CN101702881A - 选择可降低动脉粥样硬化的乳酸杆菌的用途 - Google Patents
选择可降低动脉粥样硬化的乳酸杆菌的用途 Download PDFInfo
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- CN101702881A CN101702881A CN200880011696A CN200880011696A CN101702881A CN 101702881 A CN101702881 A CN 101702881A CN 200880011696 A CN200880011696 A CN 200880011696A CN 200880011696 A CN200880011696 A CN 200880011696A CN 101702881 A CN101702881 A CN 101702881A
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- lactic acid
- acid bacillus
- bacillus mycopremna
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Abstract
本发明提供了一种乳酸杆菌菌株，所述乳酸杆菌菌株被选择用于提高BSH活性和因而降低血清LDL胆固醇、以及同时降低前炎性细胞因子TNF-α水平的能力，和用于预防和/或治疗动脉粥样硬化和其他心血管疾病，以及选择这样的菌株的方法、和含有所述菌株的产品。
Description
发明领域
本发明在此提供了乳酸杆菌菌株，所述乳酸杆菌菌株被选择用于提高BSH活性和因而降低血清LDL胆固醇、以及同时降低前炎性细胞因子TNF-α水平的能力，和用于预防和/或治疗动脉粥样硬化和其他心血管疾病，以及选择这样的菌株的方法、和含有所述菌株的产品。
发明背景
益生菌
益生菌已经显示了具有有益的健康效果(Gorbach，S.L.2000.Probiotics and gastrointestinal health.Am.J.Gastroenterol.95：S2-S4)。许多种不同的活性已归属于益生菌；然而，实现这些效果的机制是了解很少的。效果包括增强的先天和获得性免疫(Gill，H.S.，K.J.Rutherfurd，J.Prasad，and P.K Gopal.2000.Enhancement of naturaland acquired immunity by Lactobacillus rhamnosus(HN001)，Lactobacillus acidophilus(HN017)and Bifidobacterium lactis(HN019).Br.J.Nutr.83：167-176)、提高的抗炎性细胞因子产生(IL-10)(Pessi，T.，Y.Sutas，M.Hurme，and E.Isolauri.2000.Interleukin-10generationin atopic children following oral Lactobacillus rhamnosus GG.Clin.Exp.Allergy 30：1804-1808)和降低的肠道通透性(Madsen，K.，A.Cornish，P.Soper，C.McKaigney，H.Jijon，C.Yachimec，J.Doyle，L.Jewell，and C.De Simone.2001.Probiotic bacteria enhance marine andhuman intestinal epithelial barrier function.Gastroenterology121：580-591)。已经特别好地研究了动物和人类中乳酸杆菌属的各种菌株。它们在预防和治疗旅行者腹泻(Marteau，P.R.，M.de Vrese，C.J.Cellier，and J.Schrezenmeir.2001.Protection from gastrointestinaldiseases with the use of probiotics.Am.J.Clin.Nutr.73：430S-436S)、复发性的难辨梭状芽孢杆菌感染(Gorbach，S.L.1987.Bacterialdiarrhoea and its treatment.Lancet ii：1378-1382)、轮状病毒(Szajewska，H.，M.Kotowska，J.Z.Mrukowicz，M.Armanska，and W.Mikolajczyk.2001.Efficacy ofLactobacillus GG(L.GG)in preventionofnosocomial diarrhea in infants.J.Pediatr.138：361-365)以及螺杆菌感染(Mukai，T.，T.Asasaka，E.Sato，K.Mori，M.Matsumoto，and HOhori.2002.Inhibition of binding of Helicobacter pylori to theglycolipid receptors by probiotic Lactobacillus reuteri.FEMS Immunol.Med.Microbiol.32：105-110)方面可能是有效的。分离自小鼠肠道的路氏乳酸杆菌(L.Reuteri)抑制IL-10转基因敲除小鼠中结肠炎的发作(Madsen，K.L.，J.S.Doyle，L.D.Jewell，M.M.Tavernini，and R.N.Fedorak.1999.Lactobacillus species prevents colitis in interleukin10 gene-deficient mice.Gastroenterology 116：1107-1114)。使用益生菌的混合物的临床试验显示了慢性肠炎方面的显著改善(Gionchetti，P.，F.Rizzello，A.Venturi，P.Brigidi，D.Matteuzzi，G.Bazzocchi，G.Poggioli，M.Miglioli，and M.Campieri.2000.Oral bacteriotherapy asmaintenance treatment in patients with chronic pouchitis：a double-blind，placebo-controlled trial.Gastroenterology 119：305-309)。
免疫反应(Th-1/Th2/TR)
炎症是由称为细胞因子的细胞间信号蛋白介导的，细胞因子响应于抗原刺激由上皮中的巨噬细胞和树突状细胞产生。在上皮和抗原之间接触时，上皮中的抗原递呈细胞(包括树突状细胞)传送信号到初始巨噬细胞，其然后以所谓的Th-1型反应来响应，在其中前炎性细胞因子包括TNFα、IL-1、IL-6、IL-12由巨噬细胞产生。这些细胞因子随后刺激天然杀伤细胞、T细胞和其他细胞来产生干扰素γ(IFNγ)，其是炎症的关键介质。天然巨噬细胞也可以以Th-2型反应响应抗原。这种反应被IFNγ抑制。这些Th-2型细胞产生抗炎性细胞因子例如IL-4、IL-5、IL-9和IL-10。
已知IL-10抑制IFNγ的产生从而抑制免疫反应。Th-1和Th-2型细胞以及它们各自的细胞因子产生之间的平衡限定了对给定抗原的炎症反应的程度。Th-2型细胞也可以经由免疫系统刺激免疫球蛋白的产生。在存在着降低的TNFα水平时，胃肠道中的抗炎活性与增强的上皮细胞(肠壁内层完整性)相关，并因而降低胃肠病原体和毒素引起的负面效果。
T调节性(TR)细胞被视为免疫反应的组成成分。这些细胞看起来主要精密调整保护性抗微生物免疫性以最小化有害的免疫病理(Powrie F，Maloy KJ.2003.Regulating the regulators，Science 2991030-1031)。TR细胞显示了产生提高水平的抗炎性细胞因子IL-10(Smits，H.H.，A.Engering，D.van der Kleij，E.C.de Jong，K.Schipper，T.M.van Capel，B.A.J.Zaat，M.Yazdanbakhsh，E.A.Wierenga，Y.van Kooyk，and L.Kapsenberg.2005.Selective probioticbacteria induce IL-10-producing regulatory T cells in vitro bymodulating dendritic cell function through dendritic cell-specificintercellular adhesion molecule 3-grabbing nonintegrin.J Allergy ClinImmunol.115：1260-1267)。控制TR细胞的发育和活化的因子将会允许平衡朝向TR细胞活性(来治疗自体免疫疾病和增强器官移植的存活率)或远离TR细胞活性(来强化疫苗接种和肿瘤排斥)移动(Walter J.Dobrogosz.Enhancement of human health with L.reuteri，A Probiotic，Immunobiotic and Immunoprobiotic.NUTRAfoods.2005：4(2/3)15-28)。
益生菌的免疫调节效果
益生菌鼠李糖乳酸杆菌(Lactobacillus rhamnosus)菌株GG(LGG)是潜在的益生试剂，多项研究展现了LGG定殖肠道以及调节粘膜上皮和免疫反应的能力。在单相关的已知菌丛(gnotobiotic)大鼠中，LGG提高肠上皮细胞的增殖和绒毛覆盖范围(Banasaz，M.，E.Norin，R.Holma，and T.Midtvedt.2002.Increased enterocyteproduction in gnotobiotic rats mono-associated with Lactobacillusrhamnosus GG.Appl Environ Microbiol.68：3031-3034)。在口服施用之后，LGG还调节体外鼠淋巴细胞增生反应(Kirjavainen，P.V.，H.S.ElNezami，S.J.Salminen，J.T.Ahokas，and P.F.Wright.1999.Effects of orally administered viable Lactobacillus rhamnosus GG andPropionibacterium freudenreichii subsp.shermanii JS on mouselymphocyte proliferation.Clin Diagn Lab Immunol 6：799-802)，同时副干酪乳酸杆菌(L.paracasei)改变CD4+T淋巴细胞的调节性细胞因子分布(Von der Weid T.，C.Bulliard，and E.J.Schiffrin.2001.Induction by a lactic acid bacterium of a population of CD4(+)T cellswith low proliferative capacity that produce transforming growth factorbeta and interleukin-10.Clin Diagn Lab Immunol 8：695-701)。除了适应性免疫反应之外，LGG对先天性免疫反应具有效果。LGG活化核因子kappa B(NF-κB)以及人类巨噬细胞中信号转导途径的转录信号转导物和活化物(STAT)(Miettinen，M.，A.Lehtonen，I.Julkunen，and S.Matikainen.2000.Lactobacilli and Streptococci activateNF-kappa B and STAT signaling pathways in human macrophages.JImmunol 164：3733-3740)，且鼠李糖乳酸杆菌(L.rhamnosus)刺激巨噬细胞产生白细胞介素-12(IL-12)(Hessle，C，L.A.Hanson，andA.E.Wold.1999.Lactobacilli from human gastrointestinal mucosa arestrong stimulators of IL-12 production.Clin Exp Immunol 116：276-282)。LGG还刺激儿童中免疫调节细胞因子例如IL-10的产生(Pessi，T.，Y.Sutas，M.Hurme，and E.Isolauri.2000.Interleukin-10generaion in atopic children following oral Lactobacillus rhamnosusGG.Clin Exp Allergy 30：1804-1808)并且可以调节体内的前炎性反应。先天免疫的效应细胞例如巨噬细胞、树突状细胞和嗜中性细胞，是大部分炎性反应的主要驱动者(Janeway，C.A.，Jr.and R.Medzhitov.2002.Innate immune recognition.Annu Rev Immunol 20：197-216)。先天免疫指示了对抗原的先天性和适应性反应的过程是自身的还是非自身的的想法，强调了先天性免疫在控制炎症方面的作用。
美国专利申请No.20020019043涉及通过施用产生细胞因子的革兰氏阳性细菌或产生细胞因子拮抗剂的革兰氏阳性细菌菌株来治疗炎症性肠病。在特定的实施方式中，细胞因子或细胞因子拮抗剂选自IL-10、可溶性TNF-α受体或其他TNF-α拮抗剂、IL-12拮抗剂、干扰素γ拮抗剂、IL-1拮抗剂，等等。在特定的实施方式中，革兰氏阳性细菌被遗传工程化来产生细胞因子、细胞因子拮抗剂，等等。路氏乳酸杆菌(L.reuteri)的免疫调节效果
例如，路氏乳酸杆菌(L.reuteri)的免疫调节效果由Christensen所报道，显示了益生性乳酸杆菌通过调节树突状细胞(DC)的Th1/Th2/Th3/Tr1/TR促进能力发挥它们的免疫调节效果(ChristensenH.R.，H.Frokiaer，and J.J.Pestka.2002.Lactobacilli differentiallymodulate expression of cytokines and maturation surface markers inmurine dendritic cells.J.Immunol.168：171-178)。他们显示了当鼠DC暴露于不同的乳酸杆菌菌株，包括路氏乳酸杆菌菌株的共培养物时，它们以浓度依赖性方式差异性地调节细胞因子IL-6、IL-10、IL-12和TNF-α的产生，以及差异性地增量调节MHC II类和CD86表面标志物。所有乳酸杆菌增量调节表面的MHC II类和CD86标志物——DC成熟的指示。在这项研究中特别显著的是路氏乳酸杆菌(菌株12246)是弱的IL-12诱导物，但是当与约氏乳酸杆菌(L.johnsonii)或干酪乳酸杆菌(L.casei)共培养时，它差异性地抑制前炎性细胞因子信号IL-12、IL-6和TNF-α的产生，这些是由后两个物种刺激的。IL-10产生在这些条件下保持不变。这些发现产生了他们的结论“路氏乳酸杆菌可能有助于肠树突状细胞世代的环境调节，有利于针对不带有“危险信号”的抗原的耐受性，同时完整保持了针对通过危险信号如LPS所识别的病原体的应答能力”。他们还推断，路氏乳酸杆菌的某些菌株可能具有潜在的精细靶向的治疗效果，用于诱导抗炎性IL-10的同时，减量调节IL-12和TNF-α(和IL-6)的产生，因而代表了抗衡前炎性肠细胞因子环境的可选择的治疗方法。
Smits扩展了这些观察结果，并显示了路氏乳酸杆菌具有激活DC以刺激T调节性(TR)细胞产生的能力。他们使用了与人类单核细胞源性DC体外共培养的三种不同的乳酸杆菌物种。两种乳酸杆菌，人类路氏乳酸杆菌菌株(ATCC 53609)和干酪乳酸杆菌，而非植物乳酸杆菌(L.plantarum)菌株，激活了这些DC以刺激TR细胞的发育。这些TR细胞显示了产生提高水平的IL-10，并能够以IL-10依赖性方式抑制旁路T细胞的增殖(Smits，H.H.，A.Engering，D.van der Kleij，E.C.de Jong，K.Schipper，T.M.M.van Capel B.A.J.Zaat，M.Yazdanbakhsh，E.A.Wierenga，Y.van Kooyk，and L.Kapsenberg.2005.Selective probiotic bacteria induce IL-10-producing regulatory Tcells in vitro by modulaing dendritic cell function through dendriticcell-specific intercellular adhesion molecule 3-grabbing nonintegrin.JAllergy Clin Immunol.115：1260-1267)。关于路氏乳酸杆菌-DC相互作用的这些研究被认为与Hori(Hori S，T.Nomura，and S.Sakaguchi.2003.Control of regulatory T cell development by the transcriptionfactor Foxp3.Science.299：1057-1061)的突破性研究有关，Pasare和Medzhitov(Pasare C.and R.Medzhitov.2003.Toll pathway-dependentblockade of CD4+Cd25+T cell-mediated suppression by dendritic cells.Science 299：1033-1036)提供了对路氏乳酸杆菌的免疫生物作用方式之一的有价值的见解。
神经生长因子(NGF)除了它对神经元细胞生长的活性之外，在几种体外和体内实验系统中，包括结肠炎模型中具有显著的抗炎效果。Ma等人(2004)探索了人上皮细胞系中路氏乳酸杆菌对细胞因子和NGF合成以及对TNF-α的IL-8反应的效果的机制。他们推断，路氏乳酸杆菌具有对人上皮细胞的有效地直接抗炎活性，其可能与摄食的益生菌的活性相关。他们还推断，路氏乳酸杆菌上调不平常的抗炎分子NGF，并且抑制NF-κB向核的转位(Ma，D.，P.Forsythe，and J.Bienenstock.2004.Live L.reuteri is essential for theinhibitory effect on tumor necrosis factor alpha-induced interleukin-8expression.Infect.Immun.72：5308-5314)。
各种各样的乳酸杆菌属物种的菌株，包括路氏乳酸杆菌已经用于益生菌制剂。路氏乳酸杆菌是动物胃肠道的天然发生的习居菌之一，通常在健康动物包括人类的肠中发现。已知它具有抗微生物活性。参见，例如，美国专利Nos.5,439,678、5,458,875、5,534,253、5,837,238和5,849,289。当路氏乳酸杆菌细胞在存在甘油的缺氧条件下生长时，它们产生称为β-羟基-丙醛(3-HPA)的抗微生物物质。动脉粥样硬化
动脉粥样硬化疾病和它的心血管后果是美国和其他地方的死亡和发病的主要原因。动脉粥样硬化(atherosclerosis)，来自希腊词语“粥”或“粘性物”和“硬化”，被定义为动脉的内壁上粥样硬化或病变的存在。病变，也称为斑块，由脂肪沉淀物和其他物质组成。
使得动脉粥样硬化特别危险的是看起来它对大的重要的动脉具有特别的偏好。当充满斑块的病变的碎片从动脉的内壁上破裂时，脂肪物质向下游流动到直接供应心脏和脑部的较小的动脉，在这里它们被阻塞，阻挡富含营养物和氧气的血液到达这些重要器官。如果发生完全的阻塞，结果可能是心脏病发作或中风(Little，W.C，M.Constantinescu，R.J.Applegate，M.A.Kutcher，M.T.Burrows，F.R.Kahl，and W.P.Santamore.Can coronary angiography predict the site ofa subsequent myocardial infarction in patients with mild-to-moderatecoronary artery disease？Circulation.1988.78：1157-66)。传统上，动脉粥样硬化被认为是脂质代谢紊乱。与动脉粥样硬化相关的风险因素包括LDL的高血液水平、高半胱氨酸、高血压、吸烟、肥胖和糖尿病。治疗已经集中于调节胆固醇水平，例如通过某些乳酸杆菌提高胆汁盐新陈代谢。
当评估使用乳酸杆菌(LAB)作为有效的益生菌的潜力时，许多人认为评估LAB抵抗胆汁酸的影响的能力是必需的。胆汁酸在肝脏中从胆固醇合成，与甘氨酸或牛磺酸结合从胆囊分泌到十二指肠中。它们的功能是乳化膳食的脂质。人类中最常见的初级胆汁酸是胆酸和鹅脱氧胆酸，它们是肝脏中胆固醇新陈代谢的主要终产物。作为肠中微生物活性的结果，这些酸然后经历化学修饰，如脱结合和脱羟基，此时氨基酸从结合型上水解下来(Cardona，M.E.，V.deVanay，T.Midtvedt，and K.E.Norin.Probiotics in gnotobiotic mice.Conversion of cholesterol to coprostanol in vitro and in vivo and bileacid deconjugation in vitro.Microb Ecol Health Dis.2000.12：219-224；Dunne，C，L.O′Mahony，L.Murphy，G.Thornton，D.Morrissey，S.O′Halloran，M.Feeney，S.Flynn，G.Fitzgerald，D.Daly，B.Kiely，G.C.O′Sullivan，F.Shanahan，and J.K.Collins.In vitro selection criteria forprobiotic bacteria of human origin：correlation with in vivo findings.Am J ClinNutr.2001.73(suppl)：386S-392S)。某些胃肠道(GI)细菌，例如肠球菌、双歧杆菌和乳酸杆菌表达胆汁盐水解酶(BSH)，它们催化结合胆汁酸的水解，其产生游离的甘氨酸或牛磺酸以及未结合的胆汁酸分子(Tanaka，H.，K.Doesburg，T.Iwasaki，and I.Mierau.Screening of lactic acid bacteria for bile salt hydrolase activity.J DairySci.1999.82：2530-2535；Bateup，J.M.，M.A.McConnell，H.F.Jenkinson，and G.W.Tannock.Comparison of Lactobacillus strainswith respect to bile salt hydrolase activity，colonization of thegastrointestinal tract，and growth rate of the murine host.Appl EnvironMicrobiol.1995.61(3)：1147-1149；Tannock，G.W.，J.M.Bateup，andH.F.Jenkinson.Effect of sodium taurocholate on the in vitro growth oflactobacilli.Microb Ecol.1997.33：163-167)。
对于BSH如何影响胃肠道中的细菌功能存在着两种主要的假说。一种是，某些细菌将胆汁盐脱结合以使用氨基酸牛磺酸作为电子受体，而另一种声称，酶通过脱结合降低胆汁盐毒性，因为脱结合型是较低可溶性的，具有降低的洗涤剂活性，从而保护了细菌。结合的和脱结合的胆汁酸已经被发现展现了针对大肠杆菌、克雷伯氏菌属和肠球菌属的体外抗菌活性，其中脱结合型是更为生长抑制性的(Dunne，C，L.O′Mahony，L.Murphy，G.Thornton，D.Morrissey，S.O′Halloran，M.Feeney，S.Flynn，G.Fitzgerald，C.Daly，B.Kiely，G.C.O′Sullivan，F.Shanahan，and J.K.Collins.In vitro selection criteriafor probiotic bacteria of human origin：correlation with in vivo findings.Am J Clin Nutr.2001.73(suppl)：386S-392S；Moser，S.A.and D.C.Savage.Bile salt hydrolase activity and resistance to toxicity ofconjugated bile salts are unrelated properties in lactobacilli.ApplEnviron Microbiol.2001.67(8)：3476-3480)。
发酵乳制品的潜在的降低胆固醇的效果可以由胆固醇与胆汁酸结合及胶束形成的抑制来解释。这些产品中益生细菌可能具有降胆固醇效果的机制是通过肝细胞从胆固醇产生的胆汁酸、胆酸和脱氧胆酸。这些与甘氨酸和牛磺酸结合，并进入小肠，在此它们被吸收并送往肝脏。在重吸收期间，结合胆汁酸暴露于肠内的微生物群落。发酵的食物中的细菌，例如乳酸杆菌和链球菌，水解结合胆汁酸。可能的是，在肠中具有高胆汁盐水解酶活性的乳酸杆菌菌株可以提高胆汁水解作用。这将导致更快的胆固醇转化率以产生更多的胆汁酸。在体内，胆固醇降低是由于胆汁酸通过粪便排出，因为脱结合的胆汁酸不在结肠中重吸收。这导致了从头胆汁合成的提高以保持身体的胆汁库恒定(St-Onge M-P.，E.R.Farnworth，and P.J.H.Jones.2000.Consumption of fermented and nonfermented dairy products：effects on cholesterol concentrations and metabolism.Am J Clin Nutr.71：674-681)。
胆汁酸的脱结合将降低血浆胆固醇水平。然而，这些化合物可能进一步在大肠中被厌氧细菌转化成次级胆汁酸，次级胆汁酸已经被暗示为可能的结肠癌诱导物。次级胆汁酸对细胞系是有毒的，认为是它们对结肠粘膜发挥细胞毒性效果导致提高的细胞增殖。这些高增殖性细胞具有对诱变剂的增强的敏感性，从而提高结肠癌的风险(Hepner，G.，R.Fried，S.St.Jeor，L.Fusetti，and R.Morin.1979.Hypercholesterolemic effect of yoghurt and milk.Am.J.Clin.Nutr.32：19-24)。幸运地，乳酸杆菌有助于降低脱结合的胆汁盐和次级胆汁盐的溶解度，从而降低了它们的生物利用率。De Boever等人(2000)的研究显示了路氏乳酸杆菌降低细菌培养物中的胆汁盐毒性。更重要地，添加路氏乳酸杆菌产生了对红细胞裂解的几乎完全的抗性，并抑制胆汁盐对HeLa细胞的毒性效应(De Boever，P.，R.Wouters，L.Verschaeve，P.Berckmans，G.Schoeters，and W.Verstraete.Protective effect of the bile salt hydrolase-active Lactobacillus reuteriagainst bile salt cytotoxicity.Appl Microbiol Biotechnol.2000.53(6)：709-14)。
动脉粥样硬化为一种免疫性疾病
科学家描绘了动脉粥样硬化发生的新的模式，表明这种病理可能产自前炎性T细胞和镇静细胞TR之间的不平衡。这是来自第二次欧洲血管基因组网络会议(Second European Vascular GenomicsNetwork Conference)的让人感兴趣的科学结果之一(EVGNConference-Hamburg，September 27th-30th 2005)。这些结果提供了对于炎症在心脏疾病中的作用的新的见解，导致了血液凝块形成和引起心脏病发作的过程的新的信息性模型的开发。
动脉粥样硬化起始于当LDL颗粒中的脂肪刺激内皮细胞时内皮中脂肪条纹的形成，并且涉及几种细胞类型，包括单核细胞和T淋巴细胞的细胞浸润。单核细胞与内皮细胞层相互作用，坚固地附着到内皮上，迁移到内皮下间隙中，在此单核细胞分化成巨噬细胞。巨噬细胞释放多种化学物质，包括细胞因子。生长因子的生产被刺激，其导致细胞增殖和基质产生，以及金属蛋白酶，这导致基质退化。因而，巨噬细胞有助于病变生长，可能促成不稳定性和血栓形成事件(Ross R.Atherosclerosis-An inflammatory disease.N Engl JMed.1999.340：115-26)。T淋巴细胞已经显示了在动脉粥样硬化的所有阶段上存在。它们的存在提供了与免疫反应的联系的进一步的证据(Kol，A.and P.Libby.1998.The mechanisms by which infectiousagents may contribute to atherosclerosis and its clinical manifestations.Trends Cardiovasc Med.8：191-99；Andreotti，F.，F.Burzotta，A.Mazza，A.Manzoli，K.Robinson，and A.Maseri.1999.Homocysteine andarterial occlusive disease：a concise review.Cardiologia.44：341-5)。
炎性物质产生的起始信号取决于称为toll样受体的受体的牵连，所述受体识别活化炎性信号转导途径的某些内源分子(K.Edfeldt，J.Swedenborg，G.K.Hansson，and Z.Yan.2002.Expression of Toll-LikeReceptors in Human Atherosclerotic Lesions：A Possible Pathway forPlaque Activation Circulation.105：1158-1161)。
Toll样受体(TLR)识别微生物基序，并活化导致细胞因子产生的一组基因。传统上，TLR被认为是微生物感染的感受器，它们的作用是诱导炎性反应。然而，TLR识别的基序不是独特于病原体的，而是全部微生物类别共有的一般性基序，不完全了解的是免疫系统如何通过TLR区分共生细菌和病原细菌。近来，数据显示了TLR尽管在炎性反应的诱导方面有作用，也通过识别共生的微生物群落在维持肠稳态方面起作用(Rakoff-Nahoum，S.，J.Paglino，F.Eslami-Varzaneh，S.Edberg and R.Medzhitov.2004.Recognition ofcommensal microflora by toll-like receptors is required for intestinalhomeostasis.Cell.23；118(2)：229-41)。
确定的是，炎症的血清标志物是心血管发病和死亡的独立的风险因素。与心血管结局相关的炎性标志物包括前炎性细胞因子例如IL-6和TNE-α、纤维蛋白原和C-反应性蛋白(CRP)(Libby，P.，P.M.Ridker，and A.Maseri.2001.Inflammation and atherosclerosis.Circulation.2002.105：1135-1143；Ridker，P.M.High sensitivityC-reactive protein：potential adjunct for global risk assessment in theprimary prevention of cardiovascular disease.Circulation.103：1813-1818).
肺炎衣原体(C.pneumonie)和幽门螺杆菌(H.pylori)在动脉粥样硬化中的作用
积累的证据表明动脉粥样硬化是一种炎症性疾病。因而，许多注意力近来集中于传染原在心血管疾病的病因学中起作用的可能性。根据他们从粥样斑块的分离或对生物体如肺炎衣原体、幽门螺杆菌、单纯性疱疹病毒和巨细胞病毒的阳性血清学研究结果的存在，已经暗示了某些传染原。
虽然有希望的研究未能提供确定的证据，肺炎衣原体看起来展现了与动脉粥样硬化的强烈相关性。肺炎衣原体已经从尸检和关节切除术样本中、以及在早期和良好发育的病变中分离。当通过免疫细胞化学和组织染色的方式研究时，在70-100％的病例中发现了相关性。传染原发挥它们的作用的可能的机制可能包括(i)对内皮、平滑肌细胞或巨噬细胞的局部效应，或(ii)通过产生细胞因子、刺激单核细胞和促进高凝固性的全身效应。
降低胆固醇水平的常规治疗
多年来已经认识到，提高的血清胆固醇浓度是与动脉粥样硬化和冠心病相关的风险因素，后者是西方国家中主要的死亡原因(Barr，D.P.，A.M.Russ，and H.A.Eder.1951.Protein-lipid relationship inhuman plasma.II.In atherosclerosis and related conditions.Am.J.Med.11：480-493)。降低胆固醇的许多药物，包括3-羟基-甲基谷氨酰辅酶A还原酶抑制物和提高胆汁酸净排出的药物，被用于治疗需降低胆固醇(HC)的个体(Suckling，K.E.，G.M.Benson，B.Bond，A.Gee，A.Glen，C.Haynes，and B.Jackson.1991.Cholesterol lowering andbile acid excretion in the hamster with cholestyramine treatment.Atherosclerosis 89：183-190)。
然而，这些化合物的不希望的副作用引起了关于它们的治疗用途的关注(Erkelens，D.W.，M.G.A.Baggen，J.J.Van Doormeal，M.Kettner，J.C.Koningsberger，and M.J.T.M.Mol.1988.Clinicalexperience with simvastatin compared with cholestyramine.Drugs 39(Suppl.)：87-90)。
乳酸杆菌作为降低胆固醇水平的治疗
除了这些治疗资源之外，益生性乳酸杆菌的摄食可能是降低人类中血清胆固醇浓度的更自然的方法。几项研究报告了在消费大剂量(680到5000ml/d)的发酵乳制品期间血清胆固醇的降低，但那些结果不能推广到更为现实的消费情况(Mann，G.V.1977.A factorin yogurt which lowers cholesterolemia in man.Atherosclerosis26：335-340；McNamara，D.J.，A.M.Lowell，and J.E.Sabb.1989.Effect of yogurt intake on plasma lipid and lipoprotein levels innormolipidemic males.Atherosclerosis 79：167-171)。
Massey显示了在起初，酸奶消费在人类成年男性中显著地降低胆固醇10到12％，但2周后，即使继续酸奶消费，浓度回到对照值(Massey，L.1984.Effect of changing milk and yoghurt consumptionon human nutrient intake and serum lipoprotein.J.Dairy Sci.67：255-262)。类似的矛盾结果在用牛奶和其发酵产品饲喂的实验动物中获得(Hepner，G.，R.S.T.Fried，S.Jeor，L.Fusetti，and R.Morin.1979.Hypocholesterolemic effect of yogurt and milk.Am.J.Clin.Nutr.32：19-24)；Rao，D.R.，C.B.Chawan，and S.R.Pulusani.1981.Influence of milk and thermophilus milk on plasma cholesterol levelsand hepatic cholesterogenesis in rats.J.Food Sci.46：1339-1341)。Rao报道了在饲喂通过嗜热链球菌(Streptococcus thermophilus)发酵的牛奶的大鼠中的HC效果(Rao，D.R.，C.B.Chawan，and S.R.Pulusani.1981.Influence of milk and thermophilus milk on plasmacholesterol levels and hepatic cholesterogenesis in rats.J.Food Sci.46：1339-1341)。Rodas发现了在用嗜酸乳酸杆菌(Lactobacillusacidophilus)饲喂的HC猪中的类似的效果(Rodas，B.Z.，S.E.Gilliland，and C.V.Maxwell.1996.Hypocholesterolemic action ofLactobacillus acidophilus ATCC 43121 and calcium in swine withhypercholesterolemia induced by diet.J.Dairy Sci.79：2121-2128)。
在研究用早先用富含脂肪的膳食饲喂的小鼠血清中路氏乳酸杆菌CRL 1098对总胆固醇、甘油三酯、以及高密度脂蛋白(HDL)与低密度脂蛋白(LDL)的比例的效果的研究中，路氏乳酸杆菌引起了甘油三酯的40％降低和高密度脂蛋白与低密度脂蛋白比例的20％增加，而没有原生微生物群落进入脾脏和肝脏的细菌转位(Taranto，M.P.，F.Sesma，A.P.Ruiz Holgado，and G.F.Valdez.1997.Bile salts hydrolase plays a key role on cholesterol removal byLactobacillus reuteri.Biotechnol.Lett.9：245-247)。这些数据表明，路氏乳酸杆菌CRL 1098在低细胞浓度下是对于小鼠的有效的降胆固醇佐剂。但是不同于在此本发明的公开内容，胆固醇的降低仅仅是由于BSH活性，而不是由于BSH活性与免疫调节效果的组合。
乳酸杆菌作为降低胆固醇水平的治疗，免疫调节途径
美国专利申请No.20050169901涉及调节细胞因子水平或活性的方法，用于心血管失调疾病的诊断、预防和治疗。与此处的本发明相比，细胞因子的调节从Th2变化到Th1细胞因子分布，其中所述变化优先地远离Th1细胞因子分布图朝向TNF-α生产的降低。作为益生菌，申请人提及了几种不同的细菌属和菌株，与在此的本发明相比较，本发明中益生菌是被选择在降低TNF-α水平和同时提高BSH活性方面有效的特定乳酸杆菌菌株。
Bukowska显示了在高胆固醇血患者中，补充益生细菌植物乳酸杆菌299v显著地降低LDL胆固醇和纤维蛋白原的浓度(BukowskaH.，J.Pieczul-Mróz，M.
K.Chelstowski，and M.Naruszewicz.1997.Decrease in fibrinogen and LDL-cholesterol levelsupon supplementation of diet with Lactobacillus plantarum in subjectswith moderately elevated cholesterol.Atherosclerosis.137：437-8)。这也在美国专利NO.6,214,336中描述了。同一小组显示了用植物乳酸杆菌补充膳食可以有助于吸烟者中代谢失调的预防和治疗。这种积极的效果被认为与纤维的细菌发酵的丙酸产生直接相关。他们表明，丙酸通过迄今未知的机制发挥了特定的抗炎作用，或许与过氧物酶增生活化的受体被布洛芬活化相关，其调节核转录因子B并降低单核细胞-巨噬细胞的炎性细胞因子的产生(M.Naruszewicz，M-LJohansson，D.Zapolska-Downar，and H.Bukowska，Effect ofLactobacillus plantarum 299v on cardiovascular disease risk factors insmokers.Am.J.Clinical Nutrition.2002.76：1249-1255)。
与此处的本发明相比，上述参考文献没有描述能够提高BSH活性和同时降低TNF-α水平的菌株。
如之前提及的，多年来公知的是，提高的BSH活性降低血清胆固醇水平并因而降低动脉粥样硬化的风险。早先还展现了的是，动脉粥样硬化是炎症性疾病，已经提出不同细胞因子的调节来停止疾病。基于这些发现，针对BSH降低和免疫调节的特性选择非致病细菌菌株。令人惊讶地，导致BSH活性提高的某些菌株同时被发现降低前炎性细胞因子TNF-α水平，附图1。因而本发明涉及例如路氏乳酸杆菌ATCC-PTA4659、路氏乳酸杆菌ATCC-6475或棒状乳酸杆菌(L.coryniformis)ATCC-PTA4660用于产品的制造的用途，用于动脉粥样硬化和其他心血管疾病的预防和/或治疗，以及同样方式选择的其他菌株和其混合物。
因而本发明的目的是提供乳酸杆菌菌株，所述菌株针对它们降低血清LDL胆固醇还是降低前炎性细胞因子TNF-α水平的能力进行了选择。根据以下的公开内容和附随的权利要求，其他目的和优点将更为明显。
附图简要描述
图1是显示乳酸杆菌属条件培养基对LPS活化的单核细胞的TNF-α生产的影响的柱形图。孵育菌株和对照24小时。
发明内容
本发明在此提供了乳酸杆菌菌株，所述乳酸杆菌菌株被选择用于提高BSH活性和因而降低血清LDL胆固醇、以及同时降低前炎性细胞因子TNF-α水平的能力，和用于预防和/或治疗动脉粥样硬化和其他心血管疾病，以及选择这样的菌株的方法、和含有所述菌株的产品。
根据以下公开内容和附随的权利要求，本发明的其他目的和特征将更为明显。
具体实施方式
本发明在此包括乳酸杆菌菌株，其已经针对它们降低炎症和提高BSH活性的能力，例如在动脉粥样硬化中，进行了选择。这样的菌株包括路氏乳酸杆菌ATCC-PTA4659，其根据布达佩斯条约于2002年9月11日保藏在美国典型培养物保藏所，10801 UniversityBlvd，Manassas，VA。路氏乳酸杆菌ATCC-PTA6475于2004年12月21日保藏在ATCC。对于公众利用这些菌株的所有限制将在专利的授权时不可撤销地取消。含有来自这些菌株的完整细胞或成分，例如在这些菌株的无细胞培养物中存在的具有这种能力的成分的产品例如食物、营养添加剂和制剂、药物或医学设备，可以按照本领域中已知的来配制，例如具有乳酸杆菌菌株的冻干的培养物或它的衍生成分的硬胶囊。在此提及的菌株的混合物以及完整细胞或其成分的混合物也处于本发明的范围之内。
实施例3中选择的菌株，例如路氏乳酸杆菌ATCC PTA-6475被添加到标准的酸奶中。路氏乳酸杆菌ATCC PTA-6475菌株利用乳品工业中生长乳酸杆菌属的标准方法来生长并冻干。这种培养物然后添加到早先发酵的牛奶中，使用传统的酸奶培养物，以10E+6CFU/克酸奶的水平，所述酸奶由人使用作为动脉粥样硬化的预防。除了酸奶之外的其他可摄食支持材料可以是，例如，牛奶、凝乳、发酵牛奶、基于牛奶的发酵产品、基于发酵的谷类的产品、基于牛奶的粉剂。
利用合适的细胞因子的模型系统被用于测定降低或提高炎症的因素。在此处提供的本发明中，使用基于人类细胞的分析。
THP-1细胞是来自白血病患者的人类单核细胞系，其维持在美国典型培养物保藏所中(ATCC No.TIB202)。这些细胞来自人类宿主使得它们对于研究人类胃肠免疫系统与人类共生细菌的相互作用是特别相关的。
本发明中的数据表明了特定菌株路氏乳酸杆菌ATCCPTA-4659和路氏乳酸杆菌ATCC PTA-6475的TNF-α生产的强大抑制作用，以及这种调节是由这两种特定菌株在晚期对数/稳定生长期期间释放到生长培养基中的物质介导的。相反地，路氏乳酸杆菌的两种其他菌株不仅不能抑制细胞对E.coli毒素的炎症性反应，本身还诱导炎症性反应。
使用含有胆汁盐的选择性的de Man，Rogosa and Sharpe(MRS)固体培养基的直接平板培养法被用于筛选分泌胆盐水解酶的菌株并测定所述酶对它的底物的比活性。BSH生产细菌的生长产生了水解作用和培养基酸化。水解作用发生，如同围绕菌落的沉淀的游离胆汁盐的晕圈形成(Dashkevicz，M.P.and S.D.Feighner.1989.Development of a differential medium for bile salt hydrolase-activeLactobacillus spp.Appl Environ Microbiol.55(1)：11-16)。
参考以下实施例，本发明的特征将更清楚地被理解，实施例不被看作是限制本发明。
实施例1.具有降低TNF-α水平的能力的菌株的评估
THP-1细胞与对照培养基或条件培养基(L-CM)一起孵育，所述条件培养基来自选定的路氏乳酸杆菌菌株、路氏乳酸杆菌ATCCPTA-4659、路氏乳酸杆菌ATCC PTA-4975、路氏乳酸杆菌ATCC55730和路氏乳酸杆菌菌株PTA-4965的生长。条件培养基(L-CM)是来自每种路氏乳酸杆菌培养物的9小时或24小时培养物的无细胞上清液。在3.5小时的孵育期间，THP-1细胞用对照培养基或E.coli衍生的LPS(其导致正常的炎症性反应中TNFα的产生)刺激，之后除去细胞，利用ELISA技术分析上清液的TNFα水平。
材料：
THP-1白血病的单核细胞系(ATCC，目录编号TIB202)
RPMI 1640培养基(Gibco-Invitrogen)
胎儿牛血清(Gibco-Invitrogen)
青霉素-链霉素溶液(Sigma)
E.coli血清型O127:B8脂多糖(Sigma，目录编号L3137)
TNF-alph/TNF-SFII人类DuoSet ELISA开发试剂盒(R&DSystems，目录编号DY210)
人类IL-10DuoSet，第二代试剂盒(R&D Systems，目录编号DY217)
方法：
使用THP-1单核细胞细胞系。将5％(v/v)的MRS培养基和5％(v/v)乳酸杆菌属条件培养基添加到合适的反应孔中。乳酸杆菌属条件培养基是来自乳酸杆菌属物种在MRS培养基中的24小时培养物的上清液。条件培养基然后通过快速真空干燥调整pH值，团粒重悬浮在等体积的培养基中。虽然湿盒被设计为以最小化蒸发液体，在48小时的孵育之后，24孔平板中的细胞悬液体积降低到约475μl。
将100ng/ml的E.coli血清型O127:B8脂多糖添加到合适的反应孔中，其在37℃湿润的5％CO2盒中孵育。
在3.5小时的孵育之后，将培养物收集到1.5mL离心管中，在1500RCF在4℃离心5分钟。收集上清液。
通过ELISA测试细胞因子表达(Quantikine TNF-alph/TNF-SFIIhuman DuoSet)。使用的培养基是含10％FBS、2％青霉素-链霉素的RPMI 1640。
结果-实施例1
在不存在L-CM的情况下将LPS添加到THP-1细胞中，在3.5小时孵育期内导致产生130pg/ml TNFα。这是THP-1细胞对毒素的预期的炎症性反应。添加生长培养基(MRS)，这作为L-CM添加的对照，导致产生132pg/ml TNFα，因而MRS不干扰对LPS的反应。添加来自路氏乳酸杆菌ATCC PTA 4659或路氏乳酸杆菌ATCCPTA 6475的24小时L-CM显著地分别降低LPS刺激的TNFα水平到仅仅13和11pg/ml。这分别代表了90和93％的LPS刺激的TNFα产生的抑制作用。
相反地，与不存在LPS的情况下的水平相比，在存在来自路氏乳酸杆菌ATCC 55730和路氏乳酸杆菌菌株PTA-4965的24小时L-CM的情况下，LPS仍然能诱导显著的TNF-α提高。尽管存在来自路氏乳酸杆菌ATCC 55730和路氏乳酸杆菌菌株ATCC PTA-4965的L-CM，LPS刺激的TNF-α产生分别提高了54％和42％(参见图1)。
用来自路氏乳酸杆菌ATCC PTA 4659或路氏乳酸杆菌ATCCPTA 6475的9小时L-CM进行的类似的实验表明，对LPS刺激的TNFα产生的抑制效果被显著降低但仍然存在。因而，将路氏乳酸杆菌菌株孵育更长的时间，使用晚期对数/生长停滞期中的L-CM的收获物，产生了抑制TNFα产生方面的改善的效力。
实施例2.直接平板分析-具有细胞外BSH活性的菌株的评估
将人类乳酸杆菌菌株在限氧条件中在37℃在MRS肉汤(Acumedia Manufacturers，Inc.Baltimore，Maryland)中生长过夜，接种在具有10％甘油(BDH Laboratory Supplies，England)带有乳酸杆菌的培养基(LCM)中。
储备培养物保存在-80℃待用。菌株获自BioGaia AB实验室，菌株在Lund(Sweden)、Raleigh(NC，United States of America)和Lantbrukcsuniversitetet(University of Agriculture)，Uppsala(Sweden)采集。
为了筛选细胞外BSH活性，将源自过夜培养物的菌株分别在含有3mM胆汁盐、GDCA(Sigma，Steinheim，Germany)、TDCA(Sigma)、GCA(Sigma)和TCA(Flulca，Sigma-Aldrich，Germany)的MRS-半胱氨酸(MRS-c)琼脂(Acumedia)平板上划线。在37℃厌氧地孵育(AnaeroGen，Oxoid，UK)平板48小时。作为胆汁酸脱连接的结果的沉淀物被可视地测量，因而是主观的，由此活性被称为无活性(-)或有活性(+)。没有添加胆汁盐的MRS-c琼脂平板用作生长和阴性对照。
实施例3.具有BSH活性和同时降低TNF-α水平能力的菌株的选择
| 菌株 | TNF-α降低 | BSH-活性 | 选择 |
| 路氏乳酸杆菌ATCCPTA-4659 | ++ | ++ | S |
| 菌株 | TNF-α降低 | BSH-活性 | 选择 |
| 路氏乳酸杆菌ATCCPTA-6475 | ++ | ++ | S |
| 路氏乳酸杆菌ATCC55730 | -- | +- | - |
| 路氏乳酸杆菌ATCCPTA-4965 | -- | -+ | - |
上表中的数据确认了令人惊讶的发现，路氏乳酸杆菌的不同菌株具有对TNFα和BSH产生的可变的效果，菌株路氏乳酸杆菌ATCCPTA-4659和路氏乳酸杆菌ATCC PTA-6475特别适合于在动脉粥样硬化中使用。
实施例4.条件培养基的用途
利用实施例1中的方法，选择来自一种有效的降低TNFα菌株的条件培养基，在这个实施例中，是来自路氏乳酸杆菌ATCCPTA-4659的培养基。通过在de Man，Rogosa，Sharpe(MRS)(Difco，Sparks，MD)中生长该菌株以更大规模地生产这种培养基。将乳酸杆菌的过夜培养物稀释到1.0的OD600(代表约109个细胞/ml)，进一步1∶10稀释，生长另外24小时。无细菌细胞的条件培养基通过在4℃在8500rpm离心10分钟来收集。将条件培养基从细胞团粒中分离，然后通过0.22μm孔过滤装置(Millipore，Bedford，Mass.)过滤。然后将条件培养基冻干并利用标准方法配制以制成片剂。这种片剂用作人类的药物以有效地治疗动脉粥样硬化。
实施例5.选定的抗炎性路氏乳酸杆菌菌株的用途
使用实施例1和2中的方法，选择一种有效地降低TNF-α和同时提高BSH活性的菌株，在这个实验中，是路氏乳酸杆菌ATCCPTA-4659。然后将路氏乳酸杆菌菌株冻干并利用标准方法配制以制成胶囊剂，105～109cfu的范围。这种胶囊剂用作人类的药物以有效地降低动脉粥样硬化。
实施例6.路氏乳酸杆菌降低动脉粥样硬化中的颈动脉斑块
总共1059位患者在基线给予有效的超声测量，跟踪1年。在基线和跟踪时，使用同样的超声波成像系统和传感器(Acuson Xp10128，ART upgraded，7.5-MHz线性阵列传感器，孔径尺寸38mm，SIEMENS)。B-模式图像调整参数被预设到固定值，在调查的过程中不改变。受试者背卧位，头部稍微向左转，用几个不同的声波角度扫描右侧颈动脉，纵向和横向地，从紧靠锁骨上方到尽可能远的分支末端。斑块被定义为与邻近的内膜-中层厚度(IMT)相比，血管壁向管腔的局部凸出至少50％。在每个受试者中，分别在常见的颈动脉、分叉和内部颈动脉的近壁和远壁记录了最多6个斑块。对于每个斑块，用平行于血管壁以及尽可能垂直于最大斑块厚度的点的传感器记录了静止图像，局部放大选择设置到38mm×20mm。全部的记录在使用Super VHS磁带的Panasonic 7650录像机上进行。
基线时，1059人存在着斑块(表1)。颈动脉斑块区域在任何年龄降低。基线时的平均总斑块面积(SE)是24.1mm2。在跟踪期中，在食用路氏乳酸杆菌ATCC PTA-4659(108CFU)的日剂量之后，所有的人都有总斑块面积的降低。平均降低是9.0mm2。
| 年龄 | n | 基线时的斑块面积mm2 | △斑块面积mm2 |
| ＜60 | 352 | 18.9 | 6.4 |
| 60～64 | 291 | 24.2 | 9.4 |
| 65～70 | 289 | 27.2 | 9.7 |
| ＞70 | 127 | 27.2 | 11.5 |
| SE | 24.1 | 9.0 |
虽然已经参考特定实施方式描述了本发明，要理解的是，许多改变、修改和实施方式是可能的，因而，所有这些改变、修改和实施方式都被认为处于本发明的精神和范围之内。
Claims (19)
1.一种乳酸杆菌菌株的生物学纯培养物，其中，所述乳酸杆菌菌株被选择用于提高BSH活性和因而降低血清LDL胆固醇、以及同时降低前炎性细胞因子TNF-α水平的能力，和用于预防和/或治疗动脉粥样硬化和其他心血管疾病。
2.根据权利要求1所述的生物学纯培养物，其中，所述乳酸杆菌菌株选自由路氏乳酸杆菌ATCC PTA-4659和ATCC PTA-6475和其混合物组成的组。
3.一种选择对于有效地治疗动脉粥样硬化中的炎症细菌菌株的方法，其中，所述方法包括：使用人类来源的THP-1单核细胞细胞系来鉴定有效地降低TNFα水平的菌株。
4.一种来自根据权利要求1所述的乳酸杆菌菌株的生物学纯培养物的可降低动脉粥样硬化相关炎症的成分，其中，所述成分获自所述菌株生长后的无细胞培养物上清液，并且具有降低TNFα数量的能力。
5.一种无细胞培养物上清液，其中，所述上清液自路氏乳酸杆菌菌株ATCC PTA-4659或ATCC PTA-6475和其混合物的生物学纯培养物中分离。
6.一种食物组合物，其中，所述食物组合物包括可摄食的支持物和来自乳酸杆菌菌株的可降低动脉粥样硬化相关炎症的成分，所述乳酸杆菌选自由路氏乳酸杆菌菌株ATCC PTA-4659和ATCCPTA-6475和其混合物组成的组。
7.根据权利要求6所述的食物组合物，其中，可降低炎症的成分包括乳酸杆菌菌株的生物学纯培养物的细胞。
8.根据权利要求7所述的食物组合物，其中，所述乳酸杆菌菌株选自由路氏乳酸杆菌ATCC PTA-4659和ATCC PTA-6475和其混合物组成的组。
9.一种药物组合物，其中，所述药物组合物包括药物载体和来自乳酸杆菌菌株的可降低动脉粥样硬化相关炎症的成分，所述乳酸杆菌选自由路氏乳酸杆菌菌株ATCC PTA-4659和ATCC PTA-6475和其混合物组成的组。
10.根据权利要求9所述的药物组合物，其中，所述成分包含乳酸杆菌菌株的生物学纯培养物的细胞。
11.根据权利要求11所述的药物组合物，其中，所述乳酸杆菌菌株选自由路氏乳酸杆菌ATCC PTA-4659和ATCC PTA-6475和其混合物组成的组。
12.一种营养补充剂，其中，所述营养补充剂包括可摄食的支持物和来自乳酸杆菌菌株的可降低动脉粥样硬化相关炎症的成分，所述乳酸杆菌选自由路氏乳酸杆菌菌株ATCC PTA-4659和ATCCPTA-6475和其混合物组成的组。
13.根据权利要求13所述的营养补充剂，其中，所述成分包含乳酸杆菌菌株的生物学纯培养物的细胞。
14.一种制备食物组合物的方法，其中，所述方法包括：
a.选择根据权利要求3所述的乳酸杆菌菌株；
b.从所述菌株获得抗炎成分；和
c.将所述成分添加到可摄食的支持物以提供食物。
15.一种制备药物组合物的方法，其中，所述方法包括：
a.选择根据权利要求3所述的乳酸杆菌菌株；
b.从所述菌株获得抗炎成分；和
c.将所述成分添加到药物载体以提供药物组合物。
16.一种制备营养补充剂的方法，其中，所述方法包括：
a.选择根据权利要求3所述乳酸杆菌菌株；
b.从所述菌株获得抗炎成分；和
c.将所述成分添加到可摄食的支持物以提供营养补充剂。
17.一种用于治疗或预防动脉粥样硬化相关炎症的试剂，其中，所述试剂包含来自根据权利要求1和3的乳酸杆菌菌株的抗炎成分。
18.一种治疗或预防与动脉粥样硬化相关的炎症的方法，其中，所述方法包括选择至少一种乳酸杆菌菌株，所述至少一种菌株特征在于能够降低动脉粥样硬化，以及向人类施用所述至少一种菌株的细胞。
19.根据权利要求18所述的方法，其中，所述细胞口服地施用。
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| US5837238A (en) * | 1996-06-05 | 1998-11-17 | Biogaia Biologics Ab | Treatment of diarrhea |
| JP3400282B2 (ja) * | 1997-02-21 | 2003-04-28 | 株式会社ヤクルト本社 | 脂質代謝改善剤およびそれを含有する食品 |
| SE510753C2 (sv) * | 1997-08-05 | 1999-06-21 | Probi Ab | Användning av en stam av Lactobacillus för tillverkning av ett läkemedel för reduktion av fibrinogenhalten i blod |
| ATE259829T1 (de) * | 1998-10-20 | 2004-03-15 | Vlaams Interuniv Inst Biotech | Verwendung eines zytokine-produzierenden lactococcus stammes zur behandlung von kolitis |
| AUPR101600A0 (en) * | 2000-10-25 | 2000-11-16 | Atheromastat Pty Ltd | Compositions and methods for diagnosis and treatment of cardiovascular disorders |
| AUPS194902A0 (en) * | 2002-04-24 | 2002-06-06 | Atheromastat Pty Ltd | Compositions and methods for diagnosis and treatment of cardiovascular disorders |
| CN102755646A (zh) * | 2002-07-19 | 2012-10-31 | 艾博特生物技术有限公司 | TNF α相关疾病的治疗 |
| US7105336B2 (en) * | 2002-10-07 | 2006-09-12 | Biogaia Ab | Selection and use of lactic acid bacteria for reducing inflammation caused by Helicobacter |
| TWI241912B (en) * | 2002-10-30 | 2005-10-21 | Food Industry Res & Dev Inst | Novel Acid-and bile salt-resistant Lactobacillus isolates having the ability to lower and assimilate cholesterol |
| US6872565B2 (en) * | 2003-01-29 | 2005-03-29 | Biogaia Ab | Product containing Lactobacillus reuteri strain ATTC PTA-4965 or PTA-4964 for inhibiting bacteria causing dental caries |
| JP2005336159A (ja) * | 2004-04-28 | 2005-12-08 | Univ Kurume | Ｎａｄｐｈオキシダーゼ活性を抑制する色素上皮由来因子の新規治療用途 |
| GB0424552D0 (en) * | 2004-11-05 | 2004-12-08 | Cambridge Theranostics Ltd | Methods and means |
| US7344867B2 (en) * | 2005-04-15 | 2008-03-18 | Eamonn Connolly | Selection and use of lactic acid bacteria for reducing inflammation in mammals |
| EP2061483A1 (en) * | 2006-09-07 | 2009-05-27 | McGill University | Oral polymeric membrane feruloyl esterase producing bacteria formulation |
-
2007
- 2007-04-11 US US11/786,356 patent/US20080254011A1/en not_active Abandoned
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2008
- 2008-03-05 RU RU2009141617/15A patent/RU2490019C2/ru not_active IP Right Cessation
- 2008-03-05 BR BRPI0810881-1A2A patent/BRPI0810881A2/pt not_active IP Right Cessation
- 2008-03-05 UA UAA200911456A patent/UA101316C2/ru unknown
- 2008-03-05 EP EP08724195A patent/EP2136824A4/en not_active Withdrawn
- 2008-03-05 JP JP2010502970A patent/JP2010523144A/ja active Pending
- 2008-03-05 AU AU2008239833A patent/AU2008239833A1/en not_active Abandoned
- 2008-03-05 CN CN200880011696A patent/CN101702881A/zh active Pending
- 2008-03-05 CA CA002683912A patent/CA2683912A1/en not_active Abandoned
- 2008-03-05 WO PCT/SE2008/050248 patent/WO2008127180A1/en active Application Filing
- 2008-03-05 KR KR1020097020740A patent/KR20100015371A/ko not_active Application Discontinuation
-
2010
- 2010-11-18 US US12/927,539 patent/US20110081328A1/en not_active Abandoned
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104160276A (zh) * | 2011-07-21 | 2014-11-19 | 生命大地女神有限公司 | 细菌组胺的产生和应用 |
| CN105062933A (zh) * | 2015-09-11 | 2015-11-18 | 北京博锦元生物科技有限公司 | 一种罗伊氏乳杆菌及其应用 |
| CN106434427A (zh) * | 2016-08-29 | 2017-02-22 | 中国疾病预防控制中心传染病预防控制所 | 乳酸杆菌益生菌cgmcc no.12421及在制备降脂药物中的应用 |
| CN111560330A (zh) * | 2020-05-12 | 2020-08-21 | 天津科技大学 | 一种具有免疫调节、抗炎和抗宫颈癌作用的干酪乳杆菌及应用 |
| CN111560330B (zh) * | 2020-05-12 | 2022-04-26 | 天津科技大学 | 一种具有免疫调节、抗炎和抗宫颈癌作用的干酪乳杆菌及应用 |
| CN111588021A (zh) * | 2020-05-25 | 2020-08-28 | 北京科拓恒通生物技术股份有限公司 | 一株可缓解和治疗冠心病的乳双歧杆菌Probio-M8及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2008239833A2 (en) | 2009-11-26 |
| AU2008239833A1 (en) | 2008-10-23 |
| US20080254011A1 (en) | 2008-10-16 |
| RU2009141617A (ru) | 2011-05-20 |
| KR20100015371A (ko) | 2010-02-12 |
| UA101316C2 (ru) | 2013-03-25 |
| EP2136824A4 (en) | 2010-12-08 |
| EP2136824A1 (en) | 2009-12-30 |
| CA2683912A1 (en) | 2008-10-23 |
| RU2490019C2 (ru) | 2013-08-20 |
| JP2010523144A (ja) | 2010-07-15 |
| US20110081328A1 (en) | 2011-04-07 |
| WO2008127180A1 (en) | 2008-10-23 |
| BRPI0810881A2 (pt) | 2014-10-21 |
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