CN111544455B - 益生菌株或其代谢产物用于制备降胆固醇的组合物的用途 - Google Patents
益生菌株或其代谢产物用于制备降胆固醇的组合物的用途 Download PDFInfo
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Abstract
本发明涉及微生物领域,尤其涉及降胆固醇的益生菌株及其组合物与用途。本发明提供一种降胆固醇的益生菌株及其组合物与用途,该益生菌是胚芽乳杆菌,寄存编号为DSM 33162,该益生菌株或其代谢产物可有效减少胆固醇的含量、提升SCARB1基因、APOA1基因、及LDLR基因的表现量,以促进胆固醇代谢的功效、且可有效降低人体血液中总胆固醇、以及低密度脂蛋白的含量,因此可用于制备降低胆固醇的组合物的用途。
Description
技术领域
本发明涉及微生物领域,尤其涉及降胆固醇的益生菌株及其组合物与用途。
背景技术
相关文献统计显示,全球约有三分之一人口死于心血管疾病(Cardiovasculardisease, CVD),为全球死因排行中的第一名,心血管疾病又称为循环系统疾病,是指人体内运送血液的器官和组织所产生的疾病,因此所有心脏及血管的病变都可称为心血管疾病,如中风、心肌梗塞等。其中高胆固醇血症在心血管疾患者中有高达七成的盛行率,亦为造成冠状动脉疾病、中风、与周边血管疾病等血管粥状硬化的主要危险因子。
然而,高胆固醇血症大多是没有明显的症状,仅有头晕、颈部僵硬与血压升高等非典型症状。当血管阻塞的程度越来越严重时,就会出现狭心症、心肌梗塞、中风、或间歇性跛行等严重的并发症。因此,为降低发生心血管疾病的风险,控制血液中胆固醇含量即成为首要的目标。
其中,目前为预防心血管疾病仅能透过改善生活、饮食、以及运动习惯,并避免如香烟等危险因子等方式改善。否则则须以药物进行控制,其中该些药物主要为化学合成而得,且可分为两大类:一是预防血栓、抗血小板凝结的药物,二是控制高血压、胆固醇、糖尿病的药物,然而这两类药物常伴随着较强的副作用。例如血管紧张素相关的拮抗药可能会引起高血钾,使肌肉出现无力或心跳过慢等症状;或是强效降胆固醇药物的他汀(Statins)类药物可能会使肝功能指数上升、或有头痛、恶心、疲倦等副作用。且这些药物必须长期服用以控制病情,然而长期服用药物对于个体所造成的副作用更无法自根本改善个体身体健康。
综合上面所述,因应心血管疾病的高发生率,且基于现代人生活水平提高且对于保健概念提高,研发一种能有效预防心血管疾病,并能有效控制血液中胆固醇含量,又能避免合成药物对于人体产生的副作用的由天然植物的有效成分组成的组合物,着实有其必要性。
发明内容
因此,本发明的一目的在提供一种用于降胆固醇的益生菌株,其中该益生菌株是一胚芽乳杆菌 (Lactobacillus plantarum),寄存编号是DSM 33162。
本发明的又一目的在提供一种如前所述的益生菌株或其代谢产物用于制备降胆固醇的组合物的用途。
本发明的另一目的在提供一种用于降胆固醇的组合物,包含一有效量的如前所述的益生菌株或其代谢产物。
在本发明的一实施例中,该益生菌株是具有活性或去活性的菌株。
在本发明的又一实施例中,该益生菌株或其代谢产物是提升清道夫受体B1(Scavenger Receptor Class B Member 1, SCARB1)基因、载脂蛋白A1 (ApolipoproteinA1, APOA1)基因、及/或低密度脂蛋白受体 (Low-density lipoprotein receptor, LDLR)基因的表现量,以促进胆固醇的代谢;且该益生菌株的浓度至少为0.5% (w/w)。
在本发明的另一实施例中,该益生菌株或其代谢产物是降低人体血液中总胆固醇、及/或低密度脂蛋白的含量。
本发明的胚芽乳杆菌TCI507的活性菌株、去活性菌株、或其代谢产物在体外能可有效减少胆固醇的含量,显示其可用于人体降胆固醇的潜力;而在细胞实验中发现本发明的胚芽乳杆菌TCI507或其代谢产物可有效提升SCARB1基因、APOA1基因、及LDLR基因的表现量,显示其可促进胆固醇代谢的功效;在人体试验中更发现本发明的胚芽乳杆菌TCI507或其代谢产物可有效降低人体血液中总胆固醇、以及低密度脂蛋白的含量,显示其具有人体降胆固醇的功效;且因高胆固醇体质容易引起高血压、动脉硬化、心肌梗塞等心血管疾病,因此本发明的胚芽乳杆菌TCI507或其代谢产物可应用于心血管保健的用途。故,本发明的胚芽乳杆菌TCI507或其代谢产物可用于制备降低胆固醇的组合物的用途,该组合物是一食品、一饮品、一营养补充剂、或一医药品,且该组合物是粉末、颗粒、溶液、或胶体的剂型,并可通过口服等方式给予一个体。
以下将配合图式进一步说明本发明的实施方式,下述所列举的实施例是用以阐明本发明,并非用以限定本发明的范围,任何熟习此技艺者,在不脱离本发明的精神和范围内,当可做些许更动与润饰,因此本发明的保护范围当视后附的申请专利范围所界定者为准。
附图说明
图1是本发明的一实施例的胚芽乳杆菌TCI507降低总胆固醇含量的柱形图;
图2是本发明的一实施例的胚芽乳杆菌TCI507提升SCARB1基因、APOA1基因、及LDLR基因表现量的柱形图;*p值<0.05;**p值<0.01; ***p值<0.001;
图3是本发明的一实施例的胚芽乳杆菌TCI507降低人体血液中总胆固醇含量的柱形图;*p值<0.05;
图4是本发明的一实施例的胚芽乳杆菌TCI507降低人体血液中低密度脂蛋白含量的柱形图;**p值<0.01。
具体实施方式
本发明的胚芽乳杆菌 (Lactobacillus plantarum)是一种可降胆固醇以促进心血管保健的益生菌株 (Probiotic bacteria)。本发明是一新颖的胚芽乳杆菌,本文命名为TCI507,于2019年5月24日DSMZ-德国 微生物保藏中心,寄存编号DSM 33162,本发明经由体外实验证实本发明的胚芽乳酸杆菌TCI507或其代谢产物可有效减少胆固醇的含量;经由细胞实验证实本发明的胚芽乳酸杆菌TCI507或其代谢产物可有效提升SCARB1基因、APOA1基因、及LDLR基因的表现量,以促进胆固醇代谢的功效;经由人体试验证实本发明的胚芽乳酸杆菌TCI507或其代谢产物可有效降低人体血液中总胆固醇、以及低密度脂蛋白的含量。显示本发明的胚芽乳酸杆菌TCI507或其代谢产物可用于制备降胆固醇的心血管保健的组合物的用途,且该组合物是一医药品、或一食品,可通过口服等方式给予一个体。
使用Excel软件进行统计分析。数据以平均值±标准偏差 (SD)表示,个组之间的差异以学生t检验(student's t-test)分析。
定义
本文中所使用数值为近似值,所有实验数据皆表示在20%的范围内,较佳为在10%的范围内,最佳为在5%的范围内。
益生菌株 (probiotic或probiotic bacteria)是一微生物,其菌体、混合菌株、萃取物或代谢产物对于宿主本身是具有正面影响,通常源自于人体内、有益于肠道健康的活菌,亦可指外来补充、对身体可能有益的某些微生物,其中该益生菌株的代谢产物是该益生菌株的分泌物,包含培养该菌的培养液。
依据本发明,有关细菌培养的操作程序与参数条件等是落在熟习此项技术的人士的专业素养与例行技术范畴内。
如本文中所使用的,用语「代谢产物」意为培养细菌时,经该细菌代谢后所分泌至细菌培养液中的物质,包含培养该菌的培养液。
依据本发明,医药品可利用熟习此技艺者所详知的技术而被制造成一适合于非经肠地道(parenterally)或局部地(topically)投药的剂型,这包括,但不限于:注射品(injection)[例如,无菌的水性溶液(sterile aqueous solution)或分散液(dispersion)]、无菌的粉末(sterile powder)、外部制剂(external preparation)以及类似物。
依据本发明,医药品可进一步包含有一被广泛地使用于药物制造技术的医药上可接受的载剂(pharmaceutically acceptable carrier)。例如,该医药上可接受的载剂可包含一或多种选自于下列的试剂:溶剂(solvent)、缓冲液(buffer)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、崩解剂(disintegrating agent)、分散剂(dispersing agent)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizingagent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润湿剂(wetting agent)、润滑剂(lubricant)、吸收延迟剂(absorptiondelaying agent)、脂质体(liposome)以及类似物。有关这些试剂的选用与数量是落在熟习此项技术的人士的专业素养与例行技术范畴内。
依据本发明,该医药上可接受的载剂包含有一选自于由下列所构成的群组中的溶剂:水、生理盐水(normalsaline)、磷酸盐缓冲生理盐水(phosphate buffered saline,PBS)、含有醇的水性溶液(aqueous solution containing alcohol)以及它们的组合。
依据本发明,该医药品可以一选自于由下列所构成的群组中的非经肠道途径(parenteral routes)来投药:皮下注射(subcutaneous injection)、表皮内注射(intraepidermal injection)、皮内注射(intradermal injection)以及病灶内注射(intralesional injection)。
依据本发明,食品产品可被当作食品添加物(food additive),通过习知方法于原料制备时添加,或是于食品的制作过程中添加,而与任一种可食性材料配制成供人类与非人类动物摄食的食品产品。
依据本发明,食品产品的种类包括但不限于:饮料(beverages)、发酵食品(fermented foods)、烘培产品(bakery products)、健康食品(health foods)以及膳食补充品(dietary supplements)。
本发明提供一种胚芽乳杆菌 (Lactobacillus plantarum)TCI507或其代谢产物用于制备降胆固醇的组合物的用途,本发明胚芽乳杆菌代谢产物是取该胚芽乳杆菌TCI507的培养液所获得。该胚芽乳杆菌TCI507或其代谢产物可用于提升SCARB1基因、APOA1基因、及/或LDLR基因的表现量,以促进胆固醇的代谢;亦可降低人体血液中总胆固醇、及/或低密度脂蛋白的含量。
同时,本发明用于降胆固醇的组合物,亦可包含一有效量的胚芽乳杆菌TCI507或其代谢产物,以及一医药上可接受的载体,该组合物是一医药品、或一食品。
以下将详细说明本发明的胚芽乳杆菌TCI507或其代谢产物于试管实验中降低胆固醇含量的功效测试;其提升肝脏细胞中SCARB1基因、APOA1基因、及LDLR基因表现量的功效测试;以及其降低人体血液中总胆固醇、以及低密度脂蛋白的含量的功效测试,证实本发明的胚芽乳杆菌TCI507或其代谢产物具有促进胆固醇的代谢及降低人体胆固醇的功效,而能用于制备降胆固醇的组合物。
实施例1 本发明的胚芽乳杆菌TCI507降胆固醇的功效
在本发明的一实施例为测试本发明的胚芽乳杆菌 (Lactobacillus plantarum)TCI507降胆固醇的功效,于试管进行体外降低胆固醇含量的实验。首先,将1%的胚芽乳杆菌TCI507的菌种培养在含有5000 ppm胆固醇的MRS (de Man, Rogosa and Sharpe,本实施例是使用BD Difco™Lactobacilli MRS Broth,编号为DF0881175)培养液的试管中,于37℃培养24小时后,将菌液以5000 rpm离心10分钟后,搜集5 mL的上清液并使用胆固醇定量试剂套组 (Cholesterol Quantitation Kit,购于西格玛奥瑞奇,美国,编号为MAK043)进行胆固醇总含量检测。其中,以MRS作为空白控制组;以已知具有降胆固醇功效的胚芽乳杆菌LP1及LP2二菌株作为控制组;且该培养液是取55g的MRS溶于1L纯水中再于121℃下灭菌15分钟所制成。
本发明的胚芽乳杆菌TCI507降胆固醇的实验测试结果如图1所示。经本发明的胚芽乳杆菌TCI507作用后,可大幅降低87%的胆固醇含量,且相较于二正控制组的胚芽乳杆菌株,降低更高比例的胆固醇。此结果显示本发明的胚芽乳杆菌TCI507可有效降低胆固醇含量,可用于人体降胆固醇的心血管保健用途。
实施例2 本发明的胚芽乳杆菌TCI507提升SCARB1基因、APOA1基因、及LDLR基因表现量的功效
本发明的一实施例为测试本发明的胚芽乳杆菌TCI507调控胆固醇相关基因表现量的功效,使用人类肝脏上皮细胞HepG2 (购自美国典型培养物保藏中心ATCC,编号ATCC®HB-8065™)进行实验。其中,该细胞是培养于含有10%的胎牛血清 (Fetal Bovine Serum,购自Gibco,美国)、1%青霉素-链霉素 (购自Gibco,美国)的DMEM (Dulbecco's ModifiedEagle Medium,购自Gibco,美国,12100-046)细胞培养液中。
首先,将0.5x105个HepG2细胞培养于6孔培养盘的每孔中,于37oC培养16小时,接着将细胞分成以下五组:(1) 仅加入前述细胞培养液的空白控制组、(2) 仅加入前述细菌培养液(即空培液)的空白控制组、(3) 加入1% LP1代谢产物的正控制组、(3) 加入1% LP2代谢产物的正控制组、(4) 加入1%本发明胚芽乳杆菌TCI507代谢产物的实验组,并将该些组别的细胞分别于37oC下作用24小时后,测试各组HepG2细胞中胆固醇代谢相关基因的表现量。接着,将HepG2细胞以细胞裂解液 (购自Geanaid公司,中国台湾,编号RBD300) 回收细胞后,使用RNA萃取试剂套组 (购自Geneaid公司,中国台湾,编号RBD300)分别收集该五组细胞内的RNA,接着利用SuperScript® III反转录酶 (购自Invitrogene公司,美国,编号18080-051)以2000 ng的萃取RNA为模板并以引物产生 mRNA反转录的相应cDNA产物,接着利用ABI StepOnePlusTM Real-Time PCR system (Thermo Fisher Scientific公司,美国),以及KAPA SYBR FAST (购自Sigma公司,美国,编号38220000000)将该五组反转录后产物分别以表1的组合引物进行定量实时聚合酶连锁反应 (Quantitative real-timepolymerase chain reaction, qPCR)试验,条件为 95°C反应1 分钟预热后,再进行以下95°C反应15秒、58°C反应15秒、72°C反应30秒的总共 40个循环的程序。用以定量SCARB1基因、APOA-1基因、LDLR基因、ABCA1基因、及CETP基因的mRNA表现量,其中定量数值是取由阈值循环数(Ct),而目标基因的mRNA相对量是推导自方程式2-△Ct,其中△Ct=Ct目标基因-Ct ACTB (β-肌动蛋白,beta-actin) ,再利用Excel软件进行非成对单尾student t-test以决定变异系数与是否在统计上具有显着差异 (*p值<0.05; **p值<0.01; ***p值<0.001)。
表1、定量实时反转录聚合酶连锁反应的组合引物
SCARB1 (Scavenger receptor class B member 1)基因编码的蛋白质SRB1(Scavenger receptor class B type 1)是高密度脂蛋白 (High-density lipoprotein,HDL)的细胞膜上受体。高密度脂蛋白会收集血液中的胆固醇,并将其沉积于肝脏待最终被代谢掉,在此过程中SR-B1扮演了关键的角色。因此,SCARB1基因表现量上升与降低血液中胆固醇相关。
APOA1 (Apolipoprotein A1)基因编码的蛋白质APOA-1为血液中高密度脂蛋白中主要的蛋白质成分,其经水解加工后,会执行促进胆固醇从组织流出至肝脏排泄的功能。APOA-I附着于细胞膜并促进胆固醇和磷脂从细胞内部向外移动,并与APOA-I结合形成HDL。APOA-I亦会引发胆固醇酯化反应,将胆固醇转化为可以完全整合到HDL中并通过血液运输的形式。
ABCA1 (ATP binding cassette subfamily A member 1)基因编码的蛋白质ABCA1主要功能为将胆固醇从细胞内运送到胞外,为APOA-1的受体。因此,APOA1基因及ABCA1基因的表现量上升与降低血液中胆固醇相关。
LDLR (Low density lipoprotein receptor)基因编码的蛋白质LDLR为低密度脂蛋白 (Low-density lipoprotein, LDL)的受体,LDLR位于不同种类细胞的表面,会与在血液中的低密度脂蛋白结合并将其运输到细胞中,低密度脂蛋白进入细胞后,会被分解并释放出胆固醇。LDLR在调节血液中胆固醇含量扮演关键的角色,其在肝脏细胞数量特别多,其中肝脏是负责从体内去除过量胆固醇的器官。肝脏细胞表面的LDLR数量决定了从血液中去除胆固醇的速度。因此,LDLR基因的表现量上升与降低血液中胆固醇相关。
CETP (Cholesteryl ester transfer protein)基因编码的蛋白质CETP为一种血浆蛋白,主要功能为协助胆固醇由高密度脂蛋白转移至低密度脂蛋白,此基因的突变会导致高密度脂蛋白血症,以及动脉粥様硬化。因此,CETP基因的表现量上升与降低血液中胆固醇相关。
本发明的胚芽乳杆菌TCI507提升肝脏细胞中SCARB1基因、APOA1基因、及LDLR基因表现量的结果如图2所示。经本发明的胚芽乳杆菌TCI507作用后,相较于空培液组,能显着提高SCARB1基因、APOA1基因、及LDLR基因的表现量,且皆较已知具有降低胆固醇功效的LP1及LP2能更加地提升该三基因的表现量;而CETP基因及ABCA1基因则差异不大。此结果显示本发明的胚芽乳杆菌TCI507能有效提升SCARB1基因、APOA1基因、及LDLR基因的表现量,能促进胆固醇的代谢,并可用于人体降胆固醇的心血管保健用途。
实施例3 本发明的胚芽乳杆菌TCI507降低人体低密度脂蛋白的功效
本发明的一实施例为试验本发明的胚芽乳杆菌TCI507于降低人体低密度胆固醇的功效,首先募集6位受试者,每日服用一颗内含5 x 109 CFU/cap的本发明胚芽乳杆菌TCI507的胶囊,并分别于服用前、服后两周后、及服用四周后,测试受试者血液中总胆固醇、以及低密度胆固醇的变化,其中是委外给检验单位进行各受试者血液样品中总胆固醇及低密度胆固醇的含量。
本发明的胚芽乳杆菌TCI507降低人体血液总胆固醇含量的结果如图3所示;降低人体血液中低密度脂蛋白含量的结果如图4所示。服用前受试者血液中的总胆固醇含量约为210 mg/dL,低密度脂蛋白含量约为148 mg/dL;服用本发明的胚芽乳杆菌TCI507两周后,能使受试者血液中总胆固含量降低至约195 mg/dL,低密度脂蛋白则降低至约137 mg/dL;服用本发明的胚芽乳杆菌TCI507四周后,能使受试者血液中总胆固含量显着地降低至约194 mg/dL,且相较于服用前降低了7.2%,而服用四周后低密度脂蛋白则显着地降低至约131 mg/dL,相较于服用前降低了11%。此些结果显示,本发明的胚芽乳杆菌TCI507可有效降低人体血液中总胆固醇、以及低密度脂蛋白的含量,可用于人体降胆固醇的心血管保健用途。
综上所述,本发明的胚芽乳杆菌TCI507的活性菌株、去活性菌株、或其代谢产物在体外能可有效减少胆固醇的含量,显示其可用于人体降胆固醇的潜力;而在细胞实验中发现本发明的胚芽乳杆菌TCI507或其代谢产物可有效提升SCARB1基因、APOA1基因、及LDLR基因的表现量,显示其可促进胆固醇代谢的功效;在人体试验中更发现本发明的胚芽乳杆菌TCI507或其代谢产物可有效降低人体血液中总胆固醇、以及低密度脂蛋白的含量,显示其具有人体降胆固醇的功效;且因高胆固醇体质容易引起高血压、动脉硬化、心肌梗塞等心血管疾病,因此本发明的胚芽乳杆菌TCI507或其代谢产物可应用于心血管保健的用途。故,本发明的胚芽乳杆菌TCI507或其代谢产物可用于制备降低胆固醇的组合物的用途,该组合物是一食品、一饮品、一营养补充剂、或一医药品,且该组合物是粉末、颗粒、溶液、或胶体的剂型,并可通过口服等方式给予一个体。
【生物材料寄存】
【寄存地址】德国布伦瑞克市38124因霍芬大街7B;
【寄存机构】DSMZ-德国微生物保藏中心;
【寄存日期】2019年5月24日;
【寄存号码】DSM33162。
Claims (6)
1.一种益生菌株或其代谢产物用于制备降胆固醇的组合物的用途,其中该益生菌株是一胚芽乳杆菌(Lactobacillus plantarum),寄存编号是DSM 33162。
2.根据权利要求1所述的用途,其特征在于,所述益生菌株是具有活性或去活性的菌株。
3.根据权利要求1所述的用途,其特征在于,所述益生菌株的浓度至少为0.5%(w/w)。
4.根据权利要求1所述的用途,其特征在于,所述益生菌株或其代谢产物是提升清道夫受体B1(Scavenger Receptor Class B Member 1,SCARB1)基因、载脂蛋白A1(Apolipoprotein A1,APOA1)基因、及/或低密度脂蛋白受体(Low-density lipoproteinreceptor,LDLR)基因的表现量,以促进胆固醇的代谢。
5.根据权利要求1所述的用途,其特征在于,所述益生菌株或其代谢产物是降低人体血液中总胆固醇、及/或低密度脂蛋白的含量。
6.根据权利要求1所述的用途,其特征在于,所述组合物是一食品、一饮品、一营养补充剂、或一医药品。
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KR20110018898A (ko) * | 2008-05-13 | 2011-02-24 | 오위 테르비슬리쿠 피마 바이오테흐놀로지아테 아렌두스케스쿠스 | 자연 면역을 증가시키는 프로바이오틱인 단리된 락토바실러스 플란타룸 균주 인듀시아 dsm 21379와, 이를 포함하는 식품과 의약적 제제 |
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