CN115243567A - 含有乳酸菌的组合物 - Google Patents
含有乳酸菌的组合物 Download PDFInfo
- Publication number
- CN115243567A CN115243567A CN202180019029.2A CN202180019029A CN115243567A CN 115243567 A CN115243567 A CN 115243567A CN 202180019029 A CN202180019029 A CN 202180019029A CN 115243567 A CN115243567 A CN 115243567A
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- lactobacillus
- lactic acid
- cells
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Abstract
本发明的课题在于提供对抑制过敏发作有效的含有乳酸菌的组合物。更具体而言,本发明是一种含有属于动物乳杆菌的乳酸菌的组合物,该组合物作为例如饮食品组合物、药物组合物、饲料组合物和卫生用组合物等提供。而且,本发明提供预防过敏发作的方法。
Description
技术领域
本发明涉及具有抗过敏作用的含有乳酸菌的组合物。
背景技术
过敏性疾病通过各种因素例如遗传因素、环境因素(例如,婴幼儿期的生育环境、肠道菌群等)的相互作用而控制其发作。
认为肠道细菌影响宿主的免疫系统的发育(非专利文献1),作为与过敏性疾病具有一定关系的肠道细菌,可举出乳酸菌。此外,也有报道表明在婴幼儿期与宠物生活的环境作为过敏性疾病的环境因素是重要的,例如,通过在婴幼儿期与宠物(狗、猫等)接触而产生的人与宠物的微生物串扰可抑制过敏发作(非专利文献2和3)。Fujimura等人报道过在饲养狗的环境中暴露于屋尘的小鼠的肠道菌群中乳酸菌的约氏乳杆菌(LactobacillusJohnsonii)的比率显著上升,约氏乳杆菌对抑制过敏性的呼吸道疾病发挥重要的作用(非专利文献4)。
另一方面,Taylor等人给患有过敏性疾病的母亲所生的婴儿服用嗜酸乳杆菌(Lactobacillus acidophilus)直至出生后6个月为止,以分析乳酸菌对过敏发作的影响,结果表明在出生后1岁的时候,给药组与安慰剂给药组的特应性皮炎的发病率没有显著性差异,嗜酸乳杆菌给药组中IgE抗体的阳性率较高(非专利文献5)。
如上表明了乳酸菌对过敏性疾病有一定的影响,但却显示出相反的结果(非专利文献5为阴性结果,非专利文献4为阳性结果),需要进一步分析哪些菌种对抑制过敏更有效更实用。
现有技术文献
非专利文献
非专利文献1:Macphers和Harris,Nat Rev Immunol.4:478-485 2004.
非专利文献2:Hesselmar等,Clin Exp Allergy.29:611-617 1999.
非专利文献3:Fall等,JAMA Pediatr.169e153219 2015
非专利文献4:Fujimura等,Proc Natl Aca Sci USA 14:805-810 2014.
非专利文献5:Tylor等,J Allergy Clin Immuno.119:184-191 2007.
发明内容
鉴于上述情况,本发明的课题在于提供对抑制过敏发作有效的含有乳酸菌的组合物。
本发明人等认为狗的肠道细菌对宿主的免疫系统有某些影响,并对健康犬与特应性犬的肠道菌群进行了比较,选择了在健康犬中占优势的细菌。具体而言,在从健康犬粪便中分离的240株中,184株属于上述选择的细菌,对这些细菌进行了基于16sRNA基因的系统分类解析。其结果,鉴定出拟杆菌(Bacteroides)属、肠球菌(Enterococcus)属、乳杆菌属(Lactobacillus)和链球菌(Streptococcus)属的4属13种,其中将至今尚未报道过与过敏发作有关的乳杆菌属(Lactobacillus)的动物乳杆菌(L.animalis)作为解析对象。
本发明人等将动物乳杆菌给小鼠的特应性皮炎模型和过敏性哮喘模型口服给药时,观察到抑制由过敏引发的各症状的效果。而且得知动物乳杆菌表现出比此前报道过具有抑制过敏效果的约氏乳杆菌(L.johnsonii)更高的抑制过敏效果。
本发明是基于上述见解而完成的。
即,本发明涉及以下的(1)~(7)。
(1)一种组合物,其中,含有属于动物乳杆菌的乳酸菌或其菌体处理物。
(2)根据上述(1)所述的组合物,其中,上述乳酸菌是以保藏编号NITE BP-03137、保藏编号NITE BP-03138、保藏编号NITE BP-03139和/或保藏编号NITE BP-03140保藏的动物乳杆菌菌株。
(3)根据上述(1)或(2)所述的乳酸菌或组合物,其具有抗过敏活性。
(4)根据上述(1)~(3)中任一项所述的组合物,其中,上述组合物为饮食品组合物。
(5)根据上述(1)~(3)中任一项所述的组合物,其中,上述组合物为药物组合物。
(6)根据上述(1)~(3)中任一项所述的组合物,其中,上述组合物为饲料组合物。
(7)根据上述(1)~(3)中任一项所述的组合物,其中,上述组合物为卫生用组合物。
根据本发明,可提供发挥比以往报道的乳酸菌种更高的抑制过敏的效果的乳酸菌种。
附图说明
图1表示使用特应性皮炎模型的解析结果(1)。在螨抗原的经皮给药开始的4周后(A)和7周后(B),测定每1小时的模型小鼠的抓挠行为的次数(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01。
图2表示使用特应性皮炎模型的解析结果(2)。是从螨抗原的经皮给药开始到10周为止每周对皮肤症状进行评分而得的结果(左图)(n=8)。数据表示平均值,误差条表示标准误差。此外示出模型小鼠的螨抗原给药后的皮肤症状的照片(右图)。
图3表示使用特应性皮炎模型的解析结果(3)。是从螨抗原的经皮给药开始到10周为止每周测定背部皮肤的厚度而得的结果(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
图4表示使用特应性皮炎模型的解析结果(4)。是计数在螨抗原的最终给药的翌日从模型小鼠采集的耳廓淋巴结中存在的CD3+CD4+T细胞(A)、CD19+IgE+B细胞(B)和CD11c+CD40+树突状细胞(C)的个数而得的结果(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。未受损(Intact)是使用未经过螨处置的小鼠的结果,对照(Control)是使用未给药乳酸菌的模型小鼠的结果(在以下的图中相同)。
图5表示使用特应性皮炎模型的解析结果(5)。测定在螨抗原的最终给药的翌日从模型小鼠采集的耳廓淋巴结中产生的各种细胞因子的量(A:IL-4、B:IL-9、C:IL-13、D:IL-17、E:TNFα)(n=8)。ND为检出限以下。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
图6表示使用特应性皮炎模型的解析结果(6)。测定在螨抗原的最终给药的翌日从模型小鼠采集的耳廓皮肤组织中产生的各种细胞因子的量(A:IL-1α、B:IL-4、C:IL-5、D:IL-9、E:IL-13、F:IL-17)(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
图7表示使用特应性皮炎模型的解析结果(7)。测定在螨抗原的最终给药的翌日从模型小鼠采集的耳廓皮肤组织中产生的各种细胞因子的量(A:IL-33、B:TNFα、C:TSLP)(n=8)。数据表示平均值,误差条表示标准误差。*P<0.05。
图8表示使用特应性皮炎模型的解析结果(8)。由在螨抗原的最终给药的翌日从模型小鼠采集的血液制备血清,测定该血清中的总IgE量(n=8)。误差条表示标准误差。
图9表示使用过敏性哮喘模型的解析结果(1)。是计数在螨抗原的最终诱导的翌日从模型小鼠采集的肺门淋巴结中存在的CD3+CD4+T细胞(A)、CD19+IgE+B细胞(B)和CD11c+CD40+树突状细胞(C)的个数而得的结果(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
图10表示使用过敏性哮喘模型的解析结果(2)。测定在螨抗原的最终诱导的翌日从模型小鼠采集的肺门淋巴结中产生的各种细胞因子的量(A:IL-4、B:IL-5、C:IL-9、D:IL-13、E:IL-17)(n=8)。ND为检出限以下。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
图11表示使用过敏性哮喘模型的解析结果(3)。是计数在螨抗原的最终诱导的翌日从模型小鼠采集的肺泡清洗液中的嗜酸性粒细胞(A)和中性粒细胞(B)而得的结果(n=8)。数据表示平均值,误差条表示标准误差。**P<0.01,*P<0.05。
具体实施方式
本发明的第1实施方式是含有属于动物乳杆菌(Lactobacillus animalis)的乳酸菌或其菌体处理物的组合物(以下也记载为“本发明的组合物”)。作为本发明的实施方式中使用的动物乳杆菌,例如,除了用NCBI登录号NZ_AYYW00000000.1登录了其基因序列的菌种之外,优选2020年2月21日(原保藏日)在独立行政法人制品评价技术基础机构生物技术中心的专利微生物保藏中心(NPMD)(邮政编码292-0818,日本千叶县木更津市上总鎌足2-5-8)保藏的、以保藏编号NITE P-03137(识别名称:L11-2)、保藏编号NITE P-03138(识别名称:L13-1)、保藏编号NITE P-03139(识别名称:L41-1)和保藏编号NITE P-03140(识别名称:M08-1)特定的菌株等。应予说明,以保藏编号NITE P-03137、保藏编号NITE P-03138、保藏编号NITE P-03139和保藏编号NITE P-03140特定的菌株其后基于布达佩斯条约,从原保藏单位移管至国际保藏单位(“原保藏的保藏证明”和“存活证明”的发行日:2021年3月4日),保藏编号分别为保藏编号NITE BP-03137、保藏编号NITE BP-03138、保藏编号NITEBP-03139和保藏编号NITE BP-03140。上述保藏菌株可以从上述保存机关获得。
动物乳杆菌的培养方法没有特别限定,作为乳酸菌的培养方法,只要是本领域技术人员通常选择的方法,则任何方法均可。例如,可以在培养温度为20~50℃、优选为25~40℃、厌氧条件下培养。
用于动物乳杆菌繁殖的培养基没有特别限定,可以使用本领域技术人员通常选择的培养基。作为这样的培养基,例如,只要为以适合菌种的组成含有下述成分的培养基即可:碳源(葡萄糖,半乳糖、甘露糖、乳糖、蔗糖、纤维二糖、海藻糖等)、氮源(氨、硫酸铵、氯化铵、硝酸铵等)、无机盐类(氯化钠、氯化钾、硫酸钾、硫酸镁、氯化钙、硝酸钙等)、有机成分(蛋白胨、酵母提取物、肉提取物、大豆粉等),可优选使用MRS培养基、LBS培养基等。
作为本发明的菌体处理物,例如,可举出菌体的培养物和发酵物,作为所含的乳酸菌的状态,可以为活菌体或死菌体中的任一状态。此外,作为菌体处理物,可举出对乳酸菌进行例如加热、膏化、干燥、冷冻、溶菌、破碎、提取等而得的物质,除去菌体破碎物、菌体培养物和发酵物的固体成分而得的上清液等,但不限于这些。
另外,本发明的组合物中,除动物乳杆菌或其菌体处理物以外可以含有其它的物质。作为其它的物质,没有特别限制,例如,可以含有乳糖、葡萄糖、甘露醇、蔗糖、糊精、环糊精、淀粉、纤维素、胶原蛋白、柠檬酸、醋酸、食盐、维生素类等。
本发明的组合物具有抑制过敏发作的效果,可以根据使用目的,例如,作为饮食品组合物、药物组合物、饲料组合物和卫生用组合物等提供,但不限于这些组合物。
本发明的组合物为药物组合物时,其剂形没有特别限定,例如,可举出片剂、胶囊剂、颗粒剂、散剂、糖浆剂、液体制剂、栓剂或注射剂等。这些制剂可根据常规方法制备。此外,在液体制剂的情况下,可以在使用时溶解或悬浮于水或其它的适当溶剂。另外,片剂、颗粒剂可以用公知的方法包衣。注射剂的情况下,可以使本发明的抗体或其功能性片段溶于水而制备,可以根据需要溶解于生理食盐水或葡萄糖溶液,另外可以添加缓冲剂、保存剂。
本发明的组合物作为饮食品组合物提供时,其形态没有特别限制,例如,可以为清凉饮料、营养饮料等饮料,糖果、口香糖、果冻、奶油和冰淇淋等点心类,乳饮料、发酵乳、饮料酸奶、黄油等乳制品,其它补充剂等。
本发明的组合物作为卫生用组合物提供时,其形态没有特别限制,例如,可以为牙膏、护肤霜、香皂、洗发水、化妆品、气雾剂、喷雾、涂布剂等,也可以为非人类动物用的卫生用组合物。
此外,本发明的组合物可以为非人类动物可摄取的饲料组合物和动物用的药物组合物。在此提及的动物饲料除了所谓的作为动物所需的营养源摄取的食物以外,也包括作为动物的嗜好品给予的动物用的补充剂等。
本发明的第2实施方式是一种预防过敏发作的方法(以下也记载为“本发明的预防方法”),包括将本发明的药物组合物向对象进行给药。
在此“预防”是指以预先阻止过敏发作为目的的处置。
本发明的预防方法的对象没有特别限定,可以是被分类为哺乳类的任意动物,例如,除了人以外,可以为狗、猫、兔等宠物,牛、猪、羊、马等家畜动物等。特别优选的“哺乳动物”是人和狗。
本说明书被翻译成英语且包括单数形式的“a”、“an”和“the”的单词的情况下,只要文章中没有明确地说明,则单数和复数的情况均包含在内。
以下示出实施例进一步进行本发明的说明,但本实施例终归只是本发明的实施方式的例示,不限定本发明的范围。
实施例
1.实验方法
1-1.从粪便分离乳酸菌以及系统分类
在从健康犬(16只)的粪便分离出的细菌240株中,选出与特应性犬的肠道菌群相比在健康犬的肠道菌群中占优势的184株,进行系统分类解析。具体而言,使用MRS液体培养基或LBS液体培养基,在厌氧条件下,在37℃将从犬采集的粪便进行静置一晩的培养。培养后,用MRS或LBS平板培养基进行细菌的分离。纯化最少进行3次。细菌的系统分类基于16SrRNA测序进行。其结果,鉴定出拟杆菌属、肠球菌属、乳杆菌属和链球菌属的4属13种,从其中选择至今尚未报道过与过敏发作有关的乳杆菌属的动物乳杆菌(L.animalis),作为解析对象。应予说明,作为本实施例的阳性对照,使用被认为与过敏发作有关的约氏乳杆菌(L.johnsonii)。本实施例中使用的动物乳杆菌是将以保藏编号NITE BP-03137、保藏编号NITE BP-03138、保藏编号NITE BP-03139和保藏编号NITE BP-03140保藏的菌株以菌数为1:1:1:1的比率混合而成的。
1-2.利用疾病模型小鼠的解析
本实施例中采用的全部动物实验得到麻布大学动物实验专门委员会的承认后实施。
1-2-1.特应性皮炎模型
使用6周龄的雌性NC/Nga小鼠(Charles River Laboratories Japan株式会社)实施实验。适应1周后,每只小鼠口服给药动物乳杆菌或约氏乳杆菌0.2ml(109)2周后,开始螨抗原(粉尘螨,Dermatophagoides farinae)的致敏。在螨抗原的致敏前进行颈背部皮肤的剃毛,在颈背部进行10次的胶带剥离后,使用移液管将螨悬浮液30μl(0.25mg/ml)经皮给药至两个耳廓各10μl。螨抗原的给药一周2次,实施12周,每周实施瘙痒行为的监测、皮肤症状的评分、背部皮肤的厚度测定。
瘙痒行为的监测是在用摄像机记录的小鼠行为中,将用后肢、前肢或舌头咬或抓挠螨抗原涂布部位(耳廓和背部皮肤)的行为作为1次瘙痒行为,记录60分钟内的瘙痒行为的次数。
皮肤观察是分别对耳廓部、背部皮肤的结痂·溃疡形成、发红进行评分(将症状的程度按0~4的等级进行评分),将其累计值作为累积分数进行评价。
背部皮肤的厚度使用游标卡尺每周测定1次。
在螨抗原最终给药的翌日,在异氟醚吸入麻醉下从小鼠进行采血,其后,进行安乐死,进行耳廓淋巴结和耳廓皮肤的采样。
从血液中分离血清后,用ELISA法对血中总IgE量进行定量。
耳廓淋巴结是在单细胞分离后,利用流式细胞仪法,基于细胞表面抗原分离取得细胞。将得到的细胞中的辅助T细胞(CD3+CD4+T细胞)在抗CD3抗体和抗CD28抗体(VERITAS株式会社)存在下培养24~96小时后,用ELISA法测定培养上清液中的各种细胞因子的产生量。
将采集的耳廓皮肤用液氮冷冻,通过ELISA法测定利用电动均质机在500μl的PBS中进行均质化而得到的上清液中的各种细胞因子量。
1-2-2.过敏性哮喘模型
使用6周龄的雌性BALB/c小鼠(Charles River Laboratories Japan株式会社)实施实验。适应1周后,每只小鼠口服给药动物乳杆菌或约氏乳杆菌0.2ml(109)2周后,开始螨抗原(粉尘螨,Dermatophagoides farinae)的致敏。螨抗原的致敏是在异氟醚吸入麻醉下,使用移液管,将螨悬浮液30μl(1mg/ml)进行鼻腔给药。螨抗原的给药每周1次,连续实施3周。用同样的方法在第4周在异氟醚吸入麻醉下,使用移液管,将螨悬浮液5μl(0.2mg/ml)连续鼻腔诱导3天。在螨抗原最终诱导的翌日,在异氟醚吸入麻醉下从小鼠进行采血,然后安乐死,并进行肺门淋巴结、肺泡清洗液的采样。
肺泡清洗液用于清洗液中的嗜酸性粒细胞(eosinophil)和中性粒细胞(neutrophil)的个数的计数。
肺门淋巴结是在单细胞分离后,利用流式细胞仪法,基于细胞表面抗原分离取得细胞。将得到的细胞中的辅助T细胞(CD3+CD4+T细胞)在抗CD3抗体和抗CD28抗体存在下培养24~96小时后,用ELISA法测定培养上清液中的各种细胞因子的产生量。
1-3.统计分析
对于得到的数据,算出各组的平均值和标准误差,每个实验在全部组中实施多重比较检验。在多重比较检验中,利用Bartlett法等进行方差的检验,在方差的情况下,采用Dunnett’s检验。对于各检查项目,用显著性水平5和1%的水平解析各组之间的统计学上的显著性差异的有无。
2.结果
2-1.特应性皮炎模型
特应性皮炎是由于瘙痒与皮肤炎症交替发生使症状恶化的病理状态。因此,通过在每周1次的螨抗原的给药后立即测定每1小时的小鼠模型的瘙痒行为,来研究乳酸菌对瘙痒的影响。
根据将螨抗原进行给药而引发特应性皮炎的小鼠模型的解析结果,认为与对照小鼠(未给乳酸菌)相比,给了动物乳杆菌的小鼠和给了约氏乳杆菌的小鼠的抓挠行为的次数显著减少(图1A和B)。
此外,图2是对螨抗原给药期间的特应性皮肤症状进行评分而得的结果。特应性症状表现受个体影响差异较大,虽没有发现统计学上的显著性差异,但动物乳杆菌给药组和约氏乳杆菌给药组与对照组相比皮肤症状的减轻程度高。此外,若对动物乳杆菌给药组与约氏乳杆菌给药组进行比较,则动物乳杆菌给药组的症状减轻程度更大。
随着特应性皮炎的症状恶化,发生表皮增厚·细胞浸润,皮肤的厚度增大。因此,测定模型小鼠的背部皮肤的厚度。其结果,动物乳杆菌给药组和约氏乳杆菌给药组与对照组相比皮肤厚度的减少显著。其中,观察到动物乳杆菌给药组的厚度减少具有统计学上的意义,即便与约氏乳杆菌给药组相比较也有明显的减少(图3)。
最终解剖后,采集耳廓淋巴结,用流式细胞仪法计数淋巴结中的与过敏有关的免疫细胞(辅助T细胞(CD3+CD4+T细胞)、IgE阳性B细胞(CD19+IgE+B细胞)和活化的树突状细胞(CD11c+CD40+树突状细胞))的个数。其结果发现,在全部细胞中,动物乳杆菌给药组和约氏乳杆菌给药组中的细胞数的减少。特别是辅助T细胞和IgE阳性B细胞与对照组相比较,观察到显著的减少,其中,动物乳杆菌给药组的减少显著(图4)。
接下来,将从耳廓淋巴结采集的辅助T细胞在CD3和CD28抗体的存在下培养,测定了炎症性细胞因子(IL-4、IL-9、IL-13、IL-17和TNFα)的产生量。其结果,与对照组相比较,在动物乳杆菌给药组和约氏乳杆菌给药组中,任一炎症性细胞因子的产生量均显著地减少(图5)。特别是动物乳杆菌给药组与约氏乳杆菌给药组相比,观察到炎症性细胞因子的产生量的显著减少。
测定耳廓皮肤组织中的炎症性细胞因子(IL-1α、IL-4、IL-5、IL-9、IL-13和IL-17)量,结果与耳廓淋巴结的结果同样地,在动物乳杆菌给药组和约氏乳杆菌给药组中,观察到显著的细胞因子量的减少(图6)。此外,将对耳廓皮肤组织中的与瘙痒有关的细胞因子(IL-33、TNFα和TSLP(thymic stromal lymphopoietin,胸腺基质淋巴细胞生成素))量进行定量而得的结果示于图7。虽没有观察到TSLP的显著减少,但IL-33和TNFα等来自角质形成细胞的细胞因子在动物乳杆菌给药组和约氏乳杆菌给药组中,与对照相比较,观察到产生量的显著减少。
接下来,测定由模型小鼠制备的血清中的总IgE量。其结果,在动物乳杆菌给药组和约氏乳杆菌给药组中,观察到血清中总IgE量的显著减少(图8)。
2-2.过敏性哮喘模型
对过敏性哮喘模型小鼠进行最终解剖后,采集肺门淋巴结,与特应性皮炎模型同样地,用流式细胞仪法解析淋巴结中的过敏相关免疫细胞(辅助T细胞、IgE阳性B细胞和活性化树突状细胞)的个数。其结果,对于全部的过敏相关免疫细胞,观察到动物乳杆菌给药组和约氏乳杆菌给药组的肺门淋巴结中的各细胞数的显著减少。特别是动物乳杆菌给药组的减少显著(图9)。
接下来,将从肺门淋巴结采集的辅助T细胞在CD3和CD28抗体的存在下培养,测定炎症性细胞因子(IL-4、IL-5、IL-9、IL-13和IL-17)的产生量。其结果,与对照组相比较,在动物乳杆菌给药组和约氏乳杆菌给药组中,任一炎症性细胞因子的产生量均显著地减少(图10)。特别是动物乳杆菌给药组与约氏乳杆菌给药组相比,观察到炎症性细胞因子的产生量的显著减少。
将过敏性哮喘模型小鼠最终解剖时使用PBS清洗肺,并使用流式细胞仪法对该清洗液(肺泡清洗液,BALF)中的嗜酸性粒细胞数和中性粒细胞数进行计数(图11)。对于任一的细胞种,在动物乳杆菌给药组和约氏乳杆菌给药组中均观察到细胞数的减少,特别是在动物乳杆菌给药组中,观察到显著的细胞数的减少。
产业上的可利用性
本发明提供发挥抑制过敏发作的效果的组合物,除了医学、兽医学领域以外,还可期待在饮食品制造领域中的利用。
保藏编号
保藏编号NITE BP-03137
保藏编号NITE BP-03138
保藏编号NITE BP-03139
保藏编号NITE BP-03140。
Claims (7)
1.一种组合物,其中,含有属于动物乳杆菌的乳酸菌或其菌体处理物。
2.根据权利要求1所述的组合物,其中,所述乳酸菌是以保藏编号NITE BP-03137、保藏编号NITE BP-03138、保藏编号NITE BP-03139和/或保藏编号NITE BP-03140保藏的动物乳杆菌菌株。
3.根据权利要求1或2所述的乳酸菌或组合物,其具有抗过敏活性。
4.根据权利要求1~3中任一项所述的组合物,其中,所述组合物为饮食品组合物。
5.根据权利要求1~3中任一项所述的组合物,其中,所述组合物为药物组合物。
6.根据权利要求1~3中任一项所述的组合物,其中,所述组合物为饲料组合物。
7.根据权利要求1~3中任一项所述的组合物,其中,所述组合物为卫生用组合物。
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JP2008545428A (ja) * | 2005-05-31 | 2008-12-18 | ザ・アイムス・カンパニー | ネコ科動物プロバイオティックであるラクトバシラス |
WO2009116382A1 (ja) * | 2008-03-19 | 2009-09-24 | 森下仁丹株式会社 | 血中リン濃度上昇抑制剤 |
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