CN100396770C - 新的微生物鼠李糖乳杆菌gm-020及其治疗肥胖的用途 - Google Patents
新的微生物鼠李糖乳杆菌gm-020及其治疗肥胖的用途 Download PDFInfo
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- CN100396770C CN100396770C CNB2004100301698A CN200410030169A CN100396770C CN 100396770 C CN100396770 C CN 100396770C CN B2004100301698 A CNB2004100301698 A CN B2004100301698A CN 200410030169 A CN200410030169 A CN 200410030169A CN 100396770 C CN100396770 C CN 100396770C
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Abstract
本发明提供了一株分离的微生物鼠李糖乳杆菌GM-020，经发现该鼠李糖乳杆菌GM-020有效于治疗肥胖及其并发症。本发明也提供用于治疗肥胖及其并发症的鼠李糖乳杆菌GM-020的用途。
Description
技术领域
本发明主要是涉及一株新的微生物鼠李糖乳杆菌GM-020及其治疗肥胖或其并发症的用途。
背景技术
肥胖通常是由于生理或生物化学功能改变而导致的体脂肪过剩，且其可显著损害健康。脂肪通常包括中性脂、磷脂和胆固醇。重量的增加取决于人的能量摄入大于能量消耗。肥胖存在两种类型：(a)单纯性肥胖(simple obesity)和(b)继发性肥胖(second obesity)。单纯性肥胖可划分为先天性肥胖(idiopathic obesity)和后天性肥胖(acquired obesity)，可占超过95％的肥胖。先天性肥胖是由大量的脂肪细胞所致，且常见于儿童期肥胖。后天性肥胖是由更大尺寸的脂肪细胞所致，且常见于成年期肥胖。继发性肥胖又被称为症状性肥胖，其通常是由内分泌或新陈代谢疾病所致。肥胖与若干慢性疾病，诸如糖尿病、心肌病(cardiopathy)、高血压、中风、胆石(biliary calculus)、痛风和某些癌相关。
目前有五种治疗肥胖的策略：减食、锻炼、行为治疗、药物治疗和康复手术(therapeutic operation)。视病人的健康危险因子和体重减轻的速度和效果而定，可选择或组合这些策略对肥胖病人进行治疗，其体重减轻的速度和效果受诸如年龄、身高、家族史和危险因子等多个因素的影响。药物治疗的机制包括抑制食欲、增加能量消耗、刺激脂肪移动、降低甘油三酯合成和抑制脂肪吸收。此等药物的实例为苯丙醇胺(phenylpropanolamine，PPA)、罗氏鲜(orlistat，XenicalTM)和诺美婷(sibutramine，ReductilTM)。然而，通过天然物质而非药物来治疗肥胖成为新的趋势。
在现有技术中，发现可使用一些微生物来治疗肥胖，或其并发症。例如，发现加氏乳杆菌(Lactobacillus gasseri)SBT0270具有降低与胆汁酸的去结合有关的胆固醇浓度的能力((Usman，B.和Hosono，A.(2001)，“加氏乳杆菌(Lactobacillus gasseri)SBT0270引起喂以富含胆固醇的饮食的大鼠中的低胆固醇血症效果”(Hypocholesterolemic effect ofLactobacillus gasseri SBT0270 in rats fed a cholesterol-enriched diet)，J.Dairy Res.68：617-624)。治疗肥胖的机制为：通过由加氏乳杆菌(L.gasseri)来吸收从由形态的胆汁酸并经粪便来排出(因为所排出的胆汁酸不能再循环回到肝脏，且需要从胆固醇来合成新的胆汁酸)，来降低该分解的胆汁酸的可溶性。此外，发现加氏乳杆菌(L.gasseri)可与胆汁酸和胆固醇组合以达成***。
鼠李糖乳杆菌(Lactobacillus rhamnosus)被认为是一种具有提高免疫的特性的潜在的益生乳酸菌。鼠李糖乳杆菌的安全性评定(Safetyassessment)亦已进行了调查。Zhou等人揭示了投药鼠李糖乳杆菌的小鼠的血液学参数(红细胞和血小板计数、血红蛋白浓度、平均红细胞体积、平均红细胞血红蛋白、和平均红细胞血红蛋白浓度)、不同的白细胞计数、血液生物化学(血浆总蛋白、白蛋白、胆固醇、和葡萄糖)、粘膜组织学(上皮细胞高度、粘膜厚度、和绒毛高度)、及其到肠道外组织(血液、肝脏、脾、肾脏和肠系膜***)的细菌位移，展示了与对照鼠相似的图谱(profile)(Zhou，J.S.，Shu，Q.，Rutherfurd，K.J.，Prasad，J.，Birtles，M.J.，Gopal，P.K.和Gill，H.S.(2000)，“BALB/c鼠中潜在的益生乳酸菌株鼠李糖乳杆菌HN001、嗜酸乳杆菌HN017，和比菲德氏菌HN019的安全性评定”比菲德氏菌(Safety assessment of potential probiotic lactic acidbacterial strains Lactobacillus rhamnosus HN001，Lb.acidophilus HN017，and Bifidobacterium lactis HN019 in BALB/c mice)，International Journal ofFood Microbiology56：87-96)。此外，Agerholm-Larsen等人揭示了投药经鼠李糖乳杆菌发酵的酸乳酪不会改变低密度的脂蛋白(LDL)-胆固醇，而仅显著降低了收缩压(Agerholm-Larsen，L.，Raben，A.，Haulrik N.，Hansen，A.S.，Manders，M.，和Astrup A.(2000)，“摄入益生乳制品8周对心血管疾病的危险因素的影响”(Effect of 8 week intake of probiotic milk products onrisk factors for cardiovascular diseases)，Eur J Clin Nutr.54(4)：288-97)。因此，可证明已知的鼠李糖乳杆菌株不会改变血浆总胆固醇(totalcholesterol)和LDL-胆固醇。另外，当投药已知的鼠李糖乳杆菌株时，并未观察到任何体重变化。
发明内容
本发明提供一株新的经分离的微生物，鼠李糖乳杆菌(Lactobacillusrhamnosus)GM-020，其以保藏编号CCTCC M 203098保藏于中国典型培养物保藏中心。
另一方面，本发明提供了包含鼠李糖乳杆菌GM-020的组合物。
另一方面，本发明提供了鼠李糖乳杆菌菌株GM-020在制备用于治疗肥胖及其并发症的药物中的应用。
另一方面，本发明提供了鼠李糖乳杆菌菌株GM-020及黑木耳在制备用于治疗肥胖及其并发症的药物中的应用。
另一方面，本发明提供一种用于治疗受验者的肥胖及其并发症的方法，该方法包括对该受验者投药一种包含微生物鼠李糖乳杆菌GM-020的组合物；其中该并发症优选是选自由高胆固醇血症、动脉粥样硬化和冠心病(coronary heart disease)所组成的组。
又一方面，本发明提供一种用于治疗受验者的肥胖及其并发症的方法，该方法包括对该受验者施以一种包含微生物鼠李糖乳杆菌GM-020和黑木耳(Auricularia polytricha)的组合物；其中该并发症优选是选自由高胆固醇血症、动脉粥样硬化、冠心病、脂肪肝和糖尿病所组成的组。
附图说明
图1说明GM-020的1000X微观图。
图2说明GM-020和已知鼠李糖乳杆菌株的细胞壁蛋白；其中M代表蛋白质分子量；道(Lane)1代表鼠李糖乳杆菌(商品Antibiophilus)；道2代表鼠李糖乳杆菌GM-020；道3代表鼠李糖乳杆菌ATCC9595；道4代表鼠李糖乳杆菌ATCC10940；和道5代表鼠李糖乳杆菌ATCC14029。
图3说明GM-020的2-D总蛋白电泳。
图4说明根据实施例5的通过GM-020或/和黑木耳(wood ear)来治疗的动物模型的体重差异；其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表1X的黑木耳；d代表10X的黑木耳；e代表GM-020；f代表与GM-020组合的1X的黑木耳；且g代表与GM-020组合的10X的黑木耳。
图5说明根据实施例5的通过GM-020或/和黑木耳来治疗的动物模型的睾丸周围的脂质组织重量的差异；其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表1X黑木耳；d代表10X黑木耳；e代表GM-020；f代表与GM-020组合的1X黑木耳；且g代表与GM-020组合的10X黑木耳。
图6说明根据实施例5的通过GM-020或/和黑木耳来治疗的动物模型的肾脏周围的脂质组织重量的差异；其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表木1X耳；d代表10X黑木耳；e代表GM-020；f代表与GM-020组合的1X黑木耳；且g代表与GM-020组合的10X黑木耳。
图7说明根据实施例6的治疗之前(CHOL_0)与治疗之后(CHOL_4)的总胆固醇的血清浓度间的差异；其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01。
图8说明根据实施例6的在治疗之前(LDL-C_0)与治疗之后(LDL-C_4)的LDL-C的血清浓度；其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01。
图9说明根据实施例6的在治疗之前(LDL-C_0)与治疗之后(LDL-C_4)的LDL-C的血清浓度的差异；其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01。
图10说明根据实施例6的在治疗之前(LDL-C/HDL-C_0)与治疗之后(LDL-C/HDL-C_4)的LDL-C/HDL-C的血清浓度的差异；其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01。
具体实施方式
本发明提供一株新的微生物鼠李糖乳杆菌GM-020，其能治疗肥胖。于2003年12月18日将该株GM-020以保藏编号CCTCC M 203098保藏于中国典型培养物保藏中心。
鼠李糖乳杆菌GM-020系从人的胃分离出。
以下展示了鼠李糖乳杆菌GM-020的真细菌特征：
(a)形态学特征
(1)细胞的形状和大小：当细胞在37℃下于MRS培养基中隔夜培养后，可通过显微镜观察到杆菌，其为具有圆形边缘的杆状形状。
(2)活动力：非活动的
(3)鞭毛：无
(4)孢子形成：无孢子形成
(5)革兰氏染色：阳性
(b)培养特征：
(1)介质：MRS培养基(
0881)(如表1中所示)，最终pH值6.5±0.2
表1
| 组份 | g/L |
| 示蛋白胨(Proteose peptone) | 10.0 |
| 牛肉提取物(Beef Extract) | 10.0 |
| 酵母提取物(Yeast Extract) | 5.0 |
| 右旋糖 | 20.0 |
| 聚山梨糖醇酯八十(Polysorbate80) | 1.0 |
| 柠檬酸铵 | 2.0 |
| 乙酸钠 | 5.0 |
| 硫酸镁 | 0.1 |
| 硫酸锰 | 0.05 |
| 磷酸氢二钾(DipotassiumPhosphate) | 2.0 |
(2)培养条件：37℃厌氧培养(anaerobic culture)或需氧培养(aerobicculture)
(c)生理特征：
(1)过氧化氢酶(Catalase)：阴性
(2)氧化酶：阴性
(3)API 50CHL测试：使用API 50CHL***来识别乳杆菌。通过对一系列酶的反应进行检定，可确定该乳杆菌的特性(character)。表2中列出了GM-020的API 50 CHL测试的结果：
表2
| 酶 | 反应 | 酶 | 反应 | 酶 | 反应 |
| 甘油 | - | 甘露醇 | + | 太格糖(D-Tagatos) | + |
| 赤藓糖醇(Erythritol) | - | 山梨醇(Sorbitol) | + | 5酮基葡萄糖酸 | - |
| D-***糖 | - | α-甲基-D-葡萄糖苷 | + | 2酮基葡萄糖酸 | - |
| L-***糖 | - | N乙酰葡萄糖胺 | + | 葡萄糖酸 | - |
| 核糖 | + | 苦杏仁苷 | + | L-***糖醇 | - |
| D-木糖 | - | 熊果素(Arbutine) | + | D-***糖醇 | - |
| L-木糖 | - | 七叶苷(Esculine) | + | L-岩藻糖 | - |
| 侧金盏花醇(Adonitol) | - | 水杨苷(Salicine) | + | D-岩藻糖 | - |
| β-甲基-木糖苷 | - | 纤维二糖 | + | D-来苏糖 | - |
| D-葡萄糖 | + | 半乳糖 | + | 安茴酰牛扁碱(inuline) | - |
| D-果糖 | + | 乳糖 | + | 蔗糖 | - |
| D-甘露糖 | + | α-甲基-D-甘露糖苷 | - | 肝糖(Glycogene) | - |
| L-山梨糖 | + | 松三糖(Melezitose) | + | 木糖醇 | - |
| 鼠李糖 | + | D-棉子糖(D-Raffinose) | - | β龙胆二糖(βGentiobiose) | - |
| 卫矛糖醇(Dulcitol) | - | ***(Amidon) | - | D-松二糖(Turanose) | - |
| 肌醇(Inositol) | - | 麦芽糖 | - | 蜜二糖 | - |
| 海藻糖 | - |
(d)遗传特征：
由台湾新竹的食品工业发展研究所来确定GM-020的16S rDNA序列分析，如SEQ ID NO：1中所示。结果显示GM-020可与其它鼠李糖乳杆菌株高度同源，具有超过99％的相似性。
(e)GM-020的细胞壁蛋白：
当与其它已知的鼠李糖乳杆菌株比较时，GM-020的细胞壁蛋白显示了特定的图案。图2中展示了GM-020的细胞壁蛋白的SDS-PAGE图案。
GM-020的总蛋白可经受2-D电泳，且图3中所示的图案是特定的。
(f)用于识别GM-020的标准化检测***：
在于2003年5月29日所申请的美国专利申请案第10/446,781号中揭示了可用于识别微生物的标准检测***，该***使用经给定微生物培养与未经给定微生物培养的测试细胞系的基因表达差异来作为识别用标记。表3中列出了所测试的基因。
表3
| 基因 |
| 信号转导和转录激活因子(Signal transducer and activator of transcription)3 |
| c-rel |
| 生长相关蛋白43 |
| N-myc |
| IGF结合蛋白1 |
| IL-16 |
| 淋巴毒素α(Lymphotoxin α)(先前的肿瘤坏死因子β) |
| 干扰素诱导蛋白9-27 |
| ***生长因子 |
| 介白素10受体 |
| calpamodulin mRNA |
| 泛素交联酶(UbcH8)mRNA，复合物(comp) |
| 现代人(Homo sapiens)蛋白激酶A结合蛋白AKAP110mRNA，完全cds |
| 丙酮酸脱氢酶激酶，同功酶4 |
| 吡哆醛(吡哆醇(pyridoxine)，维生素B6)激酶 |
| MAP激酶相互作用的丝氨酸(serine)/苏氨酸(threonine)激酶1 |
| 白细胞酪氨酸激酶 |
| 神经营养酪氨酸激酶，受体，类型3(TrkC) |
| 丙酮酸脱氢酶激酶同功酶3(PDK3)mRNA，完全cds |
| 人的二酰甘油激酶ζ(diacylglycerol kinase zeta)mRNA，完全cds |
| 蛋白激酶C，α |
| 去氧鸟苷激酶(Deoxyguanosine kinase) |
| 腺苷激酶 |
| 拓扑异构酶(DNA)IIβ(180kD) |
| IkB激酶β亚单位(beta subunit)mRNA |
| stat5a(信号转导和转录激活因子5A) |
| 集落刺激因子1(M-CSF) |
| HGF |
| IL-1受体类型1 |
| 介白素7 |
| 金属硫蛋白I-B基因 |
| 介白素6(B细胞刺激因子2) |
| 可诱导的小分子细胞因子A2(Small inducible cytokine A2)(单核细胞趋化蛋白1) |
| 蛋白体(Proteasome)26S亚单位，ATPase，3 |
| 泛素交联酶E2A(RAD6同源体) |
| 胸腺嘧啶核苷激酶(thymidine kinase)1，可溶解 |
| 酪氨酸激酶2 |
| 丝氨酸/苏氨酸蛋白-激酶 |
| 转型生长因子β(Transforming growth factor beta)激活的激酶1 |
| 与Fms关联的酪氨酸激酶3 |
| 肌酸激酶B |
| 蛋白丝氨酸/苏氨酸激酶stk2 |
| 应激激活蛋白激酶3(SAPK3)mRNA. |
| 人腺苷酸激酶2(adk2)mRNA，完全cds |
| RAC-α丝氨酸/苏氨酸激酶 |
| 己糖激酶1 |
| CDC28蛋白激酶2(CKS2)mRNA |
| 超氧化物歧化酶2，线粒体 |
| 肿瘤坏死因子受体2 |
| 生长相关蛋白43 |
| 与p53相关的基因 |
| CD30 |
| 金属硫蛋白-III |
| 介白素4受体 |
| γ-干扰素可诱导的蛋白ip-30前体 |
| 干扰素-α/β受体α链前体 |
| 早期生长反应蛋白1 |
| 介白素-13受体mRNA，完全cds |
| 蛋白酶抑制剂12(PI12；neuroserpin) |
| 丝氨酸/苏氨酸蛋白激酶KKIALRE |
| 磷酸化酶激酶(Phosphorylase kinase)，β |
| 丝氨酸/苏氨酸激酶9 |
| 丝氨酸/苏氨酸激酶10 |
| 蛋白激酶丝***原激活的8(Protein kinase mitogen-activated 8)(MAP激酶) |
| 粘着斑激酶(focal adhesion kinase，FAK)mRNA，完全cds |
| 人的激活p21cdc42Hs激酶(ack)mRNA，完全cds |
| 人整合素链接激酶(integrin-linked kinase，ILK)mRNA，完全cds |
| 人鸟苷酸激酶(GUK1)mRNA，完全cds |
| BMK1α激酶mRNA，完全cds |
| 含黄素的单加氧酶5(FMO5)mRNA |
| 丙酮酸激酶，肝脏 |
| 转录延长因子S-II，hS-II-T |
| 氧化氮合酶3(内皮细胞) |
| Bcl2，p53结合蛋白Bbp/53BP2(BBP/53BP2)mRNA， |
| 调聚(telomeric)DNA序列 |
| 类stat蛋白(Fe65)mRNA，完全cds |
| IL-5受体a |
| EGF |
| FGF2 |
| 介白素2受体γ链 |
| C-C趋化因子受体类型2 |
| 鸟苷酸结合蛋白1，干扰素可诱导，67kD |
| 线粒体加工肽酶β-亚单位 |
| syntaxin 8 |
| 细胞因子抑制抗炎药物结合蛋白1(p38MAP激酶) |
| 蛋白酪氨酸激酶6 |
| 支链α-酮酸脱氢酶激酶 |
| 丝氨酸/苏氨酸激酶2 |
| 蛋白激酶，丝***原激活的4(MAP激酶4；p63)(PRKM4)mRNA |
| 酪氨酸-蛋白激酶SYK |
| 人推定(putative)丝氨酸/苏氨酸蛋白激酶PRK(prk)mRNA，完全cds |
| 腺苷酸激酶同功酶1 |
| 造血细胞激酶 |
| 甘油激酶 |
| 酪氨酸-蛋白激酶CSK |
| 一般转录因子IIB |
| 介白素6信号转导(gp130，制瘤素M受体) |
| 半胱天冬酶-8(凋亡半胱氨酸蛋白酶mch5(mach-α-1)) |
| 肿瘤蛋白p53 |
| 转型生长因子，β受体III(β聚糖，3 |
| IFN-g |
| 转型生长因子，β3 |
| TGF-β蛋白超家族，完全(complete) |
| 纤维母细胞生长因子7(角质化细胞生长因子) |
| 可诱导的小分子细胞因子A4(与鼠Mip-1b同源) |
| 肝细胞生长因子激活子inh |
| 泛激素羧基-末端水解酶同功酶11 |
| 丝氨酸/苏氨酸激酶11(色素沉着息肉综合症 |
| 周期素依赖性激酶(Cyclin-dependent kinase)抑制剂3(CDK2-相关的双特异性磷酸酶) |
| 丙酮酸脱氢酶激酶，同功酶3 |
| 肉毒硷棕榈酰基转移酶I，肝脏 |
| 蛋白激酶丝***原激活7(MAP激酶) |
| 人蛋白酪氨酸激酶mRNA，完全cds |
| 蛋白酪氨酸激酶7 |
| 淋巴细胞特定蛋白酪氨酸激酶 |
| 核糖体蛋白s6激酶 |
| 类src激酶(slk)mRNA，完全cds |
| 核苷二磷酸激酶a |
| 周期素依赖性激脢2 |
| STAT-1α/β |
| 血管生长素(Angiopoietin)-1 |
| 磷脂酶C |
| STAT2(信号转导和转录激活因子2) |
| c-src酪氨酸激酶 |
| IL-15 |
| TGFb受体相关蛋白1 |
| 膜联蛋白(Annexin)V(脂皮素V；内联蛋白II) |
| 干扰素调节因子5 |
| 干扰素-γ受体α链前体 |
| 转型生长因子，β受体II(70-80kD) |
| 现代人凋亡蛋白酶激活因子1(Apaf-1) |
| 泛激素交联酶E2B(RAD6同系物) |
| MAP/ERK激酶激酶3 |
| 磷酸化酶激酶，α2(肝脏)，肝糖储积症IX |
| 丝氨酸/苏氨酸激酶4 |
| 葡萄糖胺-6-磷酸盐脱氨酶 |
| 甲羟戊酸激酶(Mevalonate kinase) |
| 葡萄糖激酶(己糖激酶4，年青成年型糖尿病(maturity onset diabetes of the young)2) |
| 脱氧胞啶激酶 |
| 尿激酶类型胞浆素原激活因子 |
| 人线粒体肌酸激酶(CKMT)基因，完全cds |
| 胆碱激酶 |
| 人磷脂酰肌-4-磷酸5-激酶(PIPK)类型IImRNA的53K异型，完全cds |
| 白细胞粘着蛋白β亚单位 |
| c-tos |
| 磷酸烯醇丙酮酸羧基激酶(phosphoenolpyruvate carboxykinase) |
| 凋亡半胱氨酸蛋白酶mch4 |
| 单核细胞趋化蛋白1 |
| 转录因子AP-4(激活强化因子-结合蛋白 |
| 介白素-1受体，类型1前体 |
| 半胱天冬蛋白酶-10(人凋亡半胱氨酸蛋白酶mch4) |
| 人激酶(TTK)mRNA，完全cds |
| β-2肾上腺素能受体 |
| ***磺基转移酶(ste) |
| 信号转导和转录激活因子6，由介白素-4诱导 |
| 蛋白激酶clk1 |
| 介白素-8前体 |
| 现代人FAST激酶mRNA |
| 干扰素-γ受体α链前体 |
| 类胰岛素生长因子I受体前体 |
| 线粒体转录终止因子 |
| 信号转导和转录激活因子3(急性-ph |
| 现代人蛋白激酶CK1mRNA |
| 经MAP激酶激活的蛋白激酶 |
| 蛋白激酶clk3 |
| INF-b |
| 一般转录因子IIB |
| Sis，PDGF B链 |
| β-肌动蛋白 |
| 谷胱甘肽(Glutathione)S-转移酶M1 |
| IL-1b |
| MAP/ERK激酶激酶3 |
| INF-b |
| EGR-1 |
| 谷胱甘肽S-转移酶12(微粒体) |
用于识别GM-020的标准检测***将Hep G2细胞系作为测试细胞系。当将有或无GM-020的培养Hep G2细胞系的表示图案进行比较时，表4中所列出的该组基因可显著不同。
表4
| 基因 |
| 介白素10受体 |
| IL-16 |
| EGF |
| 淋巴细胞毒素α(先前的肿瘤坏死因子β) |
| 干扰素调节因子5 |
| 纤维母细胞生长因子7(角质化细胞生长因子) |
| 蛋白体26S亚单位，ATPase，3 |
| calpamodulin mRNA |
| 泛激素羧基-末端水解酶同功酶L1 |
| 己糖激酶1 |
| 人磷脂酰肌醇-4-磷酸盐5-激酶(PIPK)类型II mRNA的53K异型，完全cds |
| 线粒体转录末端因子 |
| STAT-1α/β |
| 尿激酶-类型胞浆素原激活因子 |
| 人腺苷酸激酶2(adk2)mRNA，完全cds |
| 蛋白激酶C、α |
| 原致癌基因酪氨酸-蛋白激酶FES/FPS |
| 人线粒体肌酸激酶(CKMT)基因，完全cds |
| 蛋白酪氨酸激酶6 |
| 丝氨酸/苏氨酸激酶9 |
| IkB激酶β亚单位mRNA |
| 半胱天冬酶-8(凋亡半胱氨酸蛋白酶mch5(mach-α-1)) |
| Bcl2、p53结合蛋白Bbp/53BP2(BBP/53BP2)mRNA， |
| 生长相关蛋白43 |
| 蛋白激酶clk3 |
| 肿瘤坏死因子可诱导的蛋白TSG-6前体 |
| 类胰岛素生长因子I受体前体 |
| 单核细胞趋化蛋白1 |
| 白细胞粘着蛋白β亚单位 |
| Sis，PDGF B链 |
| Humig mRNA |
| CD27L受体前体 |
| 视黄酸(retinoic acid)和干扰素可诱导的58K蛋白RI |
| IRF-1 |
本发明提供一种用于治疗受验者中的肥胖及其并发症的方法，该方法包括对该受验者投药一种包含GM-020的组合物。
在本发明中惊讶地发现：即使受验者摄入高能量的食物，株GM-020也具有抑制该受验者体重增加的能力，且能抑制体重。在根据本发明的一实施例中，经株GM-020来治疗的被喂以可导致肥胖的高能量的食物的ICR小鼠，与未接受治疗的对照组相比，其可保持体重无任何增加。
在本发明中也发现：株GM-020有效于调节胆固醇与脂蛋白的比率。在根据本发明的一实施例中，在喂以可导致高胆固醇血症的富含胆固醇的食物的肥胖小鼠和仓鼠中，经株GM-020治疗，可降低其血清和肝脏中总胆固醇的浓度。也可降低低密度的脂蛋白-胆固醇(LDL-C)的血清浓度。此外，可降低血清中LDL-C与高密度的脂蛋白胆固醇(HDL-C)(LDL-C/HDL-C)的比率。总结言的，株GM-020在治疗高胆固醇血症和降低动脉粥样硬化与冠心病的发病率方面是有效的。亦即，可将株GM-020用于制备一种用来治疗肥胖及其并发症(诸如高胆固醇血症)和降低动脉粥样硬化与冠心病的发病率的组合物。
本发明也提供一种用于治疗受验者中的肥胖及其并发症的方法，该方法包括对受验者投药一种包含微生物鼠李糖乳杆菌GM-020和黑木耳株的组合物；其中该并发症优选是选自由高胆固醇血症、动脉粥样硬化、冠心病、脂肪肝、和糖尿病组成的组。
在本发明中发现：与黑木耳(黑木耳)组合的株GM-020在治疗肥胖时，相比于单以黑木耳或株GM-020来进行治疗时，其可提供惊人的效果。
黑木耳，通称木耳、树耳(tree ear)等，为胶质无味可食性真菌。其与种植于亚洲的黑木耳密切相关，且已经被消费了很长时间。发现黑木耳可在春季和秋季两季中野生于针叶树上且有时在落叶树木上。通常将黑木耳干燥以备食用。当食用经干燥的黑木耳时，可食用的纤维在吸水之后可延伸约8倍到10倍。消费者可感觉到已饱而少吃。另外，据报导，黑木耳中的多聚糖具有降低兔子中的总胆固醇血清浓度的效果。
在根据本发明的一实施例中，经黑木耳和GM-020的组合来治疗的肥胖动物模型体重可被减小；相反，单单黑木耳或GM-020的投药仅能抑制体重的增加。
在本发明中发现：相比于对照组，黑木耳和株GM-020的组合具有降低该动物模型的血清和肝脏中总胆固醇和甘油三酯的浓度的能力。总结言的，可将黑木耳与株GM-020的组合用于制备一种用来治疗高胆固醇血症、脂肪肝、糖尿病和降低动脉粥样硬化和冠心病的发病率的组合物。
在根据本发明的一实施例中，治疗肥胖和高胆固醇血症和降低动脉粥样硬化和冠心病的发病率的效果与黑木耳的剂量成正比。正常地，成年人的黑木耳的每日建议剂量(1X)为6gx 0.0026x表面积。在本发明的一实施例中，较1X的黑木耳，10X的黑木耳具有更好的效果。
根据本发明，仅株GM-020、和GM-020与黑木耳的组合不会对肝脏和肾脏造成伤害。在动物模型中，当监控谷氨酸草酰乙酸转氨酶(glutamicoxaloacetic transaminase，GOT)、谷丙转氨酶(glutamic pyruvictransaminase，GPT)、尿酸和肌酸酐(creatinine)的量时，肝脏功能是正常的，此可表明投药仅仅株GM-020、或株GM-020与黑木耳的组合是一种治疗肥胖及其并发症的安全方式。在本发明中也发现：在经GM-020与黑木耳的组合进行治疗后，血清中的甘油三酯得以降低。
仅为说明的目的给出了以下实施例，且不欲限制本发明的范围。
实施例
实施例1：鼠李糖乳杆菌GM-020的分离
将通过内窥镜(endoscope)取出的人的一片胃组织培养于2mL的乳杆菌MRS培养基(
0881)中。将包含该组织的培养基平放于乳杆菌的选择性琼脂上且在37℃下培育一天。选择生长于该培养板上的单个集落并使其接受革兰氏染色。接着选择革兰氏阳氏细菌。克隆一个株，该株称为鼠李糖乳杆菌GM-020。
实施例2GM-020的细胞壁蛋白萃取和分析
收获于MRS培养基(
)中的嗜温乳杆菌的24小时大的细胞，将其于含0.1M CaCl2的0.05M Tris-HCl(pH7.5)中冲洗两次，且再次悬浮于A600为10.0的1ml相同的缓冲剂中。在8,000×g下进行离心作用5分钟后，通过含0.01M EDTA、0.01M NaCl，和2％(wt/vol)SDS的1.0ml的萃取缓冲剂(pH 8.0)，可从这些球粒(pellet)来萃取细胞壁蛋白。在室温下，将悬浮液储存60分钟，在100℃下加热5分钟并在4℃下以11,600×g进行离心作用10分钟。通过12％SDS-PAGE来分析上层清液且以Comassie蓝色来对其染色。
实施例3GM-020的2-D总蛋白电泳
连同0.5mL溶解缓冲剂C(7M尿素，4％CHAPS，2M硫脲，40mM三羟基氨基甲烷，0.5％IPG缓冲剂和5mM TBP)和100L玻璃珠，添加10mg GM-020。接着使溶液接受超声波降解处理并以10,000rpm进行离心作用30分钟。可通过Bio-rad PlusOneTM蛋白检定来测定总蛋白，并接着使其接受pH为3至10IEF的2-D电泳。通过10％凝胶并以40mA/凝胶来执行4小时的如表5中所设计的电泳。接着通过10％甲醇和7％乙酸来将凝胶固定30分钟。固定之后，通过sypro ruby染剂来对该凝胶进行着色5小时，且接着以10％甲醇和7％乙酸来对该凝胶进行脱色6小时。结果如图3所示。
表5
| 30V | 12hr |
| 100V | 0:10hr |
| 250V | 0:10hr |
| 500V | 0:10hr |
| 1000V | 0:30hr |
| 4000V | 0:30hr |
| 6000V | 60KVhr |
实施例4用于识别GM-020的标准化检测***
用于标准化检测***的GM-020的制备：在37℃乳杆菌MRS培养基(
0881)中，将株GM-020的细胞培育到静止相。在3,000g下进行离心作用15分钟后，通过2mL和1mL的1X的PBS(磷酸缓冲盐水，pH7.2)来冲洗该培养物，并接着将其悬浮于1mL的PBS(1X)中，其中细胞浓度被调节到1×109CFU/mL。将这些培养物储存在-20℃下。
刺激：通过添加新鲜的介质并培养16小时，可更新(refresh)Hep G2细胞。随后，将这些细胞分成两组，且一组用于通过乳酸菌进行培养而另一组用于不通过乳酸菌进行培养。当细胞浓度达到1×107/10mL时，通过1×107GM-020或不通过1×107GM-020来刺激细胞24小时。在刺激之后，收集这些细胞，通过PBS冲洗两次，并将其用于RNA分离。
RNA分离和标记(labelling)：根据生产商的说明通过使用Trizol试剂(Life
Gaithersburg，Md.)，从细胞萃取RNA。将8L RNA(10μg)与2L低聚dT(12-18mer，0.1g/L)充分混合并在70℃下保持10分钟，且接着通过冰来冷却2分钟。在黑暗中，将RNA与反转录标记混合液和3L Cy5-dUTP(1mM)、2L SuperScriptII(200U/L)和RNasin(1L)混合。在42℃下将混合物培育2小时以用于反转录，且通过添加1.5L的20mM EDTA来终止反应。标记之后，通过NaOH处理来移除RNA，并通过HCl来将其中和。通过STRATAGENETMPCR纯化试剂盒来迅速地纯化cDNA。
微阵列制造：通过聚合酶链反应扩增所选择的数以百计的基因，并通过260nm分光光度计(spectrophotometry)将其量化。在50％的二甲基亚砜中，将所有经纯化的PCR产物调节到0.1μg/μL的浓度，且以双份(in duplicate)打点(spot)于UltraGAPSTMTM涂布载玻片(slide)(
Inc.，Corning，N.Y.)上。印刷(printing)之后，这些微阵列为在室温下被储存于一干燥器中的载玻片容器中的在300mJoulesand下的紫外线交联。表3中列出了这些基因。
微阵列杂交：在100℃下，使以荧光标记的cDNA于杂交溶液(5xSSC，0.1％SDS和25％甲酰胺)中变性(denature)5分钟，冷却到周围温度并将其存放于载玻片上。在42℃下，进行杂交18小时。杂交之后，依次在低严格性(low-stringency)(1xSSC和0.1％SDS)、中严格性(0.1xSSC和0.1％SDS)、高严格性(0.1x SSC)缓冲剂中冲洗这些载玻片，且最后通过经压缩的N2来将其干燥。
信号检测和资料分析：为每个载玻片以相同的雷射功率和光电倍增器灵敏度级(sensitivity level)，在
4000B扫描仪(Axon
Inc.)上立即扫描经N2干燥的载玻片。可获得原始的荧光资料(10-nm分辨率)，且在Microsoft ExcelTM中来执行随后的处理和资料可视化。为比较独立杂交实验的结果，局部背景信号(local backgroundsignal)被从各个独立点的杂交信号中减去，并接着除以管家基因β-肌动蛋白(housekeeping gene β-actin)。以双份的平均值来代表各个基因的最后表达。接着可获得经GM-020以及未经GM-020培养的Hep G2细胞的基因表达图谱(expression profile)。在经GM-020培养的Hep G2中选择一群相比于未经该细菌培养的Hep G2被向上或向下调整超过2倍(fold)的基因。结果如表4中所示。
实施例5用于治疗肥胖的GM-020
动物模型：雄性ICR小鼠可购自台湾实验动物中心，并在25±1℃的温度和60±5％的湿度下，单独在光线中饲养12小时和在黑暗中饲养12小时。充分补充食物和水。将这些小鼠分为两组。一组为正常对照组而另一组为高能量组。对该正常对照组喂以正常饮食且对该高能量组喂以含48％干饲料、8％玉米油和44％浓缩牛奶的高能量饮食。每周量测小鼠的体重。根据治疗将高能量组进一步划分为如下所列出的组：(a)1X的黑木耳，(b)与GM-020组合的1X的黑木耳，(c)GM-020，(d)10X的黑木耳，(e)与GM-020组合的10X的黑木耳，(f)经生理盐水治疗的阴性对照，和(g)经PPA治疗的阳性对照。表6中显示了在喂以高能量饮食之前与之后间的体重的差异，其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表1X的黑木耳；d代表10X的黑木耳；e代表GM-020；f代表与GM-020组合的1X的黑木耳；且g代表与GM-020组合的10X的黑木耳。
表6
| 组 | 重量(％) |
| 正常对照 | 12.25±1.80 |
| 阴性对照 | 20.93±2.27 |
| 阳性对照 | 20.43±1.35 |
| 1X的黑木耳 | 22.45±1.46 |
| 10X的黑木耳 | 18.45±1.03 |
| GM-020 | 19.23±1.75 |
| 与GM-020组合的1X的黑木耳 | 21.37±1.05 |
| 与GM-020组合的10X的黑木耳 | 22.78±0.67 |
| P值 | 0.000<sup>**a，b，c，d，e，f，g</sup> |
可由Kruskal Wallis H测试来分析资料，并将正常对照组作为Dunnett测试的基线。4周之后，该高能量组的平均体重显著高于该正常对照组(p＜0.01)的平均体重。
以GM-020和/或黑木耳的治疗：对该正常对照组连续地喂以正常饮食。一天两次地施以治疗。每次PPA的剂量为4.875mg。在1X的黑木耳的膳食中，3g饮食中具有15.6mg的黑木耳，且在10X的黑木耳的膳食中，3g饮食中具有156mg的黑木耳。GM-020的剂量为109CFU/mL。
体重差异：治疗了4周后，从尾部收集血样以用于生物化学检定。通过Kruskal Wallis H测试来分析资料，并将正常对照组作为Dunnett测试的基线。结果显示于图4中。
治疗了1周后，与GM-020组合的10X的黑木耳组较该阴性对照组，体重显著减少。2周后，阳性对照组、与GM-020组合的1X的黑木耳组，和与GM-020组合的10X的黑木耳组，较该阴性对照组体重显著减少。3周后，阳性对照组、1X的黑木耳组、GM-020组、与GM-020组合的1X的黑木耳组，和与GM-020组合的10X的黑木耳组，较该阴性对照组体重显著减少。这些结果论证GM-020和黑木耳在治肥胖方面是有效的。
睾丸周围的脂质组织重量的差异：将鼠杀死，且提取睾丸周围的脂质组织并称重。通过Kruskal Wallis H测试来分析资料，且将该正常对照组的资料作为Dunnett测试的基线。结果显示于图5中。
根据图5，仅阳性对照组和与GM-020组合的10X的黑木耳组较该阴性对照组，显示了显著的减少。
肾脏周围的脂质重量的差异：将鼠杀死，且提取该肾脏周围的脂质组织并称重。以Kruskal Wallis H测试来分析资料，且将该正常对照组的资料作为Dunnett测试的基线。结果显示于图6中。
根据图6，1X的黑木耳组、10X的黑木耳组、与GM-020组合的1X的黑木耳组，和与GM-020组合的10X的黑木耳组较阴性对照组，具有显著的减少。另一方面，该阳性对照组、GM-020组、和阴性对照组展示了很小的差异。
脂肪代谢物的血清浓度：从尾部收集血样以用于生物化学检定。将血样静置于室温下1小时，且以2,500rpm进行离心作用10分钟。取上层血清用于检定。
通过TRIGLYCERIDES GPO LIQUID REAGENTTM(台湾)来检定每组的甘油三酯(TG)的浓度，并通过Autoanalyzer HitachiTM 7150来量测吸收作用。通过CHOLESTEROL LIQUID REAGENTTM(
台湾)来检定总胆固醇(CHOL)的浓度，并通过Autoanalyzer HitachiTM 7150来量测吸收作用。根据选择性地抑制方法和酶测定(
日本)来检定HDL-C和LDL-C的浓度，并通过Autoanalyzer HitachiTM 7150来量测吸收作用。
通过Kruskal Wallis H测试来分析资料，并将该正常对照组的资料作为Dunnett测试的基线。结果显示于表7中：其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表1X的黑木耳；d代表10X的黑木耳；e代表GM-020；f代表与GM-020组合的1X的黑木耳；且g代表与GM-020组合的10X的黑木耳。
表7
| 组 | CHOL | TG | HDL | LDL |
| 阴性对照 | 232.00±16.88 | 86.60±22.40 | 126.39±7.37 | 11.21±1.40 |
| 正常对照 | 135.80±6.67 | 120.00±20.35 | 86.90±3.14 | 4.22±0.56 |
| 阳性对照 | 219.08±11.22 | 75.83±9.93 | 123.19±4.20 | 10.04±0.93 |
| 1X的黑木耳 | 182.50±8.24 | 82.08±7.32 | 100.57±3.58 | 12.39±1.03 |
| 10X的黑木耳 | 176.83±9.84 | 63.92±4.62 | 93.51±6.02 | 9.74±1.07 |
| GM-020 | 204.75±8.90 | 96.56±10.20 | 121.64±8.47 | 14.04±3.10 |
| 与GM-020组合的1X的黑木耳 | 190.08±4.85 | 55.75±4.38 | 105.38±3.10 | 10.83±1.51 |
| 与GM-020组合的10X的黑木耳 | 164.20±8.64 | 57.30±4.61 | 97.93±5.42 | 8.04±0.94 |
| P值 | 0.000<sup>**a，c，d，f，g</sup> | 0.000 | 0.000<sup>**a，c，d，f，g</sup> | 0.014<sup>*a</sup> |
与GM-020组合的1X的黑木耳组和与GM-020组合的10X的黑木耳组较该阴性对照组，具有较低的甘油三酯的血清浓度。另一方面，1X的黑木耳组、10X的黑木耳组和GM-020组较该阴性对照组，具有很小的差异。此外，1X的黑木耳组、10X的黑木耳组、与GM-020组合的1X的黑木耳组，和与GM-020组合的10X的黑木耳组具有较低的总胆固醇和HDL-C的血清浓度。就LDL-C的浓度而言，除了该正常对照组的外的各组显示了很小的差异。
脂肪代谢物的肝脏浓度；杀死鼠，且取右叶肝脏。根据已知的方法来萃取脂肪。
就各个试样而言，可如上所述来检定甘油三酯(TG)和总胆固醇(CHOL)的浓度。
通过Kruskal Wallis H测试来分析资料，且将正常对照组的资料作为Dunnett测试的基线。结果显示于表8中：其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；c代表1X的黑木耳；d代表10X的黑木耳；e代表GM-020；f代表与GM-020组合的1X的黑木耳；且g代表与GM-020组合的10X的黑木耳。
表8
| 组 | CHOL | TG |
| 阴性对照 | 25.75±2.17 | 135.00±11.92 |
| 正常对照 | 21.80±0.58 | 65.60±6.56 |
| 阳性对照 | 26.75±1.48 | 103.58±11.41 |
| 1X的黑木耳 | 20.75±0.85 | 85.50±3.76 |
| 10X的黑木耳 | 22.00±0.72 | 84.83±8.56 |
| GM-020 | 19.44±0.85 | 88.56±6.41 |
| 与GM-020组合的1X的黑木耳 | 21.25±0.70 | 83.25±6.27 |
| 与GM-020组合的10X的黑木耳 | 20.90±0.81 | 77.50±7.82 |
| P值 | 0.000<sup>**c，e，f，g</sup> | 0.004<sup>*a，c，d，e，f，g</sup> |
1X的黑木耳组、GM-020组、与GM-020组合的1X的黑木耳、和与GM-020组合的10X的黑木耳组中的每一个皆具有较低的总胆固醇的血清浓度。就甘油三酯而言，1X的黑木耳组，10X的黑木耳组、与GM-020组合的1X的黑木耳组，和与GM-020组合的10X的黑木耳组中的每一个都显著减少。
肝脏和肾脏功能分析：以如上所述的方法来处理血样。
就各个样本而言，可根据Jaffe反应的方法(
日本)来检定肌酸酐的浓度，并通过Autoanalyzer HitachiTM 7150来量测吸收作用。通过GOT(ASAT)IFCC modTM(
德国)来检定GOT的浓度，且通过Autoanalyzer HitachiTM 7150来量测吸收作用。通过GPT(ALAT)IFCCmodTM(
德国)来检定GPT的浓度，且通过AutoanalyzerHitachiTM 7150来量测吸收作用。根据尿酸酶-过氧化物酶方法(日本)来检定尿酸(UA)的浓度，且通过Autoanalyzer HitachiTM7150来量测吸收作用。
通过Kruskal Wallis H测试来分析资料，且将该正常对照组的资料作为Dunnett测试的基线。结果显示于表9中：其中**代表p＜0.01；a代表阴性对照；b代表阳性对照；；c代表1X的黑木耳；d代表10X的黑木耳；e代表GM-020；f代表与GM-020组合的1X的黑木耳；且g代表与GM-020组合的10X的黑木耳。
表9
| 组 | GOT | GPT | Creatinine | UA |
| 正常对照组 | 134.00±23.11 | 72.67±6.98 | 0.52±0.04 | 2.66±0.92 |
| 阴性对照 | 79.20±6.22 | 49.00±9.18 | 0.52±0.02 | 3.90±1.33 |
| 阳性对照 | 117.50±12.95 | 47.00±6.17 | 0.56±0.03 | 2.42±0.50 |
| 1X的黑木耳 | 107.00±14.77 | 37.33±2.77 | 0.47±0.02 | 5.20±0.91 |
| 10X的黑木耳 | 120.00±15.78 | 57.42±5.68 | 0.46±0.02 | 2.88±0.57 |
| GM-020 | 109.67±17.30 | 36.22±3.05 | 0.47±0.03 | 1.96±0.40 |
| 与GM-020组合的1X的黑木耳 | 150.00±21.71 | 44.91±3.93 | 0.45±0.02 | 2.12±0.48 |
| 与GM-020组合的10X的黑木耳 | 76.40±13.5 | 37.50±3.95 | 0.39±0.03 | 2.10±0.36 |
| P值 | 0.072 | 0.002<sup>**b，c，e，f，g</sup> | 0.002<sup>**g</sup> | 0.006 |
这些组中的结果的差异并不显著。表明在经GM-020和/或黑木耳治疗之后，肝脏和肾脏功能的指数并未受到影响。
实施例6：用于治疗高胆固醇血症的GM-020
动物模型：雄性仓鼠系购自台湾实验动物中心，并于25±1℃的温度和60±5％的湿度下，单独在光线中饲养12小时并在黑暗中饲养12小时。充分补充食物和水。将这些鼠分为两组：一组为正常对照(NC)组且另一组为富含胆固醇的饮食的组。对该正常对照组喂以正常饮食且对该富含胆固醇的饮食的组喂以含24％蛋白、14％脂肪、2％胆固醇、48％碳水化合物、6％纤维素和6％矿物质与维生素混合物的富含2％胆固醇的饮食。
通过GM-020的治疗：对正常对照组连续地喂以正常饮食。一天两次地施以治疗。依照治疗将富含胆固醇的饮食的组进一步划分为如下所列出的组：(a)加氏乳杆菌，(b)GM-020，(c)生孢乳杆菌(L.sporogenes)，和(d)经生理盐水处理的阴性对照(Control)。每次的剂量为109CFU/mL。
脂肪代谢物的血清浓度：在治疗之前和治疗之后，从眶周的静脉收集血样以用于生物化学检定。将血样静置于室温下1小时，且以2,500rpm进行离心作用10分钟。取上层血清以用于检定。
就各个样本而言，可如上所述来检定总胆固醇(CHOL)、HDL-C、LDL-C、和甘油三酯(TG)的浓度。通过Kruskal Wallis H测试来分析资料，且将该正常对照组的资料作为Dunnett测试的基线。表10中显示了在喂以富含胆固醇的饮食之前与之后间的脂肪含量的差异，其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01；a代表阴性对照；b代表加氏乳杆菌；c代表GM-020；d代表生孢乳杆菌。
表10：
| HDL-C_0 | HDL-C_4 | LDL-C_0 | LDL-C_4 | CHOL_0 | CHOL_4 | TG_0 | TG_4 | |
| NC | 117.6±10.8 | 119.5±11.5 | 105.4±8.4 | 243.6±25.2 | 398.8±31.2 | 485.5±70.4 | 421.0±59.9 | 365.8±65.9 |
| Control | 70.5±3.6 | 64.9±5.0 | 23.5±1.3 | 20.8±1.8 | 104.0±4.1 | 96.8±5.3 | 224.0±23.1 | 180.7±14.8 |
| 加氏乳杆菌 | 141.3±10.5 | 103.1±3.8 | 179.4±21.2 | 211.2±23.9 | 531.6±32.9 | 653.0±45.1 | 585.8±103.0 | 822.6±59.1 |
| GM-020 | 108.8±14.2 | 118.7±8.4 | 106.9±9.0 | 136.5±19.8 | 412.0±63.0 | 420.4±53.0 | 483.3±67.5 | 760.5±98.7 |
| 生孢乳杆菌 | 104.9±23.7 | 82.8±3.0 | 127.1±6.6 | 202.3±11.6 | 414.5±18.1 | 541.5±51.9 | 439.5±42.0 | 687.8±131.0 |
| P值 | 0.008<sup>a**</sup> | 0.000<sup>d***</sup> | 0.000<sup>a，b***</sup> | 0.000<sup>a，c***</sup> | 0.000<sup>a***</sup> | 0.000<sup>a***</sup> | 0.008<sup>a**</sup> | 0.000<sup>b，c，d***</sup> |
根据该结果，在喂以富含胆固醇的饮食4周以后，该富含胆固醇的饮食的组较正常对照组，展示了显著的CHOL、HDL-C、LDL-C和TG增加，且这些富含胆固醇的饮食的子组在彼此之间展示了很小的差异。
就TG而言，在治疗了4周之后，所有这些富含胆固醇的饮食的子组展示了较该正常对照组显著较大的TG。
就CHOL而言，在治疗了4周之后，加氏乳杆菌组、生孢乳杆菌组和阴性对照组展示了较该正常对照组显著较大的CHOL。另一方面，GM-020组展示了较该正常对照组很小的增加。图7中展示了在(治疗之前CHOL_0)与治疗之后(CHOL_4)之间的差异。表明了GM-020具有降低总胆固醇的血清浓度的能力。
就HDL-C而言，在治疗了4周之后，生孢乳杆菌组展示了较该正常对照组显著较低的HDL-C。然而，加氏乳杆菌组、GM-020组和阴性对照组展示了很小的差异。
就LDL-C而言，图8中显示了血清浓度。GM-020组展示了较该正常对照组(p＜0.1)显著减少的LDL-C。此外，在治疗了4周之后，加氏乳杆菌组和生孢乳杆菌组展示了较该正常对照组显著(p＜0.05)较低的LDL-C(参见图9)。表明了GM-020具有降低总胆固醇的血清浓度的能力。
就LDL-C/HDL/C而言，表11和图10中展示了该比率，其中*代表p＜0.1；**代表p＜0.05；***代表p＜0.01；a代表阴性对照；b代表加氏乳杆菌；c代表GM-020；d代表生孢乳杆菌。可通过Kruskal Wallis H测试来分析资料，且将该正常对照组的资料作为Dunnett测试的基线。
表11
| LDL-C/HDL-C_0 | LDL-C/HDL-C_4 | |
| NC | 0.98±0.07 | 2.13±0.47 |
| Control | 0.33±0.02 | 0.32±0.01 |
| 加氏乳杆菌 | 1.27±0.13 | 2.08±0.27 |
| GM-020 | 0.90±0.13 | 1.20±0.27 |
| 生孢乳杆菌 | 1.46±0.42 | 2.44±0.14 |
| P值 | 0.003<sup>a**</sup> | 0.000<sup>a，c***</sup> |
GM-020组较该正常对照组(p＜0.001)，展示了显著的降低。表明了GM-020具有降低LDL-C/HDL-C的能力。
虽然已说明且描述了本发明的实施例，但是所属技术领域的技术人员可作各种修改和改良。并不意欲将本发明限制于如所说明的具体实施方式，且所有不背离本发明的精神和范围的修改都属于如随附的权利要求中所界定的范围内。
Claims (8)
1.一株经分离的微生物，鼠李糖乳杆菌(Lactobacillusrhamnosus)GM-020，其以保藏编号CCTCC M 203098保藏于中国典型培养物保藏中心。
2.一种包含根据权利要求1所述的微生物的组合物。
3.鼠李糖乳杆菌菌株GM-020在制备用于治疗肥胖及其并发症的药物中的应用，其中鼠李糖乳杆菌菌株GM-020以保藏编号CCTCC M203098保藏于中国典型培养物保藏中心。
4.根据权利要求3所述的应用，其中所述药物进一步包括黑木耳。
5.根据权利要求3所述的应用，其中所述并发症选自由高胆固醇血症、动脉粥样硬化和冠心病所组成的组。
6.鼠李糖乳杆菌菌株GM-020及黑木耳在制备用于治疗肥胖及其并发症的药物中的应用，其中鼠李糖乳杆菌菌株GM-020以保藏编号CCTCC M 203098保藏于中国典型培养物保藏中心。
7.根据权利要求6所述的应用，其中所述并发症选自由高胆固醇血症、动脉粥样硬化、冠心病、脂肪肝、和糖尿病所组成的组。
8.根据权利要求6所述的应用，其中所述并发症选自由高胆固醇血症、动脉粥样硬化和冠心病所组成的组。
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| CN104106375B (zh) * | 2014-07-01 | 2015-12-02 | 云南大学 | 一株高温型黑木耳菌株 |
| EP3202891B1 (en) * | 2014-09-30 | 2021-07-28 | Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine | Uses of bacteroides in treatment or prevention of obesity or diabetes |
| CN114376235B (zh) * | 2022-01-26 | 2024-04-09 | 广州美春堂医药科技有限公司 | 一种有助于控制体内脂肪的减肥益生菌和益生元组合物及其制备方法 |
-
2004
- 2004-03-19 CN CNB2004100301698A patent/CN100396770C/zh not_active Expired - Lifetime
Non-Patent Citations (2)
| Title |
|---|
| Effect of 8 week intake of probiotic milk products on risk factors for cardiovascular diseases.. Agerholm Larsen, et al.Eur. J. Clin. Nutr.,Vol.54 No.4. 2000 |
| Effect of 8 week intake of probiotic milk products on risk factors for cardiovascular diseases.. Agerholm Larsen, et al.Eur. J. Clin. Nutr.,Vol.54 No.4. 2000 * |
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