CN100558883C - 具有产生谷氨酰胺的能力的双歧杆菌属的新菌株 - Google Patents
具有产生谷氨酰胺的能力的双歧杆菌属的新菌株 Download PDFInfo
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- CN100558883C CN100558883C CNB2004800088252A CN200480008825A CN100558883C CN 100558883 C CN100558883 C CN 100558883C CN B2004800088252 A CNB2004800088252 A CN B2004800088252A CN 200480008825 A CN200480008825 A CN 200480008825A CN 100558883 C CN100558883 C CN 100558883C
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Abstract
本发明涉及双歧杆菌属,特别是婴儿双歧杆菌的新菌株,它具有在肠道中存活,在体内产生谷氨酰胺,并且任选在体内产生精氨酸的能力,并且涉及包括所述菌株的混合物。
Description
发明领域
本发明涉及双歧杆菌属的新菌株,它具有在体内产生谷氨酰胺,并且任选产生精氨酸的能力。
发明背景
谷氨酰胺是人体内含量最丰富的氨基酸。它是组织和肠上皮细胞,结肠细胞,淋巴细胞和增殖细胞的燃料之间的“氮穿梭”。患有谷氨酰胺缺乏的患者的肠道功能受损,特别是由于丧失了防止细菌和/或肠毒素从肠腔进入门脉循环的保护作用。在循环疾病和受伤的患者体内发生了谷氨酰胺消耗,并且可能造成高感染率和肌肉消耗。
肠道给予谷氨酰胺,能够对具有不同适应症的患者产生有益健康的作用。对于加强监护单元中的具有多器官功能障碍的患者来说,给予谷氨酰胺能减少患者的感染并发症(Houdijk等,Lancet,352:772-776,1998)。在接受补充了谷氨酰胺的肠胃外营养的进行骨髓移植的患者中观察到了类似的效果(Ziegler等,Annals InternalMedicine,116:821-828,1992)。另一个例子是患有短肠综合征的患者,他们在补充谷氨酰胺之后吸收能力有显著的改善(Byrne等,Annals of Surgery,222:243-255,1995)。在化疗期间和之后进行口服谷氨酰胺补充,还表现出能显著减轻与化疗相关的口炎的持续时间和严重性。所得到的结论是,口服谷氨酰胺似乎是一种简单而又有用的措施,可以提高因为高强度癌症化疗造成的具有出现口腔疼痛的很多高危患者的舒适感(Anderson等,Cancer 1998;83:1433-9)。在进行剧烈运动之后营养补充谷氨酰胺也能降低感染发病率,特别是上呼吸道感染发病率(Castell,Amino acids 2001;20(1):49-61)。不过,谷氨酰胺对免疫抑制的确切作用尚未确定。
谷氨酰胺的主要技术难题是,在加工和保存期间,谷氨酰胺很容易转化成谷氨酸(谷氨酸盐),即谷氨酰胺是一种相对不稳定的化合物,难以将它掺入到用于口服的制剂中。另外,口服的谷氨酰胺将处在胃的酸性环境中,会被高度转化成谷氨酸,并且根本就到达不了肠道,并且以谷氨酰胺形式被吸收。
精氨酸能增强免疫功能,并且促进伤口愈合。给予精氨酸业已用于术后患者和加强监护的患者。在大部分临床研究中,精氨酸是与诸如RNA和鱼油的其他物质同时给予的。有证据表明,给予精氨酸能调节术后免疫应答。Daly,John E.,等,Surgery 112:55-67,1992证实,在手术之后给予患者添加了精氨酸,RNA和ω-3-脂肪酸的肠道营养,能通过不同的机制改善免疫防御能力。精氨酸能减少进行放化疗和手术的患者的并发症(Tepaske等,2001;Lancet 358:696-701),并且缩短停留在加强监护单元中的时间(Bauer等,1995,Critical Case Medicine 23:436-449)。
在用补充了精氨酸的饮食喂饲的动物中观察到了提高了的存活率。定量的菌落数量和计算的剩余活细菌的百分比表明了在接受精氨酸的动物中杀伤转移的生物的能力显著增强了(Adawi,D.,等,1997,Hepatology 25:642-647)。
双歧杆菌属物种,即双歧杆菌的菌株,通常以很大数量存在于人的结肠中,特别是哺乳期的婴儿体内。来自双歧杆菌物种的细菌被视作益生菌,即活的细菌在被摄入之后能对宿主产生有益的作用。人们一直认为结肠中的大量双歧杆菌物种具有有益健康的作用。不过,所述有益作用的作用过程在很多程度上尚属未知。
现有技术
Matteuzzi等[Ann.Microbiol.(Inst.Pasteur)1978;129 B,175-181]研究了来自不同栖息地的大量双歧杆菌在培养液中释放游离氨基酸的能力。所获得的数据表明,若干双歧杆菌物种能够合成生长所需要的所有氨基酸,并且还能将所述化合物释放到培养液中。发现嗜热双歧杆菌,双歧双歧杆菌和青春乳杆菌是最佳的生产菌,并且在所述培养液中最常见的氨基酸主要是丙氨酸,缬氨酸,和天冬氨酸。据推测双歧杆菌物种在胃肠道的氨基酸代谢方面起作用。
WO 01/83700(University of Maryland)披露了用于治疗和预防胃肠道损伤,新生儿坏死性小肠结肠炎(NEC)和细菌性脓毒症的组合物和方法。所述组合物包括格兰氏阳性(+)细菌,特别是乳杆菌属和双歧杆菌属,和谷氨酰胺的组合,并且应当口服或鼻口途径给予。据说该组合物能够抑制诸如格兰氏阳性(-)细菌的细菌制剂的转移。
静脉内给予谷氨酰胺是非常有效的,但是昂贵和复杂。给予谷氨酰胺的更佳途径当然是使用具有在肠道中产生大量谷氨酰胺能力的细菌菌株。不过,迄今为止,还没有披露这样的菌株。
发明概述
业已出乎意料地发现了特定的双歧杆菌属的菌株,它能够在模拟人类结肠环境的生长培养基中产生谷氨酰胺。因此,可将所述菌株用于在给哺乳动物,特别是人口服或肠道给予给药在体内产生谷氨酰胺。某些菌株还能产生精氨酸。
附图简述
图1示意性地表示用限制酶片段长度多态性(RFLP)获得的菌株CURE 19,CURE 21,CURE 26,CURE 28,和CURE 29的电泳模式,所述片段是通过以下方法获得的:分别用EcoRI和Hind III切割染色体DNA,然后通过Southern印迹杂交与干酪乳杆菌假植物亚种DSM 20008的16S rRNA基因的DIG-标记的420bp片段探针(506-926号位置,大肠杆菌编号)杂交。将Dig-标记的分子量DNA标记II(Roche)和分子量DNA标记VI(Roche)用作标准物。
图2表示用限制酶EcoRI切割菌株CURE 19(泳道1),CURE29(泳道2)和CURE 28(泳道3)的染色体DNA获得的分离的DNA片段的照片(限制性内切核酸酶分析,REA)。将高分子量DNA标记(BRL)和DNA分子量标记VI(Roche)用作标准物(泳道4)。
图3表示用限制酶Hind III切割菌株CURE 19(泳道2),CURE28(泳道3)和CURE 29(泳道4)的染色体DNA获得的分离的DNA片段的照片。将高分子量DNA标记(BRL)和DNA分子量标记VI(Roche)用作标准物(泳道1和5)。
图4表示用限制酶EcoRI切割菌株CURE 21(泳道1)和CURE 26(泳道2)的染色体DNA获得的分离的DNA片段的照片。将高分子量DNA标记(MD,USA)和DNA分子量标记VI(Roche)用作标准物(泳道3)。
图5表示用限制酶Hind III切割菌株CURE 21(泳道2)和CURE 26(泳道3)的染色体DNA获得的分离的DNA片段的照片。将高分子量DNA标记(MD,USA)和DNA分子量标记VI(Roche)用作标准物(泳道1和4)。
发明的描述
本发明涉及双歧杆菌属的菌株,它具有在肠道中存活,并且在体内产生谷氨酰胺的能力。谷氨酰胺特别是在人类结肠中产生的。在本文中,存活表示业已在不同的采样时机在来自个体的粪便中分离到了所述细菌菌株。因此,所述细菌很明显是暂时在它们的宿主中生长和存活。本发明的双歧杆菌的菌株能够在pH低于7,特别是5.5-6.5的营养培养基上生长。Rogosa琼脂是这种培养基的一种例子,另一个例子是MRS。
根据优选方面,所述新菌株还具有同化氨的能力。
本发明特别涉及属于婴儿双歧杆菌物种的菌株。
根据特殊方面,本发明还涉及双歧杆菌属的菌株,它具有通过以下方法获得的位于分子大小大约为2840kb的单DNA片段上的16SrRNA基因:用Hind III切割染色体DNA,然后通过琼脂糖凝胶电泳分离片段,并且通过Southern印迹杂交与干酪乳杆菌假植物亚种DSM 20008的16S rRNA基因的DIG-标记的420bp片段探针(506-926号位置,大肠杆菌编号)杂交。例如,所述菌株是2002年8月23目保藏在德意志微生物保藏中心的菌株:婴儿双歧杆菌CURE 19(DSM 15158);婴儿双歧杆菌CURE 21(DSM 15159);婴儿双歧杆菌CURE 26(DSM 15160);婴儿双歧杆菌CURE 28(DSM15161);婴儿双歧杆菌CURE 29(DSM 15162)。
根据另一方面,本发明还涉及双歧杆菌属的菌株,它具有通过以下方法获得的位于分子大小大约为895kb的单DNA片段上的16SrRNA基因:EcoRI切割染色体DNA,然后通过琼脂糖凝胶电泳分离片段,并且通过Southern印迹杂交与干酪乳杆菌假植物亚种DSM20008的16S rRNA基因的DIG-标记的420bp片段探针(506-926号位置,大肠杆菌编号)杂交。根据优选方面,所述菌株能够产生谷氨酰胺,而没有减少谷氨酸。
本发明特别涉及菌株婴儿双歧杆菌CURE 21和婴儿双歧杆菌CURE 26,这两种菌株于2002年8月23日保藏在德意志微生物保藏中心,保藏号分别为DSM 15159和DSM 15160,或它们的变体。所述菌株能够产生谷氨酰胺,而没有减少谷氨酸。
根据另一方面,本发明还涉及双歧杆菌属的菌株,它具有通过以下方法获得的位于分子大小大约为3420kb的单DNA片段上的16SrRNA基因:用EcoRI切割染色体DNA,然后通过琼脂糖凝胶电泳分离片段,并且通过Southern印迹杂交与干酪乳杆菌假植物亚种DSM 20008的16S rRNA基因的DIG-标记的420bp片段探针(506-926号位置,大肠杆菌编号)杂交。根据优选方面,所述菌株具有产生精氨酸的能力。
本发明还特别涉及业已于2002年8月23日保藏在德意志微生物保藏中心,并且业已赋予了保藏号的以下菌株,即婴儿双歧杆菌CURE19,DSM 15158,婴儿双歧杆菌CURE 28,DSM 15161,和婴儿双歧杆菌CURE 29,DSM 15162,及其变体。所述菌株除了能够产生谷氨酰胺之外,还能产生精氨酸。
业已从来自婴幼儿的粪便中分离了所述新的菌株,并且通过在pH低于7的琼脂上培养进行了选择。随后通过核糖体分型和REA对所述菌株进行表征。
本发明的另一个目的是包括与载体组合的一种或多种本发明的双歧杆菌属的菌株的组合物。载体的例子是麦片粥,乳酸发酵的食物,菊粉,乳果糖,果糖寡糖,抗性淀粉,β-葡聚糖和瓜耳豆胶。为了改善双歧杆菌繁殖,并且分别提高谷氨酰胺和精氨酸的产量,并且增强结肠中的氨同化,应当向该组合物中添加饮食纤维。饮食纤维有,例如菊粉,果糖寡糖,麦芽糖糊精,β-葡聚糖和瓜耳豆胶。因此,本发明还涉及如本文所披露的额外包括饮食纤维的组合物。
本发明的组合物,如悬浮液,片剂,胶囊,粉剂可以口服。它们还可以作为灌肠剂给药。
本发明的组合物可以是食物组合物,其中,所述载体是食物。所述生产谷氨酰胺的双歧杆菌属菌株可以提供给婴幼儿,成人,运动员,和希望保持体形的普通消费者,以便改善肌肉功能,并且避免在运动之后出现免疫抑制。还可以将能产生精氨酸的双歧杆菌属菌株提供给希望保持体形,并且避免对免疫功能产生负面影响的普通消费者。
本发明的组合物可以是药物组合物,其中,所述载体是可以治疗上可接受的载体。可以在用于肠道进食的制剂中额外使用能产生谷氨酰胺的菌株,以及能产生精氨酸的菌株。
本发明的氨同化双歧杆菌属菌株可以提供给暂时肾衰竭的患者,如在手术和并发症之后进行加强监护的患者或在其他疾病,如严重感染,中毒之后的患者中出现的情况。在这种情况下,预计肾脏功能可以恢复,并且治疗的目的是减轻来自肠道的氮负荷,并且避免对透析的需要。可以给患有肝衰竭和脑病的患者给予氨同化菌株,例如,肝炎或中毒或在酗酒之后给药。在这种场合下,减少对来自肠道的含氮物质的吸收,能改善脑病和肝脏功能。可以给予婴幼儿所述氨同化双歧杆菌属菌株,使得老年人或具有妨碍他们的肝脏将氨转化成尿素的能力或具有对来自肠道的氮的较高的同化的疾病的消费者,例如,患有轻度至中度的慢性肾或肝脏衰竭的患者不再需要移植或透析。
根据特殊方面,本发明的组合物还可以包括一种或多种乳杆菌属菌株。
除了乳杆菌本身的任选的有益效果之外,所述细菌可以保护双歧杆菌免受氧气的有害影响。
根据另一个方面,本发明涉及用于治疗的属于婴儿双歧杆菌物种的一种或多种菌株。
本发明涉及菌株婴儿双歧杆菌CURE 19,DSM 15158;婴儿双歧杆菌CURE 21,DSM 15159;婴儿双歧杆菌CURE 26,DSM 15160;婴儿双歧杆菌CURE 28,DSM 15161;婴儿双歧杆菌CURE 29,DSM15162;或其变体中的一种或多种在制备药物中的用途,所述药物用于治疗具有多器官功能障碍和肠衰竭的加强监护患者,用于化疗患者和患有炎性疾病的患者中的预防,或用于在大手术之后进行术后给药。
实验
菌株的分离
所有菌株都是从一周至一岁的婴幼儿粪便中分离的。所述粪便样品在稀释溶液(0.9%[w/v]NaCl,0.1%[w/v]蛋白胨,0.1%[w/v]Tween 80,0.02%[w/v]半胱氨酸-HCl)中进行系列稀释,并且涂布在Rogosa琼脂平板上。根据在Rogosa琼脂,pH 5.4上生长的能力选择分离物,并且从一个个体进行重复分离。在37℃下培养72小时之后,从Rogosa琼脂平板上挑选分离物。通过属特异性PCR将它们鉴定到属的水平(Roy等,2000;FEMS Microbiological Letters 191:17-24),并且通过16S rDNA测序鉴定到种的水平(Pettersson等,2002;Systematic and Applied Microbiology 23:332-336)。所述菌株可以从相同的个体中至少分离两次,在两次采样之间有1-4周的间隔,这一事实强烈地暗示了所述菌株具有胃肠道中集群的某种能力。通过核糖体分型,即16S rRNA基因的限制片段长度多态性RFLP,并且通过REA,即限制性内切核酸酶分析鉴定所述菌株。
分离以下菌株:
1)婴儿双歧杆菌CURE 19;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“酸”味。
2)双歧杆菌CURE 20;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“酸”味。
3)婴儿双歧杆菌CURE 21;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“酸”味。
4)双歧杆菌CURE 22;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“好”味。
5)双歧杆菌CURE 23;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“好”味。
6)婴儿双歧杆菌CURE 24;能够在Rogosa琼脂上生长和发酵麦片粥到某种程度,发酵后有“好”味。
7)双歧杆菌CURE 25;能够在Rogosa琼脂上生长和发酵麦片粥。
8)婴儿双歧杆菌CURE 26;能够在Rogosa琼脂上生长和发酵麦片粥。
9)齿双歧杆菌CURE 27;能够在Rogosa琼脂上生长和发酵麦片粥。
10)婴儿双歧杆菌CURE 28;能够在Rogosa琼脂上生长和发酵麦片粥。
11)婴儿双歧杆菌CURE 29;能够在Rogosa琼脂上生长和发酵麦片粥。
12)婴儿双歧杆菌CURE 30;能够在Rogosa琼脂上生长和发酵麦片粥。
谷氨酰胺生产
通过以下方法测定了分离的菌株1-12在培养液中的谷氨酰胺生产。
所述测试菌株在生长培养基(培养液)中在37℃下培养4天,所述培养基是根据Matteuzzi等(Ann.Microbil.(Inst.Pasteur,1978,129B:175-181)披露的培养基改进的。所述培养液由以下成分组成:乙酸钠,10g/l;抗坏血酸,10g/l;硫酸铵((NH4)2SO4),5g/l;磷酸氢二钾(K2HPO4),3g/l;磷酸二氢钾(KH2PO4),3g/l;MgSO4x7H2O,0.32g/l;FeSO4x7H2O,0.01g/l;MnSO4H2O,0.007g/l;NaCl,0.01g/l;酵母提取物,0.5g/l;葡萄糖,20g/l;Tween 80,1ml/l。在高压灭菌之前,用1M NaOH将pH调节到6.18-6.24。
在接种细菌之前以及在测试菌株生长之后,测定培养液中谷氨酰胺的浓度。在生长之后,对所述培养物进行离心和消毒过滤,并且随后在-80℃下冷冻无细胞的上清液。在添加磺基水杨酸并且用氢氧化锂调节pH之后,用自动分析仪(Biochrom 20,Pharmacia Biotech)分析氨基酸。
在下面的表1中示出了在生长不同的测试菌株之后,营养液中谷氨酰胺和谷氨酸浓度的提高。
表1.在生长测试双歧杆菌属菌株之后在培养液中谷氨酰胺的浓度提高和谷氨酸减少/生产。
#来自三种分开的培养物的三种样品的平均值。
所有测试菌株都产生了一些谷氨酰胺,而在12种测试菌株中只有7种具有相对高的谷氨酰胺产量(>20μmol/l)。对于除了两种菌株(CURE 21和CURE 26)以外的所有来说,谷氨酰胺的增加是与培养基中谷氨酸的明显减少同时出现的。没有添加细菌的培养基中谷氨酸的平均起始浓度为223μmol/l,而谷氨酰胺的含量为零。三种菌株CURE 20,CURE 23和CURE 24消耗了培养基中所有可利用的谷氨酸,而CURE 28使谷氨酸的浓度降低了247μmol/l,CURE 29降低了220μmol/l,CURE 22降低了187μmol/l,CURE 19降低了128μmol/l,CURE 30降低了160μmol/l,CURE 27降低了151μmol/l,而CURE 25降低了47μmol/l。可以推测这些细菌是否将谷氨酸转化成了谷氨酰胺。用两种菌株CURE 21和CURE 26产生了谷氨酰胺,而培养基中谷氨酸的浓度没有任何降低。与其他菌株相比,它们提高了培养液中谷氨酸的含量。
精氨酸生产
测试菌株在37℃下在生长培养基(培养液)中生长4天之后,测定每一种测试菌株的氨基酸生产,所述培养基是根据Matteuzzi等(1978)披露的培养基改进的。所述培养液由以下成分组成:乙酸钠,10g/l;抗坏血酸,10g/l;硫酸铵((NH4)2SO4),5g/l;磷酸氢二钾(K2HPO4),3g/l;磷酸二氢钾(KH2PO4),3g/l;MgSO4x7H2O,0.32g/l;FeSO4x7H2O,0.01g/l;MnSO4H2O,0.007g/l;NaCl,0.01g/l;酵母提取物,0.5g/l;葡萄糖,20g/l;Tween 80,1ml/l。在高压灭菌之前用1M NaOH将pH调节到6.18-6.24。
在接种细菌之前以及在测试菌株生长之后,测定培养液中氨基酸的浓度。在生长之后,对所述培养物进行离心和消毒过滤,并且随后在-80℃下冷冻无细胞的上清液。在添加磺基水杨酸并且用氢氧化锂调节pH之后,用自动分析仪(Biochrom 20,Pharmacia Biotech)分析氨基酸。
在表2中示出了在不同的测试菌株生长之后培养液中精氨酸和瓜氨酸浓度的提高。
表2.在测试菌株生长之后培养液中精氨酸和瓜氨酸浓度的提高。
#来自三种分开的培养物的三种样品的平均值。
§来自两种分来的培养物的两种样品的平均值。
12种测试菌株中有3种菌株的精氨酸浓度提高了超过10μmol/l,这三种菌株是CURE 19,CURE 28和CURE 29。所述菌株中有两种还具有非常显著的瓜氨酸生产(>100μmol/l),这两种菌株是CURE 19和CURE 28。瓜氨酸是通过精氨酸脱氨或通过NO-合酶和NO的产生而生产的。瓜氨酸的生产还体现了在较早的步骤中精氨酸的生产。
参见表3,在测试菌株生长期间,还有其他氨基酸渗透到了培养液中。CURE 21不能产生任何瓜氨酸精氨酸,但是能产生大量的天冬氨酸和酪氨酸。CURE 26不会产生任何瓜氨酸,但是能产生非常少量的精氨酸和多种不同的氨基酸。另外,CURE 26是唯一能够提高培养液中脯氨酸浓度的测试菌株。所有测试菌株都能产生苏氨酸。
表3.除了谷氨酰胺,谷氨酸,精氨酸,和瓜氨酸之外,在测试菌株生长之后,培养液中氨基酸浓度(μmol/l)提高。
Thr-苏氨酸;Tyr-酪氨酸;Cys-半胱氨酸;Asp-天冬氨酸;Ala-丙氨酸;Gly-甘氨酸;Ile-异亮氨酸
有关数值表示来自三种或两种分开的培养物的三种或两种样品的平均值。
基因型鉴定
REA
通过限制性内切核酸酶分析REA,检验菌株的染色体DNA切割模式,参见Stahl M,Molin G,Persson A,Ahrne S & Stahl S,International Journal of Systematic Bacteriology,40:189-193,1990,由Johansson,M-L,等,Internatio-nal Journal of SystematicBacteriology 45:670-675,1995作了进一步的开发。示意性的REA可以作如下说明:制备用于本研究的菌株的染色体DNA,并且通过限制性内切核酸酶切割。在37℃下,分别用10单位EcoRI和Hind III消化0.75μg的每一种DNA;每一种内切核酸酶是分开使用的。通过使用浸泡的水平琼脂糖厚平板凝胶的凝胶电泳,根据大小分离切割的DNA片段。所述凝胶由150ml的0.9%琼脂糖(ultrapure DNA级;低电内渗透;BioRad Laboratories,Richmond,USA)组成,并且被浇铸成厚平板凝胶(150×235mm)。将0.2μg的高分子量DNA标记(Bethesda Research Laboratories,MD,USA)和0.5μg的DNA分子量标记VI(Roche,Germany)用作标准物。通过将样品DNA加样到Ficoll加载的缓冲液(2g的Ficoll,8ml的水,0.25%的溴酚兰)获得了最低的带变形和最高的分辨率。
所述凝胶在大约6-8℃下,以40V的恒定电压电泳18小时。在电泳期间,缓冲液(89mM Tris,23mM H3PO4,2mM EDTA钠,pH 8.3)是再循环的。然后用溴化乙锭(2μg/ml)将所述凝胶染色20分钟,并且在蒸馏水中退色,并且在302nm波长下使用UV透射器(UVPInc.,San Gabriel,USA)观察,并且照相。这种凝胶电泳方法提供了良好的分布和较好的带分离,可以分离低至1.2x106的分子量。
16S rRNA基因的RFLP(核糖体分型)
染色体DNA的染色体制备和限制性内切核酸酶分析是按照以前披露的方法进行的(Stahl等,1990,Stahl等,1994)。
探针是干酪乳杆菌假植物亚种DSM 20008的16S rRNA基因的420bp片段(506-926号位置,大肠杆菌编号),它是通过PCR获得的,并且通过DIG DNA标记技术,按照生产商提供的说明书(Boehringer Mannheim,Bromma,Sweden)进行。在反应中所使用的探针的量为50ng。
Southern印迹杂交。在37℃下用10U的EcoRI和HindIII(Boehringer Mannheim)消化1μg的染色体DNA 4小时。按照Stahl等,1994披露的方法通过琼脂糖凝胶电泳分离限制片段。将DIG-标记的分子量DNA标记II和分子量DNA标记VI用作标准物(Roche,Germany)。通过在120℃下烘烤30分钟,将所述DNA固定在带正电荷的尼龙膜(Roche)上。预杂交,杂交和用底物(Roche)进行的化学发光检测是按照生产商提供的说明进行的。杂交温度为68℃。在通过Hind III切割染色体DNA时,在所有菌株(CURE 19,21,26,28和29)中的检测得到了分子量为大约2840kb的单一带。在通过EcoRI切割染色体DNA时,16S rRNA的基因在菌株CURE 21和26中终止于分子量为大约895kb的单片段,而菌株CURE 19,28和29获得了分子量为大约3420kb的另一个带。
体内试验
试验1.乳酸杆菌属和双歧杆菌属菌株对DDS在大鼠中诱导的结肠炎
的影响
本研究的目的是比较乳酸杆菌属和双歧杆菌属菌株对DDS(右旋糖苷硫酸钠)在大鼠中诱导的结肠炎的影响。
将Sprague Dawley大鼠分成六个组,一个对照组(不给予细菌的结肠炎),和分别给予不同的细菌菌株(分别为植物乳杆菌299v,类干酪乳杆菌8700:2,加氏乳杆菌LG1,双歧杆菌3B1和婴儿双歧杆菌CURE 19)的五个组。在诱导结肠炎(第0天)之前,口服细菌菌株7天时间,并且与DDS(5%w/v溶解在蒸馏水中)组合连续给予7天时间。每天用DAI(疾病活动度指数)确定结肠炎的程度。采样是在第14天进行的,并且测定了肠道中的细菌转移和数量。
与对照组相比,在接受植物乳杆菌299v,双歧杆菌3B1和双歧杆菌CURE 19的组中,在第4,5,6和7天,DAI显著降低。另外,在6和7天之后,与接受类干酪乳杆菌8700:2和加氏乳杆菌LG1的组相比,在接受婴儿双歧杆菌CURE 19的组中DAI显著降低。与对照结肠炎相比,在所有组中细菌向肠系膜***中的转移显著减少,并且肠杆菌科向肝脏中的转移也显著减少。
总之,口服菌株植物乳杆菌299v,类干酪乳杆菌8700:2,加氏乳杆菌LG1,双歧杆菌3B1和婴儿双歧杆菌CURE 19能够通过减少大鼠中试验的结肠炎的转移而产生有利的作用。植物乳杆菌299v,双歧杆菌3B1和婴儿双歧杆菌CURE 19在改善DDS诱导的大鼠结肠炎的DAI方面表现出最明显的作用。在处理6天和7天之后,与其他菌株相比,婴儿双歧杆菌CURE 19在对抗结肠炎方面表现得更为有效,参见图6。
试验2.在口服之后乳杆菌属和双歧杆菌属在胃肠道中的存活
口服乳杆菌属或双歧杆菌属提供了不同的有利作用,例如,抑制与抗生素相关的腹泻(D′Souza等,2002,BMJ 324:1361)
只要所述细菌能够口服存活,并且有能力在肠道中存活并且繁殖,就可以获得有利作用。为了发现可以用作益生菌的合适的菌株,给健康对象口服了多种可能的候选菌株。通过测定所给予的菌株在粪便中出现的频率,鉴定了具有高的存活能力的菌株。本研究的目的是发现具有在人类胃肠道中存活和繁殖的出色能力的可以口服的细菌菌株。
研究设计
对于四周龄的14个自愿对象来说,给他们饮用大约20种不同的乳杆菌属和双歧杆菌属的菌株的混合物。所有菌株是存在于人体中或产乳酸食物中的典型的菌株。在给予之前,给予三周之后和给予一周之后采集粪便样品。通过活体计数和RAPD(随机扩增的多态性DNA;Johansson等,1995)测定菌群。
结论
以上结果表明,选择的菌株,即婴儿双歧杆菌CURE 19,DSM15158;双歧杆菌CURE 21,DSM 15159;婴儿双歧杆菌CURE 26,DSM 15160;婴儿双歧杆菌CURE 28,DSM 15161;和婴儿双歧杆菌CURE 29,DSM 15162能够在口服之后通过胃肠道存活。在大鼠体内进行的研究还证实了对实验结肠炎产生有利作用的潜力。
Claims (9)
1.婴儿双歧杆菌物种的菌株,它具有在肠道中存活,并且在体内产生谷氨酰胺的能力,所述菌株选自菌株婴儿双歧杆菌CURE 19,DSM15158;婴儿双歧杆菌CURE 21,DSM 15159;婴儿双歧杆菌CURE 26,DSM 15160;婴儿双歧杆菌CURE 28,DSM 15161;婴儿双歧杆菌CURE29,DSM 15162。
2.如权利要求1的菌株,其中婴儿双歧杆菌CURE 19,DSM 15158;婴儿双歧杆菌CURE 26,DSM 15160;婴儿双歧杆菌CURE 28,DSM 15161;婴儿双歧杆菌CURE 29,DSM 15162具有产生精氨酸的能力。
3.一种组合物,包括与载体组合的如权利要求1或2的一种或多种双歧杆菌属的菌株。
4.如权利要求3的组合物,其特征在于所述载体是麦片粥。
5.如权利要求3或4的组合物,其特征在于还包括饮食纤维。
6.如权利要求3-5中任意一项的组合物,其特征在于它是食物组合物。
7.如权利要求3-5中任意一项的组合物,其特征在于它是药物组合物,其中,所述载体是治疗上可接受的载体。
8.如权利要求3-7中任意一项的组合物,其特征在于还包括一种或多种乳杆菌属菌株。
9.菌株婴儿双歧杆菌CURE 19,DSM 15158;婴儿双歧杆菌CURE 21,DSM 15159;婴儿双歧杆菌CURE 26,DSM 15160;婴儿双歧杆菌CURE 28,DSM 15161;婴儿双歧杆菌CURE 29,DSM15162中的一种或多种在制备药物中的用途,所述药物用于治疗具有多器官功能障碍和肠衰竭的加强监护患者,用于化疗患者和患有炎性疾病的患者中的预防,或用于在大手术之后进行术后给药。
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EP1587913B1 (en) | 2011-01-19 |
WO2004067731A1 (en) | 2004-08-12 |
PL212096B1 (pl) | 2012-08-31 |
CN1777670A (zh) | 2006-05-24 |
US20060269533A1 (en) | 2006-11-30 |
AU2004208084B2 (en) | 2008-10-09 |
ATE496115T1 (de) | 2011-02-15 |
JP4540664B2 (ja) | 2010-09-08 |
BRPI0407176B8 (pt) | 2021-05-25 |
AU2004208084A1 (en) | 2004-08-12 |
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DK1587913T3 (da) | 2011-04-11 |
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JP2006516405A (ja) | 2006-07-06 |
US7947482B2 (en) | 2011-05-24 |
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CA2514659A1 (en) | 2004-08-12 |
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