JPWO2007020884A1 - Bifidobacteria or lactic acid bacteria having an effect of preventing infection via β-defensins and food / pharmaceutical compositions containing the same - Google Patents
Bifidobacteria or lactic acid bacteria having an effect of preventing infection via β-defensins and food / pharmaceutical compositions containing the sameInfo
- Publication number
- JPWO2007020884A1 JPWO2007020884A1 JP2007530977A JP2007530977A JPWO2007020884A1 JP WO2007020884 A1 JPWO2007020884 A1 JP WO2007020884A1 JP 2007530977 A JP2007530977 A JP 2007530977A JP 2007530977 A JP2007530977 A JP 2007530977A JP WO2007020884 A1 JPWO2007020884 A1 JP WO2007020884A1
- Authority
- JP
- Japan
- Prior art keywords
- bifidobacteria
- bifidobacterium
- strain
- defensin
- lactic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
本発明はβ―ディフェンシンの発現量を高めることにより感染予防効果を有するビフィズス菌または乳酸菌を提供する。これを動物細胞に前もってあるいは同時に感作することで、多量の大腸菌などの病原菌に感染した際にβ―ディフェンシンの発現量を飛躍的に高めることができる。また、当該ビフィズス菌及び／または乳酸菌を有効成分として含有する、β−ディフェンシンの発現量を高めることにより感染予防効果を有する食品・医薬品組成物を提供する。 The present invention provides bifidobacteria or lactic acid bacteria that have an effect of preventing infection by increasing the expression level of β-defensin. By sensitizing this to animal cells in advance or simultaneously, the expression level of β-defensin can be dramatically increased when a large amount of pathogenic bacteria such as E. coli is infected. The present invention also provides a food / pharmaceutical composition having an infection-preventing effect by increasing the expression level of β-defensin, containing the bifidobacteria and / or lactic acid bacterium as an active ingredient.
Description
本発明は、抗菌ペプチドとして知られているβ−ディフェンシンの発現を促進し、感染予防効果を発揮可能なビフィズス菌または乳酸菌、および上記菌を含有する食品・医薬品組成物に関する。 The present invention relates to bifidobacteria or lactic acid bacteria capable of promoting the expression of β-defensin known as an antibacterial peptide and exhibiting an infection preventing effect, and a food / pharmaceutical composition containing the above bacteria.
植物、昆虫、哺乳動物を含む高等動物等は、自己防衛のために抗菌物質を産生する能力を有している。特に、皮膚、消化器、呼吸器などの外部と接触する粘膜上皮細胞は、抗菌物質（内因性抗菌ペプチド）分泌能を有し、病原菌を排除する役割を果たす。 Higher animals including plants, insects and mammals have the ability to produce antibacterial substances for self-protection. In particular, mucosal epithelial cells that come into contact with the outside such as the skin, digestive organs, respiratory organs, etc. have the ability to secrete antibacterial substances (endogenous antibacterial peptides) and play a role of eliminating pathogenic bacteria.
近年、大腸菌などにより誘導される抗菌ペプチドとして、ディフェンシンが注目されている。ディフェンシンは、６つのシステイン残基による３つのＳ−Ｓ結合を持ち、Ｓ−Ｓ結合の違いからα−ディフェンシン、β−ディフェンシンに分けられる。α−ディフェンシンは主に、好中球などから、β−ディフェンシンは消化管、皮膚、口腔、気管などの上皮細胞から分泌される。 In recent years, defensin has attracted attention as an antimicrobial peptide induced by Escherichia coli and the like. Defensins have three SS bonds with six cysteine residues, and are classified into α-defensins and β-defensins based on differences in SS bonds. α-Defensin is mainly secreted from neutrophils and the like, and β-defensin is secreted from epithelial cells such as the digestive tract, skin, oral cavity and trachea.
β−ディフェンシンとしては、β−ディフェンシン１〜３（以下、ヒトβ−ディフェンシン１，２，３をｈＢＤ１，２，３と省略する場合がある）が発見されている。ｈＢＤ１は構成的に、ｈＢＤ２、３は誘導的に発現する。
As β-defensins, β-
β−ディフェンシンは、肥満細胞や樹状細胞などに対する走化性を示し、自然免疫系だけでなく、獲得免疫系でも重要な働きを示すことが示唆されている。 β-Defensin exhibits chemotaxis to mast cells, dendritic cells, etc., and has been suggested to exhibit important functions not only in the innate immune system but also in the acquired immune system.
特にヒトβ―ディフェンシン２は、大腸菌や齲蝕原因細菌（例えばＳｔｒｅｐｔｏｃｏｃｃｕｓ ｍｕｔａｎｓ）、黄色ブドウ球菌などの病原菌に対して高い抗菌作用を示すことが知られている（非特許文献１，２）。
In particular, human β-defensin 2 is known to exhibit high antibacterial action against pathogenic bacteria such as Escherichia coli, caries-causing bacteria (for example, Streptococcus mutans), and Staphylococcus aureus (Non-patent
このようなβ―ディフェンシンの抗菌作用を利用した食品または医薬品が開発できれば、感染予防上極めて有用と考えられる。実際、ヒトβ―ディフェンシン２の抗菌作用に着目し、これを食品や医薬品に利用しようとする動きがある。例えば、生体防御機構の強化可能な食品、医薬品等を提供するため、ｈＢＤ２のmRNAを増幅可能なプライマーを用いて、抗菌ペプチドの産生を誘導または増強することのできる因子を食品素材中から検出する方法が知られている（特許文献１及び、その分割出願である特許文献２）。
It would be extremely useful in preventing infection if a food or drug utilizing the antibacterial action of β-defensin could be developed. In fact, there is a movement to focus on the antibacterial action of human β-defensin 2 and to use it for food and medicine. For example, in order to provide foods, pharmaceuticals, and the like that can enhance the defense mechanism of a living body, a factor capable of inducing or enhancing the production of antibacterial peptides is detected from a food material using a primer capable of amplifying hBD2 mRNA. A method is known (
上記特許文献１および２の実施例は、複数種類の食品素材抽出液をヒト表皮角化細胞に添加して培養し、各食品素材抽出液による、ｈＢＤ２発現増強効果を観察している。しかし、該実施例で使用された食品素材抽出液については、その性状などに関し、必ずしも当業者が再現可能なほど特定されていない。特に、特許文献１および２の実施例で使用された食品として「ビフィズス菌末」なる物質の開示はあるが、該ビフィズス菌の具体的な菌種や「菌末」の特性について一切詳細な記載はいない。また、特許文献１および２の実施例では、焼酎もろみ、ローストアマランス、甘酒、ロースト小麦胚芽、ハイチュウ用濃縮ヨーグルトエキスにｈＢＤ２の誘導増強作用があることを確認しているが、一方、「ビフィズス菌末」によるｈＢＤ２発現の誘導効果あるいは誘導増強効果は確認されていない（特許文献１および２、実施例４、実施例６、票４および図２）。
In the examples of
一方、ワン・ジー（Ｗａｎｇ Ｇ）等は、ヒト結腸由来の培養細胞であるＨＴ−２９において、ビフィズス菌（ビフィドバクテリウム・ロンガム（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｌｏｎｇｕｍ））によるβ―ディフェンシン２の誘導能を評価し、熱処理されたビフィズス菌、ビフィズス菌の細胞壁および細胞壁タンパク質が、HT-29におけるｈＢＤ２の産生が誘導されることをmRNAレベルで確認したと報告している（非特許文献３）。しかし上記報告のように、ビフィズス菌または処理物自身がｈＢＤ２を誘導するのであれば、ビフィズス菌を医薬品や食品として摂取したとしても、ビフィズス菌が排除されるべき微生物と認識されてしまうことになってしまい、上記報告は、ビフィズス菌を感染予防物質として有効利用することを、反って否定することになりかねない。 On the other hand, Wang G et al. Evaluated β-defensin 2 induction ability by Bifidobacterium (Bifidobacterium longum) in HT-29, which is a cultured cell derived from human colon. It has been reported that heat treated bifidobacteria, cell walls and cell wall proteins of bifidobacteria have been confirmed at the mRNA level to induce the production of hBD2 in HT-29 (Non-patent Document 3). However, as described above, if the bifidobacteria or the processed product itself induces hBD2, even if the bifidobacteria is ingested as a medicine or food, the bifidobacteria will be recognized as a microorganism to be excluded. In other words, the above report may deny the effective use of bifidobacteria as an infection-preventing substance.
本発明は、上記状況に鑑みてなされたものであり、本発明が解決しようとする課題は、簡便な手段で抗菌ペプチドとして有用と考えられるβ−ディフェンシンの発現を促進し、その発現量を増加させることにより、より高い感染予防効果を有する、食品または医薬品に利用可能な微生物を提供することである。 The present invention has been made in view of the above situation, and the problem to be solved by the present invention is to promote the expression of β-defensin which is considered useful as an antibacterial peptide by a simple means and increase the expression level. It is to provide a microorganism that can be used for foods or pharmaceuticals, which has a higher infection prevention effect.
本発明者等は、上記課題を解決すべく、鋭意努力した。本発明者等は、各種ビフィズス菌を培養してHT-29細胞（ヒト腸上皮由来細胞株）に添加し、ｈＢＤ２の発現量へのビフィズス菌による影響を観察した。具体的には、第一の実験系において、まずビフィズス菌刺激処理を行い、一定時間後に大腸菌刺激処理を行った。第二の実験系において、ビフィズス菌と大腸菌の共培養処理（共刺激処理）を行った。第三の実験系において、ビフィズス菌単独刺激処理を行った。この検討において、HT-29細胞にビフィズス菌単独刺激を行った場合にはディフェンシン発現促進効果は認められなかった。しかし、ビフィズス菌を大腸菌よりも先にまたは同時に上皮細胞等に暴露した場合には、大腸菌などの刺激によりHT-29細胞がディフェンシンを発現する作用が促進され、大腸菌単独刺激の場合に比べてより高いディフェンシン発現量増加が導かれることが、この検討によって初めて明らかになった。本発明者等は、上記検討により、ビフィズス菌がβ―ディフェンシン発現促進効果を有することを証明したのみならず、ビフィズス菌自体はβ―ディフェンシンによる排除対象ではないことを明らかにした。この知見は、ビフィズス菌が感染予防作用を有する食品や医薬品として有効であることを強く示唆するものである。すなわち本発明は、β−ディフェンシン発現促進作用を有する微生物に関し、具体的には下記の発明を提供するものである。 The inventors of the present invention have made extensive efforts to solve the above problems. The present inventors cultured various bifidobacteria and added them to HT-29 cells (human intestinal epithelium-derived cell line), and observed the effect of bifidobacteria on the expression level of hBD2. Specifically, in the first experimental system, bifidobacteria stimulation treatment was first performed, and E. coli stimulation treatment was performed after a certain time. In the second experimental system, co-culture treatment (co-stimulation treatment) of bifidobacteria and E. coli was performed. In the third experimental system, bifidobacteria single stimulation treatment was performed. In this study, defensin expression-promoting effect was not observed when bifidobacteria single stimulation was performed on HT-29 cells. However, when bifidobacteria are exposed to epithelial cells prior to or simultaneously with E. coli, the action of HT-29 cells to express defensin is promoted by stimulation with E. coli, etc. This study revealed for the first time that a high defensin expression level was induced. The present inventors not only proved that bifidobacteria have a β-defensin expression promoting effect, but also clarified that bifidobacteria itself is not excluded by β-defensin. This finding strongly suggests that bifidobacteria are effective as a food or medicine having an infection-preventing action. That is, the present invention relates to a microorganism having a β-defensin expression promoting action, and specifically provides the following invention.
（１） β―ディフェンシンの発現量を高めることにより感染予防作用を有するビフィズス菌または乳酸菌、
（２） 動物細胞を前もって感作することで、動物細胞が微生物に接した際に、β―ディフェンシンの発現量を１０倍以上に高めることができる、予防作用を発揮するビフィズス菌または乳酸菌、
（３） 微生物感染時にβ−ディフェンシン発現量を高め殺菌作用を強めるビフィズス菌または乳酸菌、
（４） 動物細胞が微生物に接した際に、該微生物と共に動物細胞に作用することで、β−ディフェンシンの発現量を１０倍以上に高める作用を有するビフィズス菌または乳酸菌、
（５） 前記ビフィズス菌が、ビフィドバクテリウム・ビフィダム、ビフィドバクテリウム・ロンガム、ビフィドバクテリウム・ブレーベ、ビフィドバクテリウム・インファンティス、ビフィドバクテリウム・カテヌラータム、ビフィドバクテリウム・シュードロンガム、ビフィドバクテリウム・アドレッセンティスからなる群より選ばれた少なくとも１つである、上記（１）から（４）に記載のビフィズス菌。
（６） 前記ビフィズス菌が、ビフィドバクテリウム・ビフィダムＪＣＭ１２５５Ｔ菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株、ビフィドバクテリウム・ロンガムＪＣＭ１２１７Ｔ菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株の群から選ばれた少なくとも１つの菌株である、上記（１）から（４）に記載のビフィズス菌。
（７） 前記微生物が、大腸菌、サルモネラ菌、赤痢菌、コレラ菌、チフス菌、Pseudomonas aeruginosa、Streptococcus gordonii、Porphylomonas gingivalis、Actinobacillis actinomycetemcomitans、Staphylococcus epidermidis、及びStreptococcus pyogenesからなる群より選ばれた少なくとも１種の微生物であることを特徴とする、上記（２）から（４）のいずれかに記載のビフィズス菌または乳酸菌。
（８） ビフィドバクテリウム・ビフィダムＪＣＭ１２５５Ｔ菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株、ビフィドバクテリウム・ロンガムＪＣＭ１２１７Ｔ菌株の群から選ばれた少なくとも１つの菌株であることを特徴とする、動物細胞を前もって感作することで、動物細胞が微生物に接した際に、β―ディフェンシンの発現量を１０倍以上に高めることができる、予防作用を発揮するビフィズス菌。
（９） ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株の群から選ばれた少なくとも１つの菌株であることを特徴とする、動物細胞が微生物に接した際に、微生物と共に動物細胞に作用することで、β−ディフェンシンの発現量を５倍以上に高める作用を有するビフィズス菌。
（１０） β−ディフェンシンがヒトβ−ディフェンシン２である、上記（１）から（７）のいずれかに記載のビフィズス菌または乳酸菌。
（１１） 上記（１）から（１０）のいずれかに記載のビフィズス菌及び／または乳酸菌を有効成分として含有し、β−ディフェンシンの発現量を高めることにより感染予防作用を有する食品・医薬品組成物。
（１２） 上記（１）から（１０）のいずれかに記載のビフィズス菌及び／または乳酸菌を有効成分として含有し、微生物感染時にβ−ディフェンシン発現量を高めることができる、感染予防作用を有する食品・医薬品組成物。
（１３） β―ディフェンシン発現促進能を有するビフィズス菌または乳酸菌、あるいは上記いずれかの菌の処理物のいずれかを含有する、飲食品または医薬品。
（１４） ビフィズス菌がビフィドバクテリウム・ビフィダムＪＣＭ１２５５Ｔ菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株、ビフィドバクテリウム・ロンガムＪＣＭ１２１７Ｔ菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株からなる群より選ばれる少なくとも一つの菌株である、上記（１３）記載の飲食品または医薬品。
（１５） ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株（受託番号 NITE BP-123）、またはビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株（受託番号 NITE BP-31）であるビフィズス菌。
（１６）β―ディフェンシン発現促進能を有するビフィズス菌または乳酸菌を投与する工程を含む、微生物感染症の予防または治療方法。
（１７）微生物感染症の予防または治療用食品を製造するための、β―ディフェンシン発現促進能を有するビフィズス菌または乳酸菌の使用。
（１８）微生物感染症の予防または治療用医薬品を製造するための、β―ディフェンシン発現促進能を有するビフィズス菌または乳酸菌の使用。
(1) Bifidobacteria or lactic acid bacteria having an infection-preventing action by increasing the expression level of β-defensin,
(2) Bifidobacteria or lactic acid bacteria exhibiting a preventive action that can increase the expression level of β-defensin by 10 times or more when animal cells come into contact with microorganisms by sensitizing animal cells in advance.
(3) Bifidobacteria or lactic acid bacteria that increase β-defensin expression level and enhance bactericidal action during microbial infection,
(4) Bifidobacteria or lactic acid bacteria having an effect of increasing the expression level of β-defensin by 10 times or more by acting on animal cells together with the microorganisms when the animal cells contact the microorganisms,
(5) The Bifidobacterium is Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium catenulatum, Bifidobacterium The bifidobacteria according to (1) to (4) above, which is at least one selected from the group consisting of pseudoron gum and bifidobacterium addressensetis.
(6) The Bifidobacterium is Bifidobacterium bifidum JCM1255 T strain, Bifidobacterium bifidum OLB6374 strain, Bifidobacterium bifidum OLB6378 strain, Bifidobacterium longum JCM1217 T strain, Bifidobacterium The bifidobacteria according to (1) to (4) above, which is at least one strain selected from the group of Adresentis JCM1275 T strain.
(7) The microorganism is at least one selected from the group consisting of Escherichia coli, Salmonella, Shigella, Vibrio cholerae, Salmonella typhi, Pseudomonas aeruginosa, Streptococcus gordonii, Porphylomonas gingivalis, Actinobacillis actinomycetemcomitans, Staphylococcus epidermidis, and Streptococcus pyogenes. The bifidobacteria or lactic acid bacterium according to any one of (2) to (4) above, wherein
(8) Bifidobacterium bifidum JCM1255 T strain, Bifidobacterium bifidum OLB6374 strain, Bifidobacterium bifidum OLB6378 strains, at least one strain selected from the group consisting of Bifidobacterium longum JCM1217 T strain By sensitizing animal cells in advance, the expression level of β-defensin can be increased 10-fold or more when animal cells come into contact with microorganisms, and it exhibits a preventive action. Fungus.
(9) When animal cells come into contact with microorganisms, characterized in that they are at least one strain selected from the group of Bifidobacterium bifidum OLB6374 strain and Bifidobacterium adrescentis JCM1275 T strain Bifidobacteria having an effect of increasing the expression level of β-defensin by 5 times or more by acting on animal cells together with microorganisms.
(10) The bifidobacteria or lactic acid bacterium according to any one of (1) to (7) above, wherein the β-defensin is human β-defensin 2.
(11) A food / pharmaceutical composition comprising the bifidobacteria and / or lactic acid bacterium according to any one of (1) to (10) as an active ingredient and having an action to prevent infection by increasing the expression level of β-defensin .
(12) A food having an infection-preventing action, comprising the bifidobacteria and / or lactic acid bacterium according to any one of (1) to (10) as an active ingredient and capable of increasing the expression level of β-defensin during microbial infection -Pharmaceutical composition.
(13) A food / beverage product or a pharmaceutical product containing any of bifidobacteria or lactic acid bacteria having β-defensin expression promoting ability, or a processed product of any of the above bacteria.
(14) Bifidobacterium is Bifidobacterium bifidum JCM1255 T strain, Bifidobacterium bifidum OLB6374 strain, Bifidobacterium bifidum OLB6378 strain, Bifidobacterium longum JCM1217 T strain, Bifidobacterium ad The food or drink or pharmaceutical product according to (13) above, which is at least one strain selected from the group consisting of the Resentis JCM1275 T strain.
(15) Bifidobacterium which is Bifidobacterium bifidum OLB6374 strain (Accession number NITE BP-123) or Bifidobacterium bifidum OLB6378 strain (Accession number NITE BP-31).
(16) A method for preventing or treating microbial infection, comprising a step of administering bifidobacteria or lactic acid bacteria having the ability to promote β-defensin expression.
(17) Use of bifidobacteria or lactic acid bacteria having the ability to promote the expression of β-defensins for the production of foods for preventing or treating microbial infections.
(18) Use of bifidobacteria or lactic acid bacteria having the ability to promote the expression of β-defensins for the manufacture of a medicament for the prevention or treatment of microbial infections.
本発明によって、動物細胞のβ―ディフェンシン発現を促進するビフィズス菌及び乳酸菌が提供された。本発明によるビフィズス菌及び／または乳酸菌を動物に投与することで、病原菌感染時のβ―ディフェンシンの発現量を高め、病原菌感染を簡便に予防できる。また、特に大腸菌などの病原菌が侵入・増殖した際は、本発明によるビフィズス菌及び乳酸菌は、β―ディフェンシンの発現を強く促進することができ、その結果、感染予防または治療効果を発揮すると考えられる。 The present invention provides bifidobacteria and lactic acid bacteria that promote the expression of β-defensins in animal cells. By administering bifidobacteria and / or lactic acid bacteria according to the present invention to animals, the expression level of β-defensin at the time of infection with pathogenic bacteria can be increased, and infection with pathogenic bacteria can be easily prevented. In particular, when pathogenic bacteria such as Escherichia coli enter and proliferate, the bifidobacteria and lactic acid bacteria according to the present invention can strongly promote the expression of β-defensin and, as a result, are considered to exert infection prevention or treatment effects. .
以下、本発明を詳細に説明する。
本発明は、β―ディフェンシンの発現量を高めることにより感染予防作用を有するビフィズス菌または乳酸菌を提供する。本発明者らは、動物細胞におけるβ―ディフェンシン発現が大腸菌処理によって誘導される場合に、該動物細胞に対し、大腸菌処理と同時にまたは事前にビフィズス菌処理を施すことによって、β―ディフェンシン発現量が著しく増加することを確認した。本発明においてβーディフェンシン発現量とは、β―ディフェンシンタンパク質の産生量を意味する。Hereinafter, the present invention will be described in detail.
The present invention provides bifidobacteria or lactic acid bacteria that have an infection-preventing action by increasing the expression level of β-defensin. When β-defensin expression in an animal cell is induced by treatment with E. coli, the present inventors apply the Bifidobacteria treatment to the animal cell simultaneously with or in advance of the E. coli treatment, thereby reducing the β-defensin expression level. A significant increase was confirmed. In the present invention, the expression level of β-defensin means the production amount of β-defensin protein.
本発明のビフィズス菌または乳酸菌を動物細胞に接触させると、その後、該動物細胞が病原菌などの微生物に接触した場合に誘導されるβ―ディフェンシン発現量を増加させることができる。本発明のビフィズス菌または乳酸菌によるβ―ディフェンシン発現量増加効果は顕著であり、例えば、本発明のビフィズス菌または乳酸菌で動物細胞を前もって感作することで、該動物細胞が微生物に接触した場合のβ―ディフェンシン発現量を、１０倍、さらには２０倍以上に増加させることができる。したがって、本発明のビフィズス菌または乳酸菌をヒトを始めとする動物に投与すれば、その後に該動物が微生物に感染することを予防することができる。 When the bifidobacteria or lactic acid bacteria of the present invention are brought into contact with animal cells, the expression level of β-defensin induced when the animal cells come into contact with microorganisms such as pathogenic bacteria can be increased thereafter. The effect of increasing the expression level of β-defensin by the bifidobacteria or lactic acid bacteria of the present invention is remarkable. For example, when the animal cells are contacted with microorganisms by sensitizing the animal cells with the bifidobacteria or lactic acid bacteria of the present invention in advance. The expression level of β-defensin can be increased 10 times or even 20 times or more. Therefore, if the bifidobacteria or lactic acid bacteria of the present invention are administered to animals such as humans, it is possible to prevent the animals from being infected with microorganisms thereafter.
または、本発明のビフィズス菌または乳酸菌を、病原菌などの微生物と同時に動物細胞に接触させることにより、該動物細胞におけるβ―ディフェンシン発現量を増加させることもできる。本発明のビフィズス菌または乳酸菌をこのように使用した場合も、そのβ―ディフェンシン発現促進効果は顕著であり、例えば実施例にあるように、発現量を１０倍以上までに促進することも可能である。したがって、本発明のビフィズス菌または乳酸菌を、微生物に感染したヒト等の動物に投与することにより、微生物感染を緩和または治療することが可能と考えられる。 Alternatively, the expression level of β-defensin in the animal cell can be increased by bringing the bifidobacteria or lactic acid bacterium of the present invention into contact with the animal cell simultaneously with a microorganism such as a pathogen. Even when the bifidobacteria or lactic acid bacteria of the present invention are used in this way, the β-defensin expression promoting effect is remarkable. For example, as shown in the Examples, the expression level can be promoted up to 10 times or more. is there. Therefore, it is considered that microbial infection can be alleviated or treated by administering bifidobacteria or lactic acid bacteria of the present invention to animals such as humans infected with microorganisms.
本発明の乳酸菌としては、特に種類は限定されないが、例えばストレプトコッカス科のグラム陽性球菌（Ｓｔｒｅｐｔｏｃｏｃｃｕｓ，Ｐｅｄｉｏｃｏｃｃｕｓ，Ｌｅｕｃｏｎｏｓｔｏｃ の諸属）および乳酸桿菌科のグラム陽性桿菌（Ｌａｃｔｏｂａｃｉｌｌｕｓ 属）等を挙げることができる。 The type of lactic acid bacteria of the present invention is not particularly limited, and examples thereof include gram-positive cocci of Streptococcus family (genus of Streptococcus, Pediococcus, Leuconostoc) and gram-positive gonococci of Lactobacilli (genus Lactobacillus).
本発明のビフィズス菌としては、特に種類は限定されないが、例えば、ビフィドバクテリウム・ビフィダム、ビフィドバクテリウム・ロンガム、ビフィドバクテリウム・ブレーベ、ビフィドバクテリウム・インファンティス、ビフィドバクテリウム・カテヌラータム、ビフィドバクテリウム・アドレッセンティス、ビフィドバクテリウム・シュードロンガム等が挙げられる。さらに具体的には、ビフィドバクテリウム・ビフィダムＪＣＭ１２５５Ｔ菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株、ビフィドバクテリウム・ロンガムＪＣＭ１２１７Ｔ菌株、ビフィドバクテリウム・ブレーベＪＣＭ１１９２Ｔ菌株、ビフィドバクテリウム・インファンティスＪＣＭ１２２２Ｔ菌株、ビフィドバクテリウム・カテヌラータムＪＣＭ１１９４Ｔ菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株、ビフィドバクテリウム・シュードロンガムＪＣＭ１２０５Ｔ菌株等が挙げられる。The type of Bifidobacterium of the present invention is not particularly limited, and examples thereof include Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium infantis, and Bifidobacterium. Examples include Um catenulatum, Bifidobacterium addressentis, Bifidobacterium pseudolongum, and the like. More specifically, Bifidobacterium bifidum JCM1255 T strain, Bifidobacterium bifidum OLB6374 strain, Bifidobacterium bifidum OLB6378 strain, Bifidobacterium longum JCM1217 T strain, Bifidobacterium breve JCM1192 T strain, Bifidobacterium infantis JCM1222 T strains, Bifidobacterium Katenuratamu JCM1194 T strains, Bifidobacterium A Dressel down Tisdale JCM1275 T strains, Bifidobacterium shoe Delon gum JCM1205 T strains, etc. Is mentioned.
本発明において、微生物感染予防を主目的としてビフィズス菌を用いるのであれば、ビフィドバクテリウム・ビフィダムＪＣＭ１２５５Ｔ菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・ビフィダムＯＬＢ６３７８菌株、ビフィドバクテリウム・ロンガムＪＣＭ１２１７Ｔ菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株の群から選ばれた少なくとも１つの菌株を選択することが好ましいが、β-ディフェンシン発現促進効果を有するビフィズス菌株であれば、上記菌株に限らず、上記以外の菌株も使用することができる。In the present invention, if used bifidobacteria microbial infection as a primary objective, Bifidobacterium bifidum JCM1255 T strain, Bifidobacterium bifidum OLB6374 strain, Bifidobacterium bifidum OLB6378 strain Bifidobakuteri um longum JCM1217 T strain, it is preferable to select at least one strain selected from the group of Bifidobacterium a Dressel down infantis JCM1275 T strain, as long as bifidobacteria strain having β- defensin expression promoting effect, Not only the above strains but also other strains can be used.
また本発明において、ビフィドバクテリウム・ビフィダムＯＬＢ６３７４菌株、ビフィドバクテリウム・アドレッセンティスＪＣＭ１２７５Ｔ菌株は、微生物感染した動物に投与する場合、特にその効果を期待できるが、β-ディフェンシン発現促進効果を有するビフィズス菌株であれば、上記菌株に限らず、上記以外の菌株も使用することができる。In the present invention, the Bifidobacterium bifidum OLB6374 strain and the Bifidobacterium adrecentis JCM1275 T strain can be expected to be particularly effective when administered to microbially infected animals. As long as it is a bifidobacteria strain having a bacterium, not only the above strains but also strains other than those described above can be used.
本発明のビフィドバクテリウム・ビフィダムＯＬＢ ６３７４菌株は下記の条件で寄託されている。
（１） 寄託機関名：独立行政法人製品評価技術基盤機構 特許微生物寄託センター
（２） 連絡先：〒２９２−０８１８ 千葉県木更津市かずさ鎌足２−５−８
電話番号０４３８−２０−５５８０
（３）受託番号：ＮＩＴＥ ＢＰ−１２３
（４） 原寄託の受託番号（国内寄託の受託番号）：ＮＩＴＥ Ｐ−１２３
（５） 識別のための表示：Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｂｉｆｉｄｕｍ ＯＬＢ ６３７４
（６） 原寄託日： 平成１７年（2005年）８月４日
（７） ブダペスト条約に基づく寄託への移管日：2006年8月9日The Bifidobacterium bifidum OLB 6374 strain of the present invention is deposited under the following conditions.
(1) Depositary Institution: National Institute of Technology and Evaluation, Patent Microorganism Depositary Center (2) Contact: 2-5-8 Kazusa Kamashi, Kisarazu City, Chiba Prefecture 292-0818
Phone number 0438-20-5580
(3) Accession number: NITE BP-123
(4) Original Deposit Number (Domestic Deposit Number): NITE P-123
(5) Display for identification: Bifidobacterium bifidum OLB 6374
(6) Date of original deposit: August 4, 2005 (7) Date of transfer to deposit under the Budapest Treaty: August 9, 2006
本発明のビフィドバクテリウム・ビフィダムＯＬＢ ６３７４菌株は、以下の菌学的性質を有するものである。 The Bifidobacterium bifidum OLB 6374 strain of the present invention has the following mycological properties.
ビフィドバクテリウム・ビフィダムＯＬＢ ６３７４菌株は、ヒト糞便から分離されたグラム陽性偏性嫌気性桿菌である。菌形状は桿菌または分岐状の多形であり、芽胞の形成、運動性はない。ＢＬ寒天培地（栄研）平板上で本菌を塗布し、ＡｎａｅｒｏＰａｃｋ・ケンキ（三菱ガス化学製）使用による嫌気状態にて３７℃４８時間培養すると、不透明な円形半球状の光沢を有するコロニーを形成する。また本菌株は、下記に示す16S rRNA領域の種特異的プライマー（腸内フローラシンポジウム8、腸内フローラの分子生物学的検出・同定、光岡知足、松本隆広)を用いてPCR法を行うとき、PCR産物を確認できる。
BiBIF-1： CCA CAT GAT CGC ATG TGA TT （配列番号：１）
BiBIF-2: CCG AAG GCT TGC TCC CAA A （配列番号：２）Bifidobacterium bifidum OLB 6374 strain is a Gram-positive obligate anaerobic gonococci isolated from human feces. The fungus shape is gonococcus or branched polymorph, and there is no spore formation or motility. When this bacterium is applied on a BL agar medium (Eiken) plate and cultured at 37 ° C for 48 hours under anaerobic conditions using AnaeroPack Kenki (Mitsubishi Gas Chemical), colonies with opaque circular hemispherical gloss are formed. To do. In addition, when performing the PCR method using the species-specific primers of the 16S rRNA region shown below (Intestinal Flora Symposium 8, Molecular Biology Detection and Identification of Intestinal Flora, Chitomi Mitsuoka, Takahiro Matsumoto) PCR products can be confirmed.
BiBIF-1: CCA CAT GAT CGC ATG TGA TT (SEQ ID NO: 1)
BiBIF-2: CCG AAG GCT TGC TCC CAA A (SEQ ID NO: 2)
本発明で用いるビフィドバクテリウム・ビフィダムＯＬＢ ６３７８菌株は下記の条件で寄託されている。
（１） 寄託機関名：独立行政法人製品評価技術基盤機構 特許微生物寄託センター
（２） 連絡先：〒２９２−０８１８ 千葉県木更津市かずさ鎌足２−５−８
電話番号０４３８−２０−５５８０
（３） 受託番号：ＮＩＴＥ ＢＰ−３１
（４）原寄託の受託番号：ＮＩＴＥ Ｐ−３１
（５） 識別のための表示：Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ ｂｉｆｉｄｕｍ ＯＬＢ ６３７８
（６） 原寄託日： 平成１６年（2004年）１０月２６日
（７） ブダペスト条約に基づく寄託への移管日：2006年1月18日The Bifidobacterium bifidum OLB 6378 strain used in the present invention is deposited under the following conditions.
(1) Depositary Institution: National Institute of Technology and Evaluation, Patent Microorganism Depositary Center (2) Contact: 2-5-8 Kazusa Kamashi, Kisarazu City, Chiba Prefecture 292-0818
Phone number 0438-20-5580
(3) Accession number: NITE BP-31
(4) Original deposit number: NITE P-31
(5) Display for identification: Bifidobacterium bifidum OLB 6378
(6) Original deposit date: October 26, 2004 (7) Transfer date to deposit under the Budapest Treaty: January 18, 2006
本発明のビフィドバクテリウム・ビフィダムＯＬＢ ６３７８菌株は、以下の菌学的性質を有するものである。 The Bifidobacterium bifidum OLB 6378 strain of the present invention has the following mycological properties.
ビフィドバクテリウム・ビフィダムＯＬＢ ６３７８菌株は、ヒト糞便から分離されたグラム陽性偏性嫌気性桿菌であり、菌形状は桿菌または分岐状の多形であり、芽胞の形成、運動性はない。ＢＬ寒天培地（栄研）平板上で本菌を塗布し、ＡｎａｅｒｏＰａｃｋ・ケンキ（三菱ガス化学製）使用による嫌気状態にて３７℃４８時間培養すると、不透明な円形半球状の光沢を有するコロニーを形成する。また、上述の16S rRNA領域の種特異的プライマー（配列番号：１および２)を用いてPCR法を行うとき、PCR産物を確認できる。 Bifidobacterium bifidum OLB 6378 strain is a Gram-positive obligate anaerobic gonococci isolated from human feces, and the shape of the bacterium is a gonococcus or a branched polymorph, and there is no spore formation or motility. When this bacterium is applied on a BL agar medium (Eiken) plate and cultured at 37 ° C for 48 hours under anaerobic conditions using AnaeroPack Kenki (Mitsubishi Gas Chemical), colonies with opaque circular hemispherical gloss are formed. To do. In addition, when PCR is performed using the species-specific primer (SEQ ID NO: 1 and 2) of the 16S rRNA region described above, the PCR product can be confirmed.
本発明のビフィドバクテリウム・ビフィダムＯＬＢ ６３７４菌株およびビフィドバクテリウム・ビフィダムＯＬＢ ６３７８菌株は、動物細胞の微生物感染に先立って動物細胞と接触させても、微生物に感染した動物細胞に接触させても、β−ディフェンシン発現促進効果を発揮することができる。特に、動物細胞の微生物感染に先立って動物細胞と接触させる場合に際立った効果を示すことが確認されており、本発明の上記菌株を感染予防用医薬品または食品として応用した場合には、極めて優れた効果を発揮するものと期待できる。 The Bifidobacterium bifidum OLB 6374 strain and the Bifidobacterium bifidum OLB 6378 strain of the present invention can be contacted with animal cells prior to microbial infection of animal cells or with animal cells infected with microorganisms. Can also exert the effect of promoting β-defensin expression. In particular, it has been confirmed that when the animal cells are brought into contact with animal cells prior to microbial infection, the strain of the present invention is extremely excellent when applied as a drug or food for preventing infection. It can be expected to exert its effect.
本発明のビフィズス菌または乳酸菌によって感染予防可能な微生物は、特に限定されないが、主にβ−ディフェンシン感受性を有する微生物、その中でも好ましくは病原性微生物（病原菌）である。このような微生物の例として、大腸菌、Ｐｓｅｕｄｏｍｏｎａｓ ａｅｒｕｇｉｎｏｓａ、（Ｈａｒｄｅｒ Ｊ．他 Ａｍ．Ｊ．Ｒｅｓｐｉｒ Ｃｅｌｌ Ｍｏｌ．Ｂｉｏｌ．２０００年，第２２巻，ｐ．７１４−２１）、Ｓａｌｍｏｎｅｌｌａ ｅｎｔｅｒｉｔｉｄｉｓ（Ｏｇｕｓｈｉ Ｋ． 他 Ｊ．Ｂｉｏｌ．Ｃｈｅｍ．，２００１年，第２７６巻，第３２号，ｐ．３０５２１−３０５２６）、Ｓｔｒｅｐｔｏｃｏｃｃｕｓ ｇｏｒｄｏｎｉｉ，Ｐｏｒｐｈｙｌｏｍｏｎａｓ ｇｉｎｇｉｖａｌｉｓ，Ａｃｔｉｎｏｂａｃｉｌｌｉｓ ａｃｔｉｎｏｍｙｃｅｔｅｍｃｏｍｉｔａｎｓ，Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ｅｐｉｄｅｒｍｉｄｉｓ，Ｓｔｒｅｐｔｏｃｏｃｃｕｓ ｐｙｏｇｅｎｅｓ（Ｗｈａｓｕｎ Ｏ．他，Ｉｎｆｅｃｔ．Ｉｍｍｕｎ．，２００４年，第７２巻，第１号，ｐ．３５２−３５８）等を挙げることができる。また上記のほか、サルモネラ菌、赤痢菌、コレラ菌、チフス菌感染に対しても、本発明のビフィズス菌または乳酸菌は有効に予防効果を発揮するものと考えられる。 The microorganisms that can be prevented from infection by the bifidobacteria or lactic acid bacteria of the present invention are not particularly limited, but are mainly microorganisms having β-defensin sensitivity, preferably pathogenic microorganisms (pathogenic bacteria). Examples of such microorganisms include Escherichia coli, Pseudomonas aeruginosa (Harder J. et al. Am. J. Respir Cell Mol. Biol. 2000, Vol. 22, p. 714-21), Salmonella enteritidis (Ogushi K. et al. J Biol.Chem., 2001, 276, No. 32, p. , Mention may be made of 2004, No. 72, Vol, No. 1, p.352-358) or the like. In addition to the above, it is considered that the Bifidobacterium or lactic acid bacterium of the present invention effectively exerts a preventive effect against Salmonella, Shigella, cholera, and Salmonella infections.
また本発明において「動物細胞」とは、動物由来の細胞であれば特に問わないが、好ましい例として、腸、口腔内、気管、皮膚などの上皮細胞、臓器の細胞などβ−ディフェンシンを発現する細胞が挙げられる。また、in vivoの動物細胞、動物から分離したフレッシュな細胞、動物由来の初代培養細胞、動物由来の細胞株は本発明の「動物細胞」に含まれる。 In the present invention, the “animal cell” is not particularly limited as long as it is an animal-derived cell, and preferred examples include β-defensins such as epithelial cells such as intestine, oral cavity, trachea and skin, and organ cells. Cell. In vivo animal cells, fresh cells isolated from animals, primary cell cultures derived from animals, and cell lines derived from animals are also included in the “animal cells” of the present invention.
本発明のビフィズス菌または乳酸菌は、医薬品または飲食品として利用することもできる。本発明のビフィズス菌または乳酸菌を含む医薬品または食品は、β―ディフェンシン２発現促進効果を有する点で有用であり、特に、微生物感染予防または感染治療用の医薬品または飲食品として利用できる。本発明のビフィズス菌または乳酸菌を医薬品または飲食品として利用する場合には、単独の菌株を使用してもよく、または２以上の菌株を組み合わせて使用してもよい。 The bifidobacteria or lactic acid bacteria of the present invention can also be used as pharmaceuticals or foods and drinks. The pharmaceutical or food containing bifidobacteria or lactic acid bacteria of the present invention is useful in that it has an effect of promoting the expression of β-defensin 2, and can be used particularly as a pharmaceutical or food or drink for preventing or treating microbial infection. When utilizing the bifidobacteria or lactic acid bacteria of this invention as a pharmaceutical or food-drinks, a single strain may be used or two or more strains may be used in combination.
本発明のビフィズス菌または乳酸菌を上記医薬品または飲食品に使用するにあたり、その状態は問わない。例えば、本発明のビフィズス菌または乳酸菌は、生菌、死菌、または処理物であっても上記医薬品または飲食品に使用できる。例えば、本発明のビフィズス菌または乳酸菌の培養物、その濃縮物、ペースト状に加工したペースト化物、噴霧乾燥物、凍結乾燥物、真空乾燥物、ドラム乾燥物、媒体に分散させた液状物、希釈剤で希釈した希釈物、乾燥物をミルなどで破砕した破砕物などを上記医薬品または飲食品に用いることが出来る。 In using the bifidobacteria or lactic acid bacteria of the present invention for the above-mentioned pharmaceutical or food or drink, the state is not limited. For example, the bifidobacteria or lactic acid bacteria of the present invention can be used in the above-mentioned pharmaceuticals or foods and drinks even if they are live bacteria, killed bacteria, or processed products. For example, a culture of bifidobacteria or lactic acid bacteria of the present invention, a concentrate thereof, a pasted product processed into a paste, a spray-dried product, a freeze-dried product, a vacuum-dried product, a drum-dried product, a liquid material dispersed in a medium, a dilution A diluted product diluted with an agent, a crushed product obtained by crushing a dried product with a mill, and the like can be used for the pharmaceutical product or food or drink.
さらに本発明の飲食品は、、保健機能食品や病者用食品にも適用することができる。保健機能食品制度は、内外の動向、従来からの特定保健用食品制度との整合性を踏まえて、通常の食品のみならず錠剤、カプセル等の形状をした食品を対象として設けられたもので、特定保健用食品（個別許可型）と栄養機能食品（規格基準型）の２種類の類型からなる。本発明のビフィズス菌または乳酸菌を、特定保健用食品等の特別用途食品や栄養機能食品として、ヒト等の動物に投与することにより各種の感染に対する予防が可能となる。 Furthermore, the food / beverage products of the present invention can also be applied to health functional foods and foods for the sick. The health functional food system was established not only for regular foods but also for foods in the form of tablets, capsules, etc., based on domestic and foreign trends and consistency with the conventional food system for specified health use. It consists of two types of food for specified health use (individual permission type) and functional food for nutrition (standard type). It is possible to prevent various infections by administering the bifidobacteria or lactic acid bacteria of the present invention to animals such as humans as special-purpose foods such as foods for specified health use or nutritional functional foods.
本発明のビフィズス菌または乳酸菌を飲食品として利用する場合、飲食品の種類は特に限定されない。例えば、各種飲食品（牛乳、加工乳、清涼飲料、発酵乳、ヨーグルト、チーズ、その他の乳製品、パン、ビスケット、クラッカー、ピッツァクラスト、調製粉乳、流動食、病者用食品、幼児用粉乳等食品、授乳婦用粉乳等食品、栄養食品等）に加工することができる。このような飲食品の製造にあたっては、本発明のビフィズス菌または乳酸菌やその処理物をそのまま使用したり、他の食品ないし食品成分と混合するなど、通常の食品組成物における製法にしたがうことができる。また、飲食品の形状についても特に限定されず、通常用いられる飲食品の形状であれば特に問わない。、例えば、固体状（粉末、顆粒状を含む）、ペースト状、液状、懸濁状などの形状のいずれでもよく、またこれらに限定されない。 When using the bifidobacteria or lactic acid bacteria of the present invention as a food or drink, the type of the food or drink is not particularly limited. For example, various foods and drinks (milk, processed milk, soft drinks, fermented milk, yogurt, cheese, other dairy products, bread, biscuits, crackers, pizza crust, prepared milk powder, liquid food, food for the sick, infant milk powder, etc. Foods, foods such as milk powder for lactating women, nutritional foods, etc.). In the production of such foods and beverages, the bifidobacteria or lactic acid bacteria of the present invention and processed products thereof can be used as they are, or can be mixed with other foods or food ingredients, according to a production method in a normal food composition. . Moreover, it does not specifically limit about the shape of food / beverage products, Especially if it is the shape of food / beverage products used normally, it will not ask | require. For example, it may be in the form of a solid (including powder, granule), paste, liquid, suspension, etc., but is not limited thereto.
本発明のビフィズス菌または乳酸菌を含有する飲食物には、水、タンパク質、糖質、脂質、ビタミン類、ミネラル類、有機酸、有機塩基、果汁、フレーバー類等、通常の食品に含まれる成分であればいずれであっても含めることができる。上記飲食物の製造において、タンパク質源として、例えば全脂粉乳、脱脂粉乳、部分脱脂粉乳、カゼイン、ホエイ粉、ホエイタンパク質、ホエイタンパク質濃縮物、ホエイタンパク質分離物、α―カゼイン、β―カゼイン、κ−カゼイン、β―ラクトグロブリン、α―ラクトアルブミン、ラクトフェリン、大豆タンパク質、鶏卵タンパク質、肉タンパク質等の動植物性タンパク質、これら加水分解物等の、食品製造に通常使用されるタンパク質またはタンパク質含有原材料を使用することができる。糖類の供給源の例としては、加工澱粉（テキストリンのほか、可溶性澱粉、ブリティッシュスターチ、酸化澱粉、澱粉エステル、澱粉エーテル等）、食物繊維などが挙げられる。脂質源としては、例えば、ラード、魚油等、これらの分別油、水素添加油、エステル交換油等の動物性油脂；パーム油、サフラワー油、コーン油、ナタネ油、ヤシ油、これらの分別油、水素添加油、エステル交換油等の植物性油脂などが挙げられる。ビタミン類としては、例えば、ビタミンＡ、カロチン類、ビタミンＢ群、ビタミンＣ、ビタミンＤ群、ビタミンＥ、ビタミンＫ群、ビタミンＰ、ビタミンＱ、ナイアシン、ニコチン酸、パントテン酸、ビオチン、イノシトール、コリン、葉酸などが挙げられ、ミネラル類としては、例えば、カルシウム、カリウム、マグネシウム、ナトリウム、銅、鉄、マンガン、亜鉛、セレンなどが挙げられる。有機酸としては、例えば、リンゴ酸、クエン酸、乳酸、酒石酸などが挙げられる。バター、乳性ミネラル、クリーム、ホエイ、非タンパク態窒素、シアル酸、リン脂質、乳糖等の各種乳由来成分などは本発明のビフィズス菌または乳酸菌を含有する飲食品の製造に好適に用いることのできる成分の例である。。これらの成分は、２種以上を組み合わせて使用することができる。また上記原材料は、天然物、天然物加工品、合成品及び／又はこれらを多く含む食品のいずれを用いてもよい。 Foods and beverages containing bifidobacteria or lactic acid bacteria of the present invention include ingredients contained in ordinary foods such as water, proteins, carbohydrates, lipids, vitamins, minerals, organic acids, organic bases, fruit juices, and flavors. Any can be included. In the production of the above food and drink, as protein sources, for example, whole milk powder, skim milk powder, partially skim milk powder, casein, whey powder, whey protein, whey protein concentrate, whey protein isolate, α-casein, β-casein, κ -Proteins or protein-containing raw materials normally used for food production such as casein, β-lactoglobulin, α-lactalbumin, lactoferrin, soy protein, chicken egg protein, meat protein, and other hydrolysates can do. Examples of sugar sources include processed starch (in addition to text phosphorus, soluble starch, British starch, oxidized starch, starch ester, starch ether, etc.), dietary fiber, and the like. Examples of the lipid source include animal oils such as lard and fish oil, fractionated oils thereof, hydrogenated oil and transesterified oil; palm oil, safflower oil, corn oil, rapeseed oil, coconut oil, and fractionated oils thereof. And vegetable oils such as hydrogenated oil and transesterified oil. Examples of vitamins include vitamin A, carotene, vitamin B group, vitamin C, vitamin D group, vitamin E, vitamin K group, vitamin P, vitamin Q, niacin, nicotinic acid, pantothenic acid, biotin, inositol, choline. Examples of minerals include calcium, potassium, magnesium, sodium, copper, iron, manganese, zinc, and selenium. Examples of the organic acid include malic acid, citric acid, lactic acid, and tartaric acid. Various milk-derived components such as butter, dairy minerals, cream, whey, non-protein nitrogen, sialic acid, phospholipid, and lactose can be suitably used for the production of foods and beverages containing the bifidobacteria or lactic acid bacteria of the present invention. This is an example of a component that can be produced. . These components can be used in combination of two or more. Moreover, any of a natural product, a processed natural product, a synthetic product, and / or a food containing a large amount thereof may be used as the raw material.
本発明のビフィズス菌または乳酸菌は、感染予防または治療用医薬品とすることができる。上記医薬品を製造する場合、本発明のビフィズス菌または乳酸菌は、生菌、または殺菌後、破砕あるいは未粉砕した処理物として使用することができる。また、使用する菌は単独でも、複数種であってもよい。 The bifidobacteria or lactic acid bacteria of the present invention can be used as a medicament for preventing or treating infection. When manufacturing the said pharmaceutical, the bifidobacteria or lactic acid bacteria of this invention can be used as a living microbe or the processed material which was crushed or unground after disinfection. Moreover, the bacteria used may be single or multiple types.
上記医薬品中における本発明のビフィズス菌または乳酸菌の量は、その目的、用途（予防剤、治療剤等）に応じて任意に定めることができる。含量の一例として、全体量に対して０．００１〜１００％（ｗ／ｗ）、特に０．１〜１００％を示すことができるが、本発明はこれに限定されない。 The amount of the bifidobacteria or lactic acid bacteria of the present invention in the above pharmaceuticals can be arbitrarily determined according to the purpose and application (prophylactic agent, therapeutic agent, etc.). An example of the content may be 0.001 to 100% (w / w), particularly 0.1 to 100%, based on the total amount, but the present invention is not limited thereto.
本発明のビフィズス菌または乳酸菌を有効成分とする医薬品の投与量は、投与経路、ヒトを含む投与対象動物の年齢、体重、症状など、種々の要因を考慮して、適宜設定することができる。適当な投与量の一例として、有効成分として１〜１０００ｍｇ／ｋｇ／ｄａｙを挙げることができるが、本発明はこれに限定されない。例えば、長期間に亘って予防目的で摂取する場合には、上記範囲よりも少量であってもよい。また本有効成分は安全性の問題が見当たらないため、上記範囲よりも多量に使用してもさしつかえないと考えられる。 The dosage of the pharmaceutical comprising the bifidobacteria or lactic acid bacteria of the present invention as an active ingredient can be appropriately set in consideration of various factors such as the administration route, the age, weight, and symptoms of animals to be administered including humans. As an example of a suitable dose, 1-1000 mg / kg / day can be mentioned as an active ingredient, but the present invention is not limited to this. For example, when ingested for preventive purposes over a long period, the amount may be smaller than the above range. In addition, since there is no safety problem with this active ingredient, it is considered that it may be used in a larger amount than the above range.
上記医薬品の剤型は、本発明のビフィズス菌または乳酸菌を腸内に到達させるため、経口投与が可能な剤型が好ましい。本発明による医薬品の好ましい剤型の例としては、例えば錠剤、被覆錠剤、カプセル剤、顆粒剤、散剤、液剤、シロップ剤、トローチ剤等をあげることができる。これらの各種製剤は、常法に従って主薬である本発明の菌体および／または処理物に、賦形剤、結合剤、崩壊剤、滑沢剤、着色剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤などの、医薬の製剤技術分野において通常使用しうる補助剤を用いて製剤化することができる。 The above-mentioned pharmaceutical dosage form is preferably a dosage form capable of oral administration in order to allow the bifidobacteria or lactic acid bacteria of the present invention to reach the intestine. Examples of preferable dosage forms of the pharmaceutical product according to the present invention include tablets, coated tablets, capsules, granules, powders, liquids, syrups, lozenges and the like. These various preparations are prepared by adding the excipient, binder, disintegrant, lubricant, coloring agent, flavoring agent, solubilizer, suspension aid, etc. to the microbial cells and / or processed products of the present invention which are the main agents according to conventional methods. It can be formulated using an auxiliary agent that can be usually used in the pharmaceutical preparation technical field, such as a suspending agent and a coating agent.
本発明のビフィズス菌または乳酸菌は、上皮細胞などの動物細胞を前もって感作することで、当該動物細胞が多量の病原菌に接した際に、β―ディフェンシンの発現量を病原菌のみに接した場合の発現量の１０倍以上に高めて、予防作用を発揮する。
また、本発明のビフィズス菌または乳酸菌は、動物細胞が多量の大腸菌などの病原菌に接した際に、病原菌と共に存在し動物細胞に作用することで、β−ディフェンシンの発現量を１０倍以上に高める作用を有する。The bifidobacteria or lactic acid bacteria of the present invention can be obtained by sensitizing animal cells such as epithelial cells in advance, and when the animal cells are in contact with a large amount of pathogenic bacteria, the expression level of β-defensin is in contact with only the pathogenic bacteria. Increases the expression level to 10 times or more and exerts a preventive action.
In addition, the bifidobacteria or lactic acid bacteria of the present invention increase the expression level of β-defensin 10 times or more by being present together with the pathogen and acting on the animal cell when the animal cell is in contact with a large amount of pathogen such as Escherichia coli. Has an effect.
このように、本発明のビフィズス菌または乳酸菌によって、大腸菌などの病原菌より誘導されるβ―ディフェンシンの発現が著しく促進され、その量が増加することになる。本発明のビフィズス菌または乳酸菌を摂取し、本発明のビフィズス菌または乳酸菌ビフィズス菌が優位な菌叢をあらかじめ形成することにより、大腸菌などが動物体内に侵入または増殖した場合にβ―ディフェンシンの誘導を強く促進することができる。 Thus, the expression of β-defensin induced from pathogenic bacteria such as Escherichia coli is remarkably promoted and the amount thereof is increased by the bifidobacteria or lactic acid bacteria of the present invention. By ingesting the bifidobacteria or lactic acid bacteria of the present invention and forming a bacterial flora in which the bifidobacteria or lactic acid bacteria bifidobacteria of the present invention predominately, β-defensin is induced when Escherichia coli or the like invades or proliferates in the animal body. It can be strongly promoted.
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。 It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.
以下、本発明を実施例を挙げて説明するが、本発明はこれらにより限定されるものではない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated, this invention is not limited by these.
［実験例１］（ビフィズス菌での刺激処理後、大腸菌による誘導実験）
９６穴プレート（ＢＥＣＴＯＮ ＤＩＣＫＩＮＳＯＮ ｃａｔ：３５３０７２）にＨＴ−２９細胞を、３７℃、５％ＣＯ２の雰囲気下でコンフルエントにまで培養した。
ついで、培養上清を除去し、ＲＰＭＩ培地（ＧＩＢＣＯ）で洗浄した。
予め６０℃ ６０分間 熱処理を施した各ビフィズス菌のＰＢＳ懸濁液を、１×１０７ｃｅｌｌｓ／ｍｌになるようにＲＰＭＩ培地に調製し、１ｗｅｌｌあたり２００μｌ添加した。
このプレートを３７℃、５％ＣＯ２の雰囲気下、５時間培養した後、上清を除去し、ＲＰＭＩ培地で洗浄した。
別途、６０℃ ６０分間 熱処理を施したE. coli JCM1649TのＰＢＳ懸濁液を、１×１０８ｃｅｌｌｓ／ｍｌになるようにＲＰＭＩ培地に調製し、１ｗｅｌｌあたり２００μｌ添加して、一定時間３７℃、５％ＣＯ２の培養条件で培養した。陰性対照として、RPMI培地のみを１ｗｅｌｌあたり200μl添加した。
Ｅ． ｃｏｌｉの添加から１時間後、３時間後のそれぞれの培養時間後の培養上清を採取して、遠心分離機により遠心分離し（３０００ｒｐｍ、１０分、４℃）、β−ディフェンシン２の測定試料とした。[Experimental Example 1] (Induction experiment with Escherichia coli after stimulation with bifidobacteria)
HT-29 cells were cultured in a 96-well plate (BECTON DICKINSON cat: 353072) to confluence in an atmosphere of 37 ° C. and 5% CO 2 .
Subsequently, the culture supernatant was removed and washed with RPMI medium (GIBCO).
A PBS suspension of each bifidobacteria previously heat-treated at 60 ° C. for 60 minutes was prepared in RPMI medium so as to be 1 × 10 7 cells / ml, and 200 μl was added per well.
After culturing the plate in an atmosphere of 37 ° C. and 5% CO 2 for 5 hours, the supernatant was removed and washed with RPMI medium.
Separately, a PBS suspension of E. coli JCM1649 T that had been heat-treated at 60 ° C. for 60 minutes was prepared in RPMI medium to 1 × 10 8 cells / ml, and 200 μl was added per well for 37 ° C. for a certain period of time. The cells were cultured under 5% CO 2 culture conditions. As a negative control, only 200 μl of RPMI medium was added per well.
E. After 1 hour and 3 hours after the addition of E. coli, the culture supernatant after each culture time was collected and centrifuged with a centrifuge (3000 rpm, 10 minutes, 4 ° C.), and a measurement sample of β-defensin 2 It was.
［実験例２］（大腸菌とビフィズス菌とを同時に使用した誘導実験）
９６穴プレート（ＢＥＣＴＯＮ ＤＩＣＫＩＮＳＯＮ ｃａｔ：３５３０７２）にＨＴ−２９細胞を、３７℃、５％ＣＯ２の雰囲気下でコンフルエントにまで培養した。
ついで、培養上清を除去し、ＲＰＭＩ培地（ＧＩＢＣＯ）で洗浄した。
予め６０℃ ６０分間 熱処理を施したE. coli JCM1649TのＰＢＳ懸濁液と各ビフィズス菌のＰＢＳ懸濁液とをそれぞれ１×１０８ｃｅｌｌｓ／ｍｌ各ビフィズス菌のＰＢＳ懸濁液を１×１０７ｃｅｌｌｓ／ｍｌになるようにＲＰＭＩ培地に調製し、１ｗｅｌｌあたり合計で２００μｌ添加した。陰性対照として、RPMI培地のみを１ｗｅｌｌあたり200μl添加した。
このプレートを３７℃、５％ＣＯ２の雰囲気下、５時間培養した。
Ｅ． ｃｏｌｉ及びビフィズス菌の添加から１時間後、３時間後のそれぞれの培養時間後の培養上清を採取して、遠心分離機により遠心分離し（３０００ｒｐｍ、１０分、４℃）、β−ディフェンシン２の測定試料とした。[Experimental example 2] (Induction experiment using E. coli and bifidobacteria simultaneously)
HT-29 cells were cultured in a 96-well plate (BECTON DICKINSON cat: 353072) to confluence in an atmosphere of 37 ° C. and 5% CO 2 .
Subsequently, the culture supernatant was removed and washed with RPMI medium (GIBCO).
A PBS suspension of E. coli JCM1649 T and a PBS suspension of each bifidobacteria that had been heat-treated in advance at 60 ° C. for 60 minutes were each 1 × 10 8 cells / ml. It prepared to RPMI culture medium so that it might become 7 cells / ml, and 200 microliters was added in total per well. As a negative control, only 200 μl of RPMI medium was added per well.
This plate was cultured at 37 ° C. in an atmosphere of 5% CO 2 for 5 hours.
E. After 1 hour and 3 hours after the addition of E. coli and bifidobacteria, the culture supernatant after each culture time was collected, centrifuged with a centrifuge (3000 rpm, 10 minutes, 4 ° C.), and β-defensin 2 A measurement sample was used.
［実験例３］（大腸菌またはビフィズス菌単独刺激処理によるＨＴ−２９細胞の比較誘導実験）
９６穴プレート（ＢＥＣＴＯＮ ＤＩＣＫＩＮＳＯＮ ｃａｔ：３５３０７２）にＨＴ−２９細胞を、３７℃、５％ＣＯ２の雰囲気下でコンフルエントにまで培養した。
ついで、培養上清を除去し、ＲＰＭＩ培地（ＧＩＢＣＯ）で洗浄した。
別途、予め６０℃ ６０分間熱処理を施したE. coli JCM1649T（あるいは各ビフィズス菌）のＰＢＳ懸濁液を、１×１０８ｃｅｌｌｓ／ｍｌとなるようにＲＰＭＩ培地に調製し、１ｗｅｌｌあたり２００μｌ添加して、このプレートを３７℃、５％ＣＯ２の雰囲気下で培養した。陰性対照として、RPMI培地のみを１ｗｅｌｌあたり200μl添加した。
添加した後、１時間後、３時間後のそれぞれの培養時間後の培養上清を採取して、遠心分離機により遠心分離し（３０００ｒｐｍ、１０分、４℃）、β−ディフェンシン２の測定試料とした。[Experimental Example 3] (Comparative induction experiment of HT-29 cells by single stimulation treatment of E. coli or bifidobacteria)
HT-29 cells were cultured in a 96-well plate (BECTON DICKINSON cat: 353072) to confluence in an atmosphere of 37 ° C. and 5% CO 2 .
Subsequently, the culture supernatant was removed and washed with RPMI medium (GIBCO).
Separately, a PBS suspension of E. coli JCM1649 T (or each bifidobacteria) previously heat-treated at 60 ° C. for 60 minutes is prepared in RPMI medium to 1 × 10 8 cells / ml, and 200 μl is added per well. Then, this plate was cultured in an atmosphere of 37 ° C. and 5% CO 2 . As a negative control, only 200 μl of RPMI medium was added per well.
After the addition, the culture supernatant after each culture time after 1 hour and 3 hours was collected, centrifuged with a centrifuge (3000 rpm, 10 minutes, 4 ° C.), and a measurement sample of β-defensin 2 It was.
［実験例４］（β−ディフェンシン２のサンドイッチＥＬＩＳＡ法による測定）
９６穴プレート（ＮＵＮＣ ｃａｔ：４３９４５２１）にコーティングバッファー（０．１Ｍ炭酸緩衝液ｐＨ９．６）で１０００倍に希釈した抗ヒトβ−ディフェンシン２ヒツジ抗体（Ｓａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ ｃａｔ：ＳＣ−１０８５４）を１００μｌ／ｗｅｌｌ添加した。
これを３７℃で９０分間反応させ、その後、０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ（ｐＨ７．２）で３回洗浄した。
ついで、ブロッキング溶液（１％ＦＣＳ ３％ ＰＥＧ ０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ）を２００μｌ／ｗｅｌｌ添加し、３７℃で３０分間反応させた。
サンプル希釈液（３％ ＰＥＧ ０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ）で希釈した測定試料（実施例１〜３）またはヒトβ−ディフェンシン２標準溶液（ＳＩＧＭＡ ｃａｔ：Ｄ９６９０ 適宜希釈）を１００μｌ／ｗｅｌｌ添加して、３７℃で９０分間反応させた。
これを０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ（ｐＨ７．２）で３回洗浄し、１％ＦＣＳ ３％ ＰＥＧ ０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ溶液で１０００倍に希釈した抗ヒトβ−ディフェンシン２ウサギ抗体（Ｓａｎｔａ Ｃｒｕｚ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ ｃａｔ：ＳＣ−２０７９８）を１００μｌ／ｗｅｌｌ添加した。これを３７℃で６０分間反応させ、０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ（ｐＨ７．２）で３回洗浄した。
１％ＦＣＳ ３％ ＰＥＧ ０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ溶液で１００００倍に希釈したペルオキシダーゼ標識抗ウサギＩｇＧ抗体（ＣＨＥＭＩＣＯＮ ｃａｔ： ＡＰ１８８Ｐ）を１００μｌ／ｗｅｌｌ添加して、これを３７℃で６０分間反応させた。
これを０．０１Ｍ ＰＢＳ−Ｔｗｅｅｎ（ｐＨ７．２）で３回洗浄し、ＴＭＢペルオキシダーゼ基質溶液（ＫＰＬ ｃａｔ：５０−７６−００）を１００μｌ／ｗｅｌｌ添加して、３７℃で３０分間反応させた。ついで２Ｎ Ｈ２ＳＯ４を１００μｌ／ｗｅｌｌ添加した。その後に、マイクロプレートリーダーにて測定（４５０ｎｍ）を行った。
［実施例及び比較例］[Experimental Example 4] (Measurement of β-defensin 2 by sandwich ELISA method)
An anti-human β-defensin 2 sheep antibody (Santa Cruz Biotechnology cat: SC-10854) diluted 1000-fold with a coating buffer (0.1 M carbonate buffer pH 9.6) in a 96-well plate (NUNC cat: 4394521) was added at 100 μl / Well was added.
This was reacted at 37 ° C. for 90 minutes, and then washed three times with 0.01M PBS-Tween (pH 7.2).
Subsequently, a blocking solution (1% FCS 3% PEG 0.01M PBS-Tween) was added at 200 μl / well and reacted at 37 ° C. for 30 minutes.
A measurement sample (Examples 1 to 3) diluted with a sample diluent (3% PEG 0.01M PBS-Tween) or a human β-defensin 2 standard solution (SIGMA cat: D9690 appropriately diluted) was added at 100 μl / well, The reaction was carried out at 37 ° C. for 90 minutes.
This was washed three times with 0.01M PBS-Tween (pH 7.2), and diluted with a 1% FCS 3% PEG 0.01M PBS-Tween solution 1000-fold anti-human β-defensin 2 rabbit antibody (Santa Cruz Biotechnology). cat: SC-20798) was added at 100 μl / well. This was reacted at 37 ° C. for 60 minutes and washed three times with 0.01M PBS-Tween (pH 7.2).
100 μl / well of a peroxidase-labeled anti-rabbit IgG antibody (CHEMICON cat: AP188P) diluted 10,000-fold with a 1% FCS 3% PEG 0.01M PBS-Tween solution was added and reacted at 37 ° C. for 60 minutes.
This was washed 3 times with 0.01M PBS-Tween (pH 7.2), TMB peroxidase substrate solution (KPL cat: 50-76-00) was added at 100 μl / well and reacted at 37 ° C. for 30 minutes. Subsequently, 2N H 2 SO 4 was added at 100 μl / well. Thereafter, measurement (450 nm) was performed with a microplate reader.
[Examples and Comparative Examples]
得られた結果を図１〜６および表１〜３に示す。図１〜６は実験例１から３の結果を示し、縦軸は、β―ディフェンシン２の発現量（大腸菌単独刺激時のβ-ディフェンシン２発現量（タンパク質産生量）を１とした時の相対量として）を、横軸は試験試料の菌種を示す。図１,２中のE. coli JCM1649Tは、実験例1において各種ビフィズス菌の代わりに培地のみを添加・洗浄後、E. coli JCM1649Tを添加した時の結果を示す。図３,４中のE. coli JCM1649Tは、実験例2においてE. coli JCM1649Tのみを添加した時の結果を示す。実験例１，２，３におけるβ―ディフェンシン２の誘導実験では、１×１０８ ｃｅｌｌｓ／ｍｌ濃度のE. coli JCM1649T溶液を用いた。表１は図１および図２にグラフとして示された結果を数値で示したものである。表２は図３および図４にグラフとして示された結果を数値で示したものである。表３は図５および図６にグラフとして示された結果を数値で示したものである。ただし、表１から３は、図１から６に示された菌株に関する検討結果とともに、さらに数菌株に関する検討結果を追加してある。
なお、名称に「OLB」の文字が入っている菌株および「MEP」の文字が入っている菌株はヒト糞便から分離した。また、名称に「JCM」の文字が入っている菌株は、独立行政法人理化学研究所バイオリソースセンターから入手した。The obtained results are shown in FIGS. 1 to 6 show the results of Experimental Examples 1 to 3, and the vertical axis represents the relative expression when β-defensin 2 expression level (β-defensin 2 expression level (protein production level) when E. coli alone is stimulated is 1. As a quantity), and the horizontal axis indicates the species of the test sample. E. coli JCM1649 T in FIGS. 1 and 2 shows the results when E. coli JCM1649 T was added after adding and washing only the medium in place of various bifidobacteria in Experimental Example 1. E. coli JCM1649 T in FIGS. 3 and 4 shows the results when only E. coli JCM1649 T was added in Experimental Example 2. In the induction experiment of β-defensin 2 in Experimental Examples 1, 2, and 3, an E. coli JCM1649 T solution having a concentration of 1 × 10 8 cells / ml was used. Table 1 shows numerical results of the results shown as graphs in FIGS. Table 2 shows numerical results of the results shown as graphs in FIGS. 3 and 4. Table 3 shows numerical results of the results shown as graphs in FIGS. 5 and 6. In Tables 1 to 3, however, the results of studies on several strains are added together with the results of studies on the strains shown in FIGS.
The strains with the letters “OLB” and the names with the letters “MEP” were isolated from human feces. In addition, strains with “JCM” in the name were obtained from RIKEN BioResource Center.
図５及び６のグラフ並びに表３から明らかなように、大腸菌単独と比べ、各ビフィズス菌単独ではほとんどβ―ディフェンシン２の誘導能は無いことが分かる。
一方、図１及び２並びに表１に示すビフィズス菌で予めビフィズス菌で刺激処理した後に大腸菌を添加した結果によれば、いずれのビフィズス菌においても誘導効果はなかったが、発現量の増強については非常に高いレベルでβ―ディフェンシン２が発現していることが分かった。これは予想し得ないレベルであり、本発明の有効性を示すことが出来た。
また、同時に添加した系である図３及び４並びに表２の結果でも、予めビフィズス菌で刺激処理した系の図１及び２並びに表１に示す結果よりはやや劣るが、明らかに発現量の増強効果があることが分かった。As is apparent from the graphs of FIGS. 5 and 6 and Table 3, it can be seen that each bifidobacteria alone has almost no ability to induce β-defensin 2 as compared to E. coli alone.
On the other hand, according to the results of adding E. coli after bifidobacteria stimulation in advance with the bifidobacteria shown in FIGS. 1 and 2 and Table 1, there was no induction effect in any of the bifidobacteria. It was found that β-defensin 2 was expressed at a very high level. This was an unexpected level, and the effectiveness of the present invention could be demonstrated.
In addition, the results of FIGS. 3 and 4 and Table 2 that were added at the same time are slightly inferior to the results shown in FIGS. 1 and 2 and Table 1 of the system that had been previously stimulated with bifidobacteria, but the expression level was clearly enhanced. I found it effective.
本発明により、抗菌ペプチドであるβ−ディフェンシンの発現を促進するビフィズス菌及び／または乳酸菌を提供することができた。本発明のビフィズス菌および乳酸菌を動物体内に投与することにより、体内で発現する抗菌ペプチド量を増加させることができる。すなわち、本発明のビフィズス菌および乳酸菌は、感染予防または治療用の医薬品または食品として利用でき、極めて有用である。 According to the present invention, it was possible to provide bifidobacteria and / or lactic acid bacteria that promote the expression of β-defensin, which is an antibacterial peptide. By administering the bifidobacteria and lactic acid bacteria of the present invention into an animal body, the amount of antimicrobial peptide expressed in the body can be increased. That is, the bifidobacteria and lactic acid bacteria of the present invention can be used as pharmaceuticals or foods for preventing or treating infection and are extremely useful.
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| EP2397145A1 (en) * | 2010-06-18 | 2011-12-21 | Nestec S.A. | L. johnsonii La1, B. longum NCC2705 and immune disorders |
| ITMI20110792A1 (en) | 2011-05-09 | 2012-11-10 | Probiotical Spa | STRAINS OF BACTERIA BELONGING TO THE BIFIDOBACTERIUM TYPE FOR USE IN THE TREATMENT OF HYPERCOLESTEROLEMIA. |
| ITMI20110791A1 (en) | 2011-05-09 | 2012-11-10 | Probiotical Spa | BACTERIA OF BACTERIA ABLE TO METABOLIZE THE OXALATES. |
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| ITRM20110475A1 (en) * | 2011-09-09 | 2013-03-10 | Probiotical Spa | BACTERIA OF LACTIC AND / OR BIFIED BACTERIA BACTERIA, OPTIONALLY ADDED TO N-ACETYLCISTEIN AND / OR LYSOZYME MICROINCAPSULATE GASTROPROTETTO, HAVING INHIBITION ACTIVITIES / REDUCTION OF THE GROWTH OF DIFFERENT E.COLI BIOTYPES, INCLUDING E.COLI O157: H7 E |
| JP6032737B2 (en) * | 2012-09-27 | 2016-11-30 | 株式会社明治 | Method for detecting bifidobacteria |
| ITMI20130793A1 (en) | 2013-05-14 | 2014-11-15 | Probiotical Spa | COMPOSITION INCLUDING LACTIC BACTERIA FOR USE IN THE PREVENTIVE AND / OR CURATIVE TREATMENT OF THE RECURRENT CYCLES. |
| SG11201604752SA (en) * | 2013-12-10 | 2016-07-28 | Meiji Co Ltd | Antibacterial peptide-inducing agent |
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