CN105671120B - 具有肠内腐败物质的减少作用的双歧杆菌 - Google Patents
具有肠内腐败物质的减少作用的双歧杆菌 Download PDFInfo
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- CN105671120B CN105671120B CN201610085654.8A CN201610085654A CN105671120B CN 105671120 B CN105671120 B CN 105671120B CN 201610085654 A CN201610085654 A CN 201610085654A CN 105671120 B CN105671120 B CN 105671120B
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- bifidobacterium
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Classifications
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
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- A—HUMAN NECESSITIES
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- A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
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Abstract
本发明的第1课题在于有效利用安全性高的有用微生物来有效减少肠内腐败物质。本申请发明人着眼于通常在人的活体内(肠内)占优势的双歧杆菌而进行筛选,对吲哚的减少作用强、并确认到血清中的硫酸吲哚酚的减少作用的菌株进行挑选,从而完成了本申请发明。
Description
本申请是国际申请日为2011年7月5日、国际申请号为PCT/JP2011/065350、进入国家阶段的申请号为201180033393.0、发明名称为“具有肠内腐败物质的减少作用的双歧杆菌”的PCT申请的分案申请。
技术领域
本申请发明涉及肠内细菌的状态的改善方法。更具体地,涉及减少肠内细菌导致的作为腐败气味原因的吲哚系化合物的有用微生物的挑选和该挑选所得的微生物。
背景技术
由于饮食生活的混乱、生活的不规则、压力等,具有反复便秘、腹泻,或腹涨、产气等症状的人不断增多。这些症状被认为受肠内环境所影响,换言之,其原因在于肠内菌群(群落)中腐败菌成为优势。并且,肠内菌群在厌氧条件下由色氨酸产生吲哚或其衍生物等腐败气味成分。对这种肠内菌群与腐败产物的产生的关系进行了大量研究(非专利文献1)。
另外,认为吲哚通过肠内腐败菌而由色氨酸产生、并由肠道吸收后,在肝脏中被代谢为吲哚酚,进而与硫酸结合,形成硫酸吲哚酚。认为对健康人而言硫酸吲哚酚***至尿中,但对透析患者等而言则成为***等合并症的病因(非专利文献2)。
对于作为肠内有害物质的吲哚等的除去,例如,专利文献1中使用具有吲哚减少能力的嗜热双歧杆菌(ビフィドバクテイルム/サーモフィラム)。另外,专利文献2中记载了将五层龙属植物的提取物或微粉碎物与乳酸菌和/或双歧杆菌并用来改善肠内环境。进而,专利文献3中记载了利用含有丙酸菌的组合物来促进肠道内的双歧杆菌的生长,防止放出恶臭气体。另外,还报道了菊糖、低聚糖有助于改善肠内菌群(非专利文献3)。
现有技术文献
专利文献
专利文献1:日本特开2006-158216
专利文献2:日本特开2007-031345
专利文献3:日本特开2007-186529
非专利文献
非专利文献1:肠内细菌学杂志 第19卷 169-177页(2005)
非专利文献2:透析会志 24卷 3号 312-316页(1991)
非专利文献3:The Journal of Nutrition 129(7Suppl): 1438S-1441S (1999)。
发明内容
发明要解决的技术问题
已知人的活体内(肠内)生成的腐败物质会促进癌症发生、老化,认为只要可积极地减少活体内的腐败物质,即可有助于人的健康。因此首先,本申请发明中的课题在于,有效利用安全性高的有用微生物来有效地减少肠内腐败物质。
上述腐败物质主要在大肠内生成时,作为大肠内的优势微生物(菌种)的一例,有乳酸菌、双歧杆菌(双歧杆菌属)。该双歧杆菌自古以来作为在活体内发挥有用功能的微生物而被用于食品,具有饮食经验的实际成绩。因此,本申请的第1课题在于,由在人的活体内(肠内)占优势的双歧杆菌中挑选可以有效地减少腐败物质的微生物(菌株)。
然而,以往主要是利用体外的体系来寻找减少活体内(肠内)生成的腐败物质的物质或微生物。由于目前还不能在体外再现肠内菌群,因而对是否能反映实际肠内状况而进行实验存有疑问。因此,本申请发明的第2课题在于,提供合适的体外和体内的体系来作为减少在活体内(肠内)生成的腐败物质的物质或微生物的作用效果的验证或寻找体系。
进而,本申请发明的第3课题在于,提供对透析患者等具有减少作为合并症病因的硫酸吲哚酚在血清中的浓度的效果的微生物。
用于解决技术问题的手段
作为安全性高的有用的微生物,本申请发明人基于本申请发明的筛选方法,从乳酸菌和双歧杆菌中分离有效减少肠内腐败物质的菌株,从而完成了本申请发明。
作为减少在活体内(肠内)生成的腐败物质的物质或微生物的作用效果的验证体系,本申请发明人研究了下述方法:在体外进行筛选之际使用缓冲液再现菌体难以增殖的条件,评价腐败物质的减少效果(减少能力)。并且,本申请发明人确立了减少肠内细菌产生的腐败物质的微生物(乳酸菌、双歧杆菌等)的体外挑选方法和/或评价方法,该方法的特征在于,将反应溶液设定(设计)为乳酸菌、双歧杆菌基本不增殖的条件,并且为减少腐败物质所需的最低限的能量的葡萄糖量。
另外,作为减少在活体内(肠内)生成的腐败物质的物质或微生物的作用效果的验证体系,本申请发明人研究了在体内进行筛选之际使用小鼠,由血清中测量硫酸吲哚酚。并且 ,本申请发明人确立了降低血清中的硫酸吲哚酚的产生的微生物(乳酸菌、双歧杆菌等)的体内挑选方法和/或评价方法,该方法的特征在于,将低聚果糖(FOS)和/或低聚半乳糖(GOS)以及色氨酸(L-色氨酸)添加至饲料(粉饲料)中饲养小鼠,评价血清中的硫酸吲哚酚的浓度。
进而,为了挑选可有效减少腐败物质的微生物(菌株),首先,本申请发明人着眼于通常在人的活体内(肠内)占优势的双歧杆菌,对短双歧杆菌(Bifidobacterium breve)的32菌株、长双歧杆菌(Bifidobacterium longum)的92菌株、青春双歧杆菌(Bifidobacterium adolescenti)的72菌株的总计196菌株实施筛选,在体外进行评价,预挑选出9株作为安全性高的有用微生物。接着,为了验证在活体内减少腐败物质的作用、效果,对于上述挑选的9株实施动物实验,进行体内评价,挑选出吲哚减少作用强并确认到血清中的硫酸吲哚酚的减少作用的短双歧杆菌OLB6129,从而完成了本申请发明。
另外,本申请发明中,包含药物和食品,其中含有上述挑选的吲哚减少作用强、显示血清中的硫酸吲哚酚的减少作用的双歧杆菌作为有效成分。
本说明书包含作为本申请优选权基础的日本专利申请2010-152962号的说明书和/或附图中记载的内容。
发明效果
本申请发明的短双歧杆菌(B. breve)是来源于人的菌株,在该菌株自身不增殖的体系中,实现了显著减少吲哚和血清中的硫酸吲哚酚的优异效果。另外,长期被食用的B.breve的安全性高,本发明的双歧杆菌OLB6129也可以在食品领域、药品领域广泛适用或应用。
附图说明
[图1]对小鼠给予短双歧杆菌(活菌)引起的对血清中的硫酸吲哚酚的浓度的影响
[图2]对小鼠给予长双歧杆菌(活菌)引起的对血清中的硫酸吲哚酚的浓度的影响
[图3]对小鼠口服给予B. breve OLB6129(活菌)中的、B. breve OLB6129(活菌)的浓度引起的对血清中的硫酸吲哚酚的浓度的影响
[图4]在TOS丙酸琼脂培养基中检测到的便中(Fecal)和盲肠内容物(cecal)中的B. breve OLB6129的菌落数
[图5]对小鼠口服给予B. breve OLB6129(活菌)中的、有无添加FOS引起的对血清中的硫酸吲哚酚的浓度的影响
[图6]在TOS丙酸琼脂培养基中检测到的便中(Fecal)中的B. breve OLB6129的菌落数与有无添加FOS的关系。
具体实施方式
1.首先
已知人的活体内(肠内)生成的腐败物质会促进癌症发生、老化,认为只要可积极地减少活体内的腐败物质,即可有助于人的健康。作为主要在大肠内生成的腐败物质,可以列举苯酚、对甲酚、吲哚、粪臭素、氨等。这些腐败物质之中,特别是吲哚、粪臭素等是恶臭成分,另外还是有可能对健康带来不良影响的成分,因而期望减少吲哚、粪臭素。
作为大肠内的优势微生物(菌种)的一例,有乳酸杆菌、双歧杆菌(双歧杆菌属)。双歧杆菌自古以来作为在活体内发挥有用功能的微生物而被用于食品。另外,双歧杆菌被认为具有整肠作用,因而还被用于整肠剂等,也有助于肠内菌群的改善,认为通过改善肠内环境,对抑制腹泻、防止皮肤粗糙、改善花粉病、免疫力的道教等也有效。
2.用于验证、寻找减少肠内腐败物质的微生物的作用效果的评价体系
2-1.减少肠内腐败物质的微生物的体外筛选或预筛选
为了使用微生物,在肠内环境下减少肠内腐败物质(在肠内生成并产生恶臭成分等的物质),重要的是该特定的微生物在肠内是优先存在的。即,作为这种微生物应具备的性质,要求对于适应肠内环境的条件的耐性。
因此,理想的是适用符合肠内环境中存在的微生物(菌体)的状态(实际情况)的筛选方法、评价方法。因此,在体外筛选减少肠内腐败物质的物质或微生物时,本申请发明人首先使用缓冲液来再现微生物难以增殖的条件,研究了肠内腐败物质的减少效果(减少能力)的评价方法。通过采用上述条件,可以挑选即使微生物不增殖,也能够除去腐败物质的、在更接近肠内环境的条件下优异的微生物。例如,可以以设定对象微生物基本不增殖的条件、并且减少腐败物质所需的最低限的能量那样的条件,来决定反应溶液的成分、浓度。
更具体地,对于作为能量源的培养基成分的配合量,例如,使葡萄糖、乳糖、果糖等的浓度比对象微生物的通常的培养条件低,并且作为可以除去肠内腐败物质的程度,可适用0.3~0.7(w/v)%。
应予说明,筛选(评价・挑选)方法(体外试验)中,例示了对葡萄糖之类的碳源的反应溶液的浓度进行研究的结果,但即使是其它成分,也可以同样决定反应溶液的组成、浓度。
2-2.减少肠内腐败物质的微生物的体内筛选
以前,未能实施动物实验由体内充分确认血清中的硫酸吲哚酚的减少效果。血清中的硫酸吲哚酚的减少效果,虽然期待在肠内发挥,但即使将微生物(菌体)给予至活体内,也认为在到达肠内之前其大部分有可能死亡、或在到达肠内之后其有可能不能稳定维持(保持)。因此,本申请发明中,在将微生物给予至活体内后,期待有助于其存活性、稳定性等的提高而试着将低聚果糖(FOS)添加至饲料中时,可确认到血清中的硫酸吲哚酚的减少效果。
另外,动物实验中通常所使用的小鼠是幼龄的健康个体,因而活体内的腐败物质会被抑制到极少量,多数情况会低于检测限。因此,本申请发明中,在使用小鼠的动物实验中,将在活体内作为吲哚前体的色氨酸(L-色氨酸)添加至饲料(粉饲料)中,以尝试提高在活体内生成的吲哚的基线时,对于吲哚的基线,确认到了显著性上升。即,变得可以稳定作为腐败物质的指标(标志物)的血清中的硫酸吲哚酚的浓度而确切地进行评价。并且,对于特定的菌株,变得能够以与对照组比较的显著性差异的形式来评价、确认腐败物质的减少效果。
更具体地,可以将低聚果糖(FOS)和/或低聚半乳糖(GOS)以及色氨酸(L-色氨酸)以规定的浓度添加至饲料(粉饲料)中来喂养通常的小鼠(动物实验用),评价血清中的硫酸吲哚酚的浓度。此时,作为低聚果糖(FOS)和/或低聚半乳糖(GOS)的总量的浓度,设定为0.5~20(w/v)%,优选设定为0.5~15(w/v)%,更优选设定为0.5~10(w/v)%。应予说明,具体的实验结果省略,但作为低聚果糖(FOS)的浓度设定为0.5(w/v)%时,作为粪便中的活菌数,确认到了B. breve OLB6129的存活性显著提高。另外,作为色氨酸的浓度,设定为1~4(w/v)%,优选设定为1.5~3.5(w/v)%,更优选设定为2~3(w/v)%。由此,可以在体内挑选和/或评价、或确认使血清中的硫酸吲哚酚的产生降低的微生物(乳酸菌、双歧杆菌等),特别是双歧杆菌(双歧杆菌属的微生物)。
3.使肠内腐败物质减少的微生物
作为使肠内腐败物质减少的微生物,为了挑选能够有效减少腐败物质的微生物(菌株),本申请发明人以通常在人的活体内(肠内)占优势的乳酸菌、双歧杆菌、特别是双歧杆菌为对象进行了研究。并且,作为双歧杆菌,对于B. breve的32菌株、B. longum的92菌株、B. adolescentis的72菌株的总计196菌株实施筛选,在体外进行了评价。作为其结果,挑选出了B. breve的6菌株与B. longum的3菌株的总计9菌株。
进而,为了验证在活体内减少腐败物质的作用、效果,对上述挑选的9菌株实施动物实验,在体内进行了评价。作为其结果,挑选出了发挥肠内的吲哚的减少效果的菌株。
应予说明,筛选得到的短双歧杆菌 OLB6129(B. breve OLB6129)在2010年5月26日保藏于独立行政法人 产业技术综合研究所 特许生物寄托中心(联系地址: 邮编305-8566 日本国茨城县つくば市东1-1-1 つくば中心中央第6),本微生物以保藏编号FERM BP-11257进行保藏。
4.含有减少肠内腐败物质的微生物的食品或药品
4-1.含有减少肠内腐败物质的微生物的食品
本申请发明的减少肠内腐败物质的微生物(乳酸菌、双歧杆菌等,优选为B. breveOLB6129)可以添加至食品中。即,作为本申请发明的食品,可举出添加有减少肠内腐败物质的微生物的任意食品,优选可以举出添加有减少肠内腐败物质的微生物的发酵乳制品或发酵乳饮料,进一步优选可举出添加有减少肠内腐败物质的微生物(B. breve OLB6129)、以及低聚果糖(FOS)和/或低聚半乳糖(GOS)的发酵乳制品或发酵乳饮料。应予说明,已知GOS可以与FOS相同地进行利用(http://www.nyusankin.or.jp/scientific/hosono_3.html)。另外,对于低聚果糖(FOS)和/或低聚半乳糖(GOS)的添加量,以总量的浓度计,可以设定为0.5~20(w/v)%,优选设定为0.5~15(w/v)%,更优选设定为0.5~10(w/v)%。
另外,含有本申请发明的减少肠内腐败物质的微生物(乳酸菌、双歧杆菌等,优选为B. breve OLB6129)的食品可以作为肾脏透析患者用的用于预防或改善透析合并症的健康保健食品(功能性食品)适用。
4-2.
含有本申请发明的减少肠内腐败物质的微生物(乳酸菌、双歧杆菌等,优选为B.breve OLB6129)的药品可以作为肠内腐败物质的减少剂、或肾脏透析患者用的透析合并症的预防剂或改善剂适用。进而,本申请发明的药品还可作为腹涨的改善剂适用。
本申请发明的药品可以制为散剂、颗粒剂、片剂、胶囊剂、溶液剂等适宜的剂型。本申请发明的药品中可以含有低聚果糖(FOS)和/或低聚半乳糖(GOS)。应予说明,以总量的浓度计,低聚果糖(FOS)和/或低聚半乳糖(GOS)的含量可以设定为0.5~20(w/v)%,优选设定为0.5~15(w/v)%,更优选设定为0.5~10(w/v)%。制剂化中,可以添加赋形剂、粘合剂、崩解剂、润滑剂等为了制剂化而常用的辅助剂。作为赋形剂,例如有淀粉、乳糖、白糖、甲基纤维素、羧甲基纤维素、藻酸钠、磷酸氢钙、合成硅酸铝、微晶纤维素、聚乙烯基吡咯烷酮(PVP)、羟丙基淀粉(HPS)等。另外,作为粘合剂,例如有淀粉、微晶纤维素、羧甲基纤维素钠、聚乙烯基吡咯烷酮(PVP)、***树胶粉末、明胶、葡萄糖、白糖等的水溶液、或它们的水・乙醇溶液等。并且,作为崩解剂,例如有淀粉、羧甲基纤维素、羧甲基纤维素钙、微晶纤维素、羟丙基淀粉、磷酸钙等。进而,作为润滑剂,例如有巴西棕榈蜡、轻质无水硅酸、合成硅酸铝、天然硅酸铝、合成硅酸镁、氢化油、氢化植物油衍生物(Sterotex HM)、芝麻油、蜂蜡、氧化钛、干燥氢氧化铝・凝胶硬脂酸、硬脂酸钙、硬脂酸镁、滑石、磷酸氢钙、和十二烷基硫酸钠等。
本申请发明的药品理想的是口服给予,对于双歧杆菌,由于安全性得到确定,因而可以给予任意的量,例如,其给予量可以设为每1天给予双歧杆菌10亿个~5000亿个,优选为100亿个~5000亿个。
实施例
[参考例1]具有腐败物质的减少作用的微生物的挑选方法“体外试验”的条件设定
首先,对于反应溶液的组成,以双歧杆菌基本不增殖、发挥吲哚(肠内腐败物质的指标)的减少效果、并可明确地评价该效果的方式来决定反应溶液的组成。
本次实验中使用的反应溶液中,例如,将葡萄糖设定为1.0(w/v)%时,双歧杆菌会过量增殖,不能充分再现肠内的环境。即,由于双歧杆菌等微生物(菌体)在肠内基本不增殖,因而为了在接近肠内环境的状态下评价双歧杆菌等实现的腐败物质的减少效果,应当设定双歧杆菌基本不增殖的条件,以再现上述环境。因此,将葡萄糖设定为例如0.7(w/v)%以下,优选设定为0.6(w/v)%以下,更优选设定为0.55(w/v)%以下。
另外,对于本次实验中使用的反应溶液,应当设定双歧杆菌基本不增殖而提供腐败物质的减少所需的最低限能量的条件,因而认为原来将培养基成分作为底物配合是不合适的。
另一方面,对于本次实验中使用的反应溶液,例如,将葡萄糖设定为0.1(w/v)%时,双歧杆菌的活动(活性)降低,难以发挥吲哚的减少效果。这样,虽然原本双歧杆菌的每个菌种对吲哚的减少效果等变现出差异,但该差异变得难以体现,难以明确地评价其效果。因此,将葡萄糖设定为,例如,0.3(w/v)%以上,优选0.4(w/v)%以上,更优选0.45(w/v)%以上。另外,对于其它成分也相同地决定反应溶液的组成。
作为反应溶液的组成,可以按照苯酚・对甲酚・吲哚・粪臭素各20 μg、Bis-Tris0.1M、硫酸镁(MgSO4) 0.75mM、葡萄糖 0.5(w/v)%来使用,pH为6.5左右。
[实施例1]具有腐败物质的减少作用的微生物的挑选“体外试验”
对于B. breve的34菌株、B. longum的93菌株、B. adolescentis的72菌株的总计199菌株,进行静置培养时,B. breve的2菌株、B. longum的1菌株中,生长极其迟缓。因此,以上述3菌株作为实验对象,最终对于B. breve的32菌株、B. longum的92菌株、B.adolescentis的72菌株的合计196菌株进行了筛选(评价・挑选)。
将上述菌株(活菌)各1 mg混悬于参考例1中决定的反应溶液(pH:6.5、苯酚・对甲酚・吲哚・粪臭素:各20μg、Bis-Tris:0.1M、硫酸镁(MgSO4):0.75mM、葡萄糖:0.5(w/v)%)2ml中。并且,将该悬浊液(反应溶液)在37℃静置24h进行反应后,离心分离,除去双歧杆菌(菌体),将其上清的pH调整至7。
接着,将该上清用二***分2次提取,将该提取液补足至5ml后,通过气象色谱法(GC)对该溶液测定(检测)吲哚、苯酚、对甲酚、粪臭素的浓度。
应予说明,气象色谱法(GC)的分析条件如下所述。即,装备有火焰离子化探测器的检测器: GC-2014 (Shimadzu),柱(尺寸): TC-1 (GL Sciences Inc.), I.D.=0.25 mm, L=30 m, dF=0.25 mm、柱温: 60-170℃ (以5℃/min升高), 170-250℃ (以20℃/min升高)、载气: 氮、流速: 71.3 ml/min、注射器温度: 240℃、检测器温度: 250℃、注射体积: 1 μl。
该结果示于表1(B. breve的32菌株)、表2(B. longum的92菌株)、表3(B.adolescentis的72菌株)。
应予说明,整理编号以“JCM”开始的菌株保藏于下述的保藏机构。
保藏机构名:独立行政法人理化学研究所バイオリソースセンター 微生物材料开发室(联系地址:邮编351-0198 日本国埼玉县和光市広沢2-1、电话号码048-467-9560)。
[表1]
[表2]
[表3]
上述结果中,对相对于微生物(菌体)1g的吲哚的减少浓度为13mg/g-细胞 以上的菌株进行了挑选,结果符合的是B. breve的6菌株、与B. longum的3菌株的总计9菌株。应予说明,吲哚的减少浓度为13mg/g-细胞以上是指吲哚的减少率为65%以上。
[实施例2]具有腐败物质的减少作用的微生物的挑选“体内试验(动物实验)”
将上述实施例1中挑选的9菌株通过动物实验(体内试验)进行筛选(评价・挑选)。
购入Balb/c小鼠后,使之自由摄取饲料(粉末CRF-1/FOS(和光纯药工业(株)):10(w/v)%、L-色氨酸:2.5(w/v)%)1周,进行驯化。该驯化期间结束后,将规定的菌株(活菌)悬浮于生理盐水,按照1天1次的频率在午前连续给予2周。此时,生理盐水的给予容量、各菌株的给予容量、各菌株的给予浓度分别为1010cfu/ml、0.2ml/只/天、2x109cfu/只/天。在该给予期间(2周)结束时进行采全血,测定血清中的硫酸吲哚酚的浓度。
应予说明,给予小鼠的菌株(活菌)是在体外试验中挑选(筛选)的。具体地,挑选了B. breve的6菌株(MEP22023004、OLB6129、MEP22023007、MEP22023012、MEP22023015、MEP22023016)、与B. longum的3菌株(MEP22023039、MEP22023061、MEP22023078)。并且,使用等容量的生理盐水作为对照组,与规定菌株(活菌)的给予组对腐败物质的减少效果进行了比较。其结果示于图1(B. breve的6菌株)、图2(B. longum的3菌株)。
上述结果中,将B. breve的6菌株(图1)、与B. longum的3菌株(图2)以活菌给予小鼠,在该给予期间结束时测定小鼠的血清中的硫酸吲哚酚的浓度,结果在B. breveOLB6129的给予组中,确认到其浓度与对照组相比显著减少。即,对于B. breve OLB6129(FERM BP-11257)的给予组,与对照组相比,在血清中的硫酸吲哚酚的浓度中确认到了显著的减少。由该结果,暗示了B. breve OLB6129在活体内可以减少腐败物质。
[实施例3]对活体给予的 B. breve OLB6129 的浓度对腐败物质的减少效果的影响
[实验步骤]
将Balb/c小鼠(SLC, ♀, 6周龄)驯化一周后,如表4所示,基于体重分为4组,对各组,将生理盐水与生理盐水的 B. breve OLB6129(活菌)悬浊液连续在午前口服给予2周。驯化期间使全部组自由摄取饲料(粉末CRF-1/FOS(和光纯药工业(株)):10(w/v)%、L-色氨酸:2.5(w/v)%)。
[表4]
(1)B. breve OLB6129的给予期间的2周后,由尾静脈采血,测定血清中硫酸吲哚酚的浓度。将血清用超纯水(Milli-Q)稀释至100倍后,用SYRINGELESS FILTER DEVICE 0.2μm (Whatman)过滤,根据现有报道(Takayama et al., Am J Kidney Dis. 2003 Mar;41(3 Suppl 1):S142-5),通过高效液相色谱(HPLC)进行测定。
(2)在B. breve OLB6129的给予期间结束时采集便,在解剖时采集盲肠内容物,测定各自所含的B. breve OLB6129(投与菌)的菌数。
[实验结果]
在B. breve OLB6129的给予期间结束时,确认血清中硫酸吲哚酚的浓度,对于硫酸吲哚酚的浓度的减少效果,2 x 108 cfu/只/天的给予组(III)和2 x 109 cfu/只/天的给予组(IV)中,与生理盐水的给予组(对照)(I)相比具有显著差异,但2 x 107 cfu/只/天的给予组(II)cfu/只与生理盐水的给予组(对照)(I)相比,不具有显著差异(图3)。
另外,便中与盲肠内容物中的B. breve OLB6129(投与菌)以用量依存性的方式检测到(图4)。
[实施例4]对活体给予FOS的有无对腐败物质的减少效果的影响
[实验步骤]
将Balb/c小鼠(SLC, ♀, 6周龄)驯化一周后,如表5所示,基于体重分为4组,对于各组,将未添加FOS的生理盐水和生理盐水的 B. breve OLB6129(活菌)的悬浊液、添加了FOS的生理盐水和生理盐水的 B. breve OLB6129(活菌)的悬浊液连续在午前口服给予2周。驯化期间是全部组自由摄取饲料(粉末CRF-1/L-色氨酸:2.5(w/v)%)。应予说明,对于B.breve OLB6129(活菌)的浓度,在实施例3中设定为关于腐败物质的减少效果显示必要性的最低限用量即,2 x 108 cfu/只/天。
[表5]
(1)FOS的给予期间的2周后,由尾静脈采血,测定血清中硫酸吲哚酚的浓度。将血清用超纯水(Milli-Q)稀释至100倍后,用SYRINGELESS FILTER DEVICE 0.2 μm (Whatman)过滤,根据现有报道(Takayama et al., Am J Kidney Dis. 2003 Mar;41 (3 Suppl 1):S142-5),通过高效液相色谱(HPLC)进行测定。
(2)FOS的给予期间结束时,采集B. breve OLB6129给予组的便,测定通过活体内的B. breve OLB6129(投与菌)的菌数。
[实验结果]
FOS的给予期间结束时,确认血清中硫酸吲哚酚的浓度,仅B. breve OLB6129的给予组中,硫酸吲哚酚的浓度的减少效果小(图5)。另外,对于硫酸吲哚酚的浓度的减少效果,对于仅FOS的给予组,与生理盐水的给予组(I)相比,没有显著差异(图5)。另一方面,对于硫酸吲哚酚的浓度的减少效果,在B. breve OLB6129和FOS的给予组中,与生理盐水的给予组(I)等相比,具有显著差异(图5)。应予说明,对于仅B. breve OLB6129的给予组、和B.breve OLB6129与FOS的给予组的2组(OLB6129 +),测定便中的 B. breve OLB6129(投与菌)的菌数,结果在FOS的给予组中观察到活菌数显著增高(图6)。
[保藏编号]
FERM BP-11257
本说明书中引用的全部发行刊物、专利和专利申请作为参考全部引入本说明书中。
Claims (4)
1.使肠内腐败物质减少的双歧杆菌的体内筛选方法,所述方法的特征在于,将双歧杆菌、低聚果糖(FOS)和L-色氨酸给予小鼠,饲养小鼠,评价血清中的硫酸吲哚酚的浓度。
2.权利要求1所述的方法,其中,使低聚果糖(FOS)的浓度为0.5~20(w/v)%,使L-色氨酸的浓度为1~4(w/v)%。
3.权利要求1或2所述的方法,其特征在于,预先实施使肠内腐败物质减少的双歧杆菌的体外筛选方法,所述体外筛选方法由包含下列的方法组成:在双歧杆菌基本不增殖的条件下,向反应液添加为肠内腐败物质的减少所需的最低限的能量的葡萄糖的浓度,并且评价向所述反应液添加的肠内腐败物质的减少效果。
4.权利要求3所述的方法,其中,使葡萄糖的浓度为0.3~0.7(w/v)%。
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