合征或用于改善机体能量代谢的方法，所述方法包括给予对象有效量的粪肠球菌；
优选地，所述粪肠球菌活菌的含量不低于10 7CFU/g或10 7CFU/mL；更优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 8CFU/g或10 8CFU/mL；进一步优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 9CFU/g或10 9CFU/mL；最优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 10CFU/g或10 10CFU/mL。
优选地，所述代谢综合征选自代谢性疾病，心血管病或神经损伤性疾病。
更优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；所述神经损伤性疾病为阿尔兹海默症或帕金森症。
进一步优选地，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
优选地，所述方法还包括联用预防和/或治疗代谢综合征的其他组分，例如药物提取物或其他的益生菌等。更优选地，所述益生菌为食源性益生菌，进一步优选地为肠球菌科的其它菌株包括但不限于粪肠球菌(E.faecalis)、屎肠球菌(E.faecium)、鸟肠球菌(E.avium)、酪黄肠球菌(E.casseliflavus)、坚忍肠球菌(E.durans)、鸡肠球菌(E.galinarum)、芒地肠球菌(E.mundii)、恶臭肠球菌(E.maladoratum)、希拉肠球菌(E.hirae)、孤立肠球菌(E.solitarius)、棉子糖肠球菌(E.raffinosus)、假鸟肠球菌(E.pseudoavium)、粪肠球变异株(E.faecalis var)。
再一方面，本发明还提供了用于预防或治疗代谢综合征或用于改善机体能量代谢的粪肠球菌。
优选地，所述粪肠球菌活菌的含量不低于10 7CFU/g或10 7CFU/mL；更优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 8CFU/g或10 8CFU/mL；进一步优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 9CFU/g或10 9CFU/mL；最优选地，所述粪肠球菌(Enterococcus faecalis)活菌的含量不低于10 10CFU/g或10 10CFU/mL。
优选地，所述代谢综合征选自代谢性疾病、心血管病或神经损伤性疾病。
更优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；所述神经损伤性疾病为阿尔兹海默症或帕金森症。
进一步优选地，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
供选择地，所述粪肠球菌还可以联用预防和/或治疗代谢综合征的其他组分，例如药物提取物或其他的益生菌等。优选地，所述益生菌为食源性益生菌，进一步优选地为肠球菌科的其它菌株包括但不限于粪肠球菌(E.faecalis)、屎肠球菌(E.faecium)、鸟肠球菌(E.avium)、酪黄肠球菌 (E.casseliflavus)、坚忍肠球菌(E.durans)、鸡肠球菌(E.galinarum)、芒地肠球菌(E.mundii)、恶臭肠球菌(E.maladoratum)、希拉肠球菌(E.hirae)、孤立肠球菌(E.solitarius)、棉子糖肠球菌(E.raffinosus)、假鸟肠球菌(E.pseudoavium)、粪肠球变异株(E.faecalis var)。
需要说明的是，本领域技术人员也可以通过对粪肠球菌(Enterococcus faecalis)进行基因改造，改善粪肠球菌(Enterococcus faecalis)的耐受和定植能力，延长粪肠球菌(Enterococcus faecalis)在体内的作用时间，增强代谢稳定性，提高生物利用度，这样的基因优化产物也应当在本发明的范围之内。
与现有技术相比，本发明具有以下的有益效果：
1.粪肠球菌在使用时通常会产生乳酸、维生素、酶及抑菌物质，作为食品、药物或保健品等产品使用时，不仅能促进产品的风味，提高食欲；还能提高免疫力，使消化道、呼吸道疾病减少，防病抗病能力提高，可大量减少抗生素和酶的用量；
2.粪肠球菌作为益生菌，作为食品、药物或保健品等产品使用时，能改善肠道菌群环境，并改善内分泌失调。这对于代谢综合征选自肥胖症、脂肪肝或II型糖尿病患者具有更显著的作用；
3.本发明的发明人研究发现，粪肠球菌用于治疗或改善高脂饮食导致的肥胖时，可以显著改善体重，而不影响食欲，也没有腹泻等副作用，更适合用作肥胖治疗剂。
附图的简要说明
以下，结合附图来说明本发明的实施方案，其中所述的“HFD”组表示灌喂等体积饮用水的高脂诱导的HFD小鼠组，“HFD+粪肠球菌”组表示以1×10 10CFU/只/天的剂量灌喂粪肠球菌(Enterococcus faecalis)的高脂诱导的HFD小鼠组。
图1显示HFD组和HFD+粪肠球菌组两组体重变化的检测结果。
图2显示HFD组和HFD+粪肠球菌组两组的小鼠的一天平均摄食量的检测结果。
图3a是HFD组和HFD+粪肠球菌组两组小鼠在常温和寒冷刺激下肛门体温的变化图。
图3b是HFD组和HFD+粪肠球菌组两组小鼠在寒冷刺激下用红外线摄像机观察体表温度的图。
图4是显示HFD组和HFD+粪肠球菌组两组的耗氧量的检测结果的图。
图5显示用磁共振成像装置(MRI)测定HFD组和HFD+粪肠球菌组两组脂肪量和瘦肉量的结果。
图6显示HFD组和HFD+粪肠球菌组两组小鼠第八周采集肝脏样品的检测结果。
实施发明的最佳方式
下面结合实施例和附图进一步说明本发明。应当理解，下述实施例仅是对本发明的进一步阐明，而非对本发明的限制。
除非特别指明，以下实施例中所用的C57BL/6小鼠均购自南京大学模式动物研究所。所用的试剂均为分析纯级别的试剂，且可从正规渠道商购获得。所用的粪肠球菌(Enterococcus faecalis)购自北纳创联生物技术有限公司(生产编号为BNCC102668)。
粪肠球菌(Enterococcus faecalis)溶液的制作方法：将粪肠球菌冻干粉溶于灭菌蒸馏水，最终菌落数达到5×10 10CFU/mL。
本发明将HFD组和HFD+粪肠球菌组进行统计学分析，P<0.05即表示组间差异具有统计学意义。
实施例1
1.1构建高脂饮食诱导肥胖小鼠。
购买4周龄C57BL/6雄性小鼠20只，随机分为两组，每组10只，给予60％的H10060高脂饲料(华阜康)8周，诱导肥胖小鼠模型。
1.2灌胃法处理上述两组小鼠。
每日用粪肠球菌(Enterococcus faecalis)溶液灌喂一组，也就是HFD+粪肠球菌组小鼠，剂量为1×10 10CFU/只/天，同时灌喂另一组小鼠等体积的饮用水，记为HFD对照组。灌胃开始后第8周后取各种组织样品，以备后用。在此期间，每周称重，结果如表1和图1所示，并且第六周开始检测摄食量、运动量、体温(肛温)、耗氧量、MRI等指标。结果如图2-6所示。其中，“HFD组”表示灌喂等体积的饮用水的高脂诱导的HFD小鼠组，“HFD+粪肠球菌组”表示以1×10 10CFU/只/天的剂量灌喂粪肠球菌(Enterococcus faecalis)的高脂诱导的HFD小鼠组。
表1 两组每周体重变化的检测结果
Figure PCTCN2018114132-appb-000001
图1和表1显示HFD组和HFD+粪肠球菌组两组每周体重变化的检测结果。该结果表明高脂诱导的HFD小鼠每天饲喂粪肠球菌(Enterococcus faecalis)可以有效抑制体重增加，饲喂第3周开始体重有显著差异，到第8周体重差异有3.82克(参见图1，其中第3-4周是“*”，第5周是“**”，第6周是“***”，第7-8周是“**”，分别表示p<0.05，p<0.01和p<0.001)
图2显示HFD组和HFD+粪肠球菌组两组的小鼠的一天平均摄食量结果。该结果表明饲喂粪肠球菌(Enterococcus faecalis)，摄食量没有明显差异。这一结果表示，粪肠球菌(Enterococcus faecalis)不会影响食欲，体重的降低不是因为食欲减少而导致的现象。
图3是显示HFD组和HFD+粪肠球菌组两组小鼠在常温和寒冷刺激下产热和体温分析的图。通过在4度连续处理3个小时，检测体温(肛温)变化和利用红外热成像仪检测体温的结果显示，高脂诱导的HFD小鼠饲喂粪肠球菌(Enterococcus faecalis)后，显著提高了寒冷条件下体温(参见图3a，其中“***”表示p<0.001)。进一步利用远红外扫描仪检测寒冷刺激下小鼠的体表温度的变化，结果表明HFD+粪肠球菌组小鼠肩胛骨棕色脂肪位置的产热明显增强(图3b)。
图4是显示HFD组和HFD+粪肠球菌组两组的耗氧量指标的图，其为利用能量代谢仪检测小鼠能量代谢的结果。该结果表明粪肠球菌(Enterococcus faecalis)饲喂后，高脂诱导的HFD小鼠的能量消耗显著增加(参见图4，其中“*”表示p<0.05)。
图5是用磁共振成像装置(MRI)测定HFD组和HFD+粪肠球菌组两组的脂肪量和瘦肉量的结果。结果表明粪肠球菌(Enterococcus faecalis)处理会显著减少高脂诱导的HFD小鼠的脂肪量(参见图5，其中“***”表示p<0.001)。
图6是HFD组和HFD+粪肠球菌组两组小鼠第八周采集肝脏样品的检测结果。结果表明粪肠球菌(Enterococcus faecalis)有改善脂肪肝的功效
综上所述，图1-6表明肠道微生物-粪肠球菌(Enterococcus faecalis) 有效的提高机体的能量代谢，进而改善高脂诱导的HFD小鼠的肥胖。
尽管本发明已进行了一定程度的描述，明显地，在不脱离本发明的精神和范围的条件下，可进行各个条件的适当变化。可以理解，本发明不限于所述实施方案，而归于权利要求的范围，其包括所述每个因素的等同替换。

Claims (10)

  1. 粪肠球菌在制备用于预防或治疗代谢综合征或用于改善机体能量代谢的产品中的用途；
    优选地，所述产品为药物、食品、保健品或食品添加剂。
  2. 根据权利要求1所述的用途，其中，所述代谢综合征选自代谢性疾病，心血管病或神经损伤性疾病；
    优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；
    所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；
    所述神经损伤性疾病为阿尔兹海默症或帕金森症。
  3. 根据权利要求1所述的用途，其中，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
  4. 根据权利要求1-3中任一项所述的用途，其中，所述产品还包括其他组分；
    优选地，所述其他组分为药物提取物或益生菌；更优选地，所述益生菌为食源性益生菌；
    优选地，所述产品还包括药物、食品、保健品或食品添加剂中可接受的辅料；更优选地，所述可接受的辅料为淀粉和/或用于促进吸收或缓释的纳米颗粒；
    优选地，所述产品为片剂、颗粒剂、散剂、胶囊或功能性饮品；
    优选地，在所述产品中，所述粪肠球菌活菌的含量不低于10 7CFU/g或10 7CFU/mL。
  5. 用于预防或治疗代谢综合征或用于改善机体能量代谢的方法，所述方法包括给予对象有效量的粪肠球菌；
    优选地，所述粪肠球菌活菌的含量不低于10 7CFU/g或10 7CFU/mL。
  6. 根据权利要求5所述的方法，其中，所述代谢综合征选自代谢性疾病，心血管病或神经损伤性疾病；
    优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；
    所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；
    所述神经损伤性疾病为阿尔兹海默症或帕金森症。
  7. 根据权利要求5所述的方法，其中，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
  8. 用于预防或治疗代谢综合征或用于改善机体能量代谢的粪肠球菌；
    优选地，所述粪肠球菌活菌的含量不低于10 7CFU/g或10 7CFU/mL。
  9. 根据权利要求8所述的粪肠球菌，其中，所述代谢综合征选自代谢性疾病，心血管病或神经损伤性疾病；
    优选地，所述代谢性疾病为糖尿病、肥胖症、脂肪肝、糖尿病肾损伤、糖尿病大血管病变、糖尿病微血管损伤、糖尿病性视网膜病变、胰高血糖素血症、坏死性游走性红斑或高血糖素瘤；
    所述心血管病为冠心病、高血压性心脏病、瓣膜性心脏病、酒精性心肌病或糖尿病心血管并发症；
    所述神经损伤性疾病为阿尔兹海默症或帕金森症。
  10. 根据权利要求8所述的粪肠球菌，其中，所述代谢综合征选自肥胖症、脂肪肝或II型糖尿病。
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CN114042091A (zh) * 2021-10-24 2022-02-15 郑州大学 酪黄肠球菌在制备治疗代谢综合征产品中的应用方法

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