JP2021020885A - Composition for maintaining and/or improving memory/learning ability, and food, medicine, and feed containing composition - Google Patents
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Abstract
Description
本発明は、加齢（老化）に伴って発生する記憶・学習能の低下の予防・改善剤および／または加齢（老化）に伴って発生する記憶・学習能の低下の予防・改善作用を有する飲食品に関する。 The present invention provides a preventive / ameliorating agent for deterioration of memory / learning ability that occurs with aging (aging) and / or a preventive / ameliorating effect of deterioration of memory / learning ability that occurs with aging (aging). Regarding food and drink to have.
わが国は2010年に65歳以上の高齢者人口が全人口の21%を突破し超高齢社会へと突入した。高齢者の割合は今後も増加していくことが予想されており、2060年には40%に達するとされている。このような状況の中で、医療、福祉など増加する高齢人口の問題に対応することが喫緊の課題となっている。 In 2010, the elderly population aged 65 and over exceeded 21% of the total population, and Japan entered a super-aging society. The proportion of elderly people is expected to continue to increase, reaching 40% by 2060. Under such circumstances, it is an urgent issue to deal with the problems of the increasing elderly population such as medical care and welfare.
高齢人口の増加に伴い、中高年層の記憶・学習能の低下などの認知機能障害や認知症の増加が問題視されている。一般的に、加齢に伴い脳の神経細胞の微細構造に変化が起こり、異常タンパク質の沈着や細胞の脱落を経て、脳が萎縮していくことにより、認知機能が低下していくと考えられている。これらの加齢変化に加えて、脳梗塞や脳出血、異常タンパク質の過剰な蓄積などの要因が加わり、認知機能が病的に低下した状態が認知症である。 With the increase in the elderly population, the increase in cognitive dysfunction and dementia such as deterioration of memory and learning ability of middle-aged and elderly people is regarded as a problem. In general, it is thought that the microstructure of nerve cells in the brain changes with aging, and cognitive function declines as the brain atrophies through abnormal protein deposition and cell shedding. ing. Dementia is a condition in which cognitive function is pathologically impaired due to factors such as cerebral infarction, cerebral hemorrhage, and excessive accumulation of abnormal proteins in addition to these age-related changes.
2012年時点で65歳以上の高齢者のうち、認知症患者は推計15%にあたる約462万人、認知症予備軍と呼ばれる軽度認知障害者は約400万人に上るとされ、現在の日本は「認知症800万人時代」といわれている。 As of 2012, among the elderly aged 65 and over, the number of dementia patients is estimated to be about 4.62 million, and the number of people with mild cognitive impairment called the dementia reserve army is estimated to be about 4 million. It is said to be "the age of 8 million people with dementia."
認知症に対する治療薬の開発が進められているが、現時点では進行を遅らせることを目的として使用されるものであり、根本的な治療には至っていない。一方、健常な高齢者や認知症の前駆状態として位置付けられている軽度認知障害の高齢者においては、食生活の見直しや運動など適切な介入を行うことにより、記憶・学習能などの認知機能の低下を予防または改善、さらには認知症発症リスクを低減できる可能性が示されている（精神経誌 １１１, ２６−３０, （２００９））。このことから、日々の生活の中で継続して摂取することができ、かつ安全性が高く副作用のない飲食物への関心が高まっている。 The development of therapeutic agents for dementia is underway, but at present, it is used for the purpose of delaying the progression and has not reached a radical treatment. On the other hand, in healthy elderly people and elderly people with mild cognitive impairment, which is positioned as a precursor of dementia, cognitive functions such as memory and learning ability can be improved by reviewing dietary habits and performing appropriate interventions such as exercise. It has been shown that the decline can be prevented or ameliorated, and the risk of developing dementia can be reduced (Spirit Neurology 111, 26-30, (2009)). For this reason, there is increasing interest in foods and drinks that can be continuously ingested in daily life, are safe, and have no side effects.
乳酸菌は、チーズやヨーグルト、漬物などの発酵食品や乳酸菌飲料など多岐にわたり利用されており、比較的安価に供給できる上、その高い嗜好性から世界中で古くから大量に生産されている。最近では、便秘防止、下痢改善などの整腸作用、感染症の予防、免疫賦活作用など、健康上好ましい保健効果も有する健康食品として注目されている。老化や認知機能に関連したものでは、ラクトバチルス・ガセリやビフィドバクテリウム・ロングムが加齢に伴う代謝異常に対して有効であること（特許５１５５９６１、特許５１５５９６０）、ラクトバチルス・ロイテリー ＤＳＭ １７９３８株が幼若哺乳動物の認知機能の発達に有効であること（特表２０１５−５０３９１３）などが開示されている。 Lactic acid bacteria are widely used in fermented foods such as cheese, yogurt, and pickles, and lactic acid bacteria beverages. They can be supplied at a relatively low price, and because of their high palatability, they have been mass-produced all over the world for a long time. Recently, it has been attracting attention as a health food having favorable health effects such as prevention of constipation, improvement of diarrhea and other intestinal regulation, prevention of infectious diseases, and immunostimulatory effect. Regarding aging and cognitive function, Lactobacillus gasseri and Bifidobacterium longum are effective against age-related metabolic abnormalities (Patent 5155961, Patent 51595960), Lactobacillus reutery DSM 17938 strain. Is effective for the development of cognitive function in juvenile mammals (Special Table 2015-503913) and the like are disclosed.
しかしながら、加齢に伴って発生する記憶・学習能の低下に対するラクトバチルス属に属するヘテロ発酵型乳酸桿菌の作用については、未だ明らかでない。 However, the action of the heterofermentative lactic acid bacillus belonging to the genus Lactobacillus on the deterioration of memory and learning ability that occurs with aging is not yet clear.
線虫Ｃａｅｎｏｒｈａｂｄｉｔｉｓ ｅｌｅｇａｎｓ（以下、Ｃ． ｅｌｅｇａｎｓとする）は、３０２個のニューロンからなるシンプルな神経回路を用いて、様々な外部刺激を感知し、多様な応答行動をとることができる。線虫は、一定の温度で飼育されるとその飼育温度を快適な温度として記憶するため、温度勾配の上におくと過去の飼育温度へ向かうという習性を示す。例えば、２３℃で飼育されたＣ． ｅｌｅｇａｎｓは餌のない１７℃から２３℃までの温度勾配の上におかれた場合、１時間後には２３℃付近へと移動する。さらに、２３℃を記憶していたＣ． ｅｌｅｇａｎｓを新たな温度である１７℃で飼育すると、約４時間で新たな温度１７℃の記憶を獲得し、温度勾配の上で１７℃付近へと移動するようになる（Proc. Natl. Acad. Sci. USA, 72, 4061-4065 (1975); Genetics, 169, 1437-1450 (2005); J. Neurosci. Methods, 154, 45-52 (2006)）。この習性は温度走性とよばれ、記憶や学習といった神経機能の可塑性を反映したすぐれたモデル系であることが知られる（Curr. Opin. Neurobiol., 17, 712-719 (2007)）。 C. elegans Caenorhabditis elegans (hereinafter referred to as C. elegans) can sense various external stimuli and take various response behaviors by using a simple neural circuit consisting of 302 neurons. C. elegans memorizes the breeding temperature as a comfortable temperature when bred at a constant temperature, and therefore shows a habit of moving toward the past breeding temperature when placed on a temperature gradient. For example, C.I. When the elegans are placed on a food-free temperature gradient from 17 ° C to 23 ° C, they move to around 23 ° C after 1 hour. Furthermore, C.I. When elegans are bred at a new temperature of 17 ° C, they acquire a memory of the new temperature of 17 ° C in about 4 hours and move to around 17 ° C on a temperature gradient (Proc. Natl. Acad. Sci. USA, 72, 4061-4065 (1975); Genetics, 169, 1437-1450 (2005); J. Neurosci. Methods, 154, 45-52 (2006)). This habit is called thermotaxis and is known to be an excellent model system that reflects the plasticity of neural functions such as memory and learning (Curr. Opin. Neurobiol., 17, 712-719 (2007)).
発明者らの過去のレーザーによるニューロンの破壊実験から、温度走性行動に必要なニューロンが明らかにされており、温度走性行動はきわめてシンプルな神経回路を基盤とすることが知られている（Nature, 376, 344-348 (1995)）。また、発明者らの研究グループは、温度記憶が形成される過程をゲノムワイドなマイクロアレイ解析、分子遺伝学的な手法とイメージング技術により解析した。その結果、Ｃ． ｅｌｅｇａｎｓは飼育温度を記憶する際に、転写因子であるＨＳＦ−１を介して周囲の温度を全身で受容していることを見い出した。さらに、この温度の受容は遺伝子の発現変化をひき起こし、その結果、温度シグナルは女性ホルモンであるエストロゲンを介して神経回路の温度受容ニューロンであるAFDニューロンに記憶として蓄積されることが示された（Nat. Neurosci., 14, 984-92 (2011)）。 The inventors' past experiments on neuron destruction by laser have revealed the neurons required for thermotactic behavior, and it is known that thermotactic behavior is based on a very simple neural circuit (). Nature, 376, 344-348 (1995)). In addition, the inventor's research group analyzed the process of temperature memory formation by genome-wide microarray analysis, molecular genetic techniques, and imaging techniques. As a result, C.I. Elegans found that when memorizing the breeding temperature, the whole body received the ambient temperature via the transcription factor HSF-1. Furthermore, it was shown that the reception of this temperature causes a change in gene expression, and as a result, the temperature signal is accumulated as a memory in the AFD neuron, which is a temperature-receptor neuron of the neural circuit, via the female hormone estrogen. (Nat. Neurosci., 14, 984-92 (2011)).
更に、発明者らは、記憶を担う代表的な転写因子ＣＲＥＢのＣ． ｅｌｅｇａｎｓにおけるオルソログの機能する細胞を探索した結果、ＣＲＥＢのオルソログはたった一つ、ＡＦＤニューロンでのみ機能することを見い出している（EMBO Rep., 12, 855-862 (2011)）。つまり、Ｃ． ｅｌｅｇａｎｓのすべてのニューロンのなかでも、ＡＦＤニューロンはＣＲＥＢを介した温度記憶をもつ唯一のニューロンであることが示された。これらの研究から、温度記憶が形成される際の分子機構の一端が明らかになっている。 Furthermore, the inventors have found that CREB, a representative transcription factor responsible for memory, C.I. As a result of searching for cells that function in orthologs in elegans, we have found that only one CREB ortholog functions in AFD neurons (EMBO Rep., 12, 855-862 (2011)). That is, C.I. Of all neurons in elegans, AFD neurons have been shown to be the only neurons with CREB-mediated temperature memory. These studies reveal some of the molecular mechanisms by which temperature memory is formed.
線虫と哺乳動物は進化系統上離れているものの、細胞レベルの分子機構は共通する部分が大きい。哺乳動物において記憶に関わることが知られている分子が線虫の温度走性にも関与することが報告されている。例えば、哺乳類で記憶に関わる因子ＣＲＥＢ（線虫ではＣＲＨ−１）は、線虫の温度記憶の獲得に関与すること（EMBO Rep., 12, 855-862 (2011)）、哺乳類で記憶に関わる脳内伝達物質であるセロトニンは、線虫の温度走性を制御していること（PLoS One., 8, 1-10 (2013)）、哺乳類で記憶に関わる因子カルシニューリン（線虫ではＲＣＡＮ−１）は、線虫の温度走性行動に関わること（J. Mol. Biol., 427, 3457-3468 (2015)）など多数の報告がされている。 Although nematodes and mammals are evolutionarily distant, they have much in common in their cellular-level molecular mechanisms. It has been reported that molecules known to be involved in memory in mammals are also involved in the temperature tactics of C. elegans. For example, the memory-related factor CREB (CRH-1 in C. elegans) in mammals is involved in the acquisition of temperature memory in C. elegans (EMBO Rep., 12, 855-862 (2011)), and is involved in memory in C. elegans. Serotonin, a brain mediator, regulates the temperature motility of C. elegans (PLoS One., 8, 1-10 (2013)), and the memory-related factor calcinurine in C. elegans (RCAN-1 in C. elegans). ) Has been reported to be involved in the temperature-running behavior of nematodes (J. Mol. Biol., 427, 3457-3468 (2015)).
更に、線虫で神経系に対する有効性が認められる成分が、哺乳動物においても脳・神経系に対する効果を示す事例が報告されている。即ち、経口摂取したαリポ酸は、加齢で低下した線虫及び哺乳動物の連合学習行動を改善すること（Neurobiol. Aging., 26, 899-905 (2005); J. Med. Food. 15, 713-7 (2012)）、経口摂取したクルクミンは、線虫及び哺乳動物において、加齢に伴う認知障害を改善すること（Neurobiol. Aging., 39, 69-81 (2016); Geroscience., 40, 73-95 (2018)）などが報告されている。 Furthermore, there have been reports of cases in which a component that has been shown to be effective against the nervous system in nematodes also has an effect on the brain and nervous system in mammals. That is, orally ingested α-lipoic acid improves age-related decreased nematode and mammalian associative learning behavior (Neurobiol. Aging., 26, 899-905 (2005); J. Med. Food. 15). , 713-7 (2012)), Orally ingested curcumin improves age-related cognitive impairment in nematodes and mammals (Neurobiol. Aging., 39, 69-81 (2016); Geroscience., 40, 73-95 (2018)) etc. have been reported.
これらのことから、Ｃ． ｅｌｅｇａｎｓの温度走性行動は温度の受容と記憶の分子機構を解析することに適したモデル系と考えられている。 From these things, C.I. The thermotactic behavior of elegans is considered to be a suitable model system for analyzing the molecular mechanism of temperature reception and memory.
本発明は、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善する効果を有する新規乳酸菌を提供することに関する。 The present invention relates to providing a novel lactic acid bacterium having an effect of preventing and / or ameliorating a decrease in memory / learning ability that occurs with aging (aging).
本発明者らは、日常的に摂取が可能である食品素材によって、生体の種々の機能異常を予防や改善できないかという観点で、食品に使用される微生物およびそれに含まれる成分に着目し、上記課題を解決すべく鋭意研究を重ねた結果、ラクトバチルス属の複数のヘテロ発酵型乳酸桿菌の菌体または培養物に、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善する作用を見出し、本発明を完成するに至った。即ち、本発明は、下記の構成を有する。
（１）ラクトバチルス属のヘテロ発酵型乳酸桿菌の菌体または培養物を含む記憶・学習能維持および／または向上用組成物。
（２）ラクトバチルス属のヘテロ発酵型乳酸桿菌が、ラクトバチルス・ハービネンシス（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｈａｒｂｉｎｅｎｓｉｓ）種、ラクトバチルス・ラムノーサス（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｒｈａｍｎｏｓｕｓ）種、ラクトバチルス・カゼイ（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｃａｓｅｉ）種、ラクトバチルス・パラカゼイ（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｐａｒａｃａｓｅｉ）種、ラクトバチルス・ファーメンタム（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｆｅｒｍｅｎｔｕｍ）種、ラクトバチルス・ムコーサエ（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｍｕｃｏｓａｅ）種、ラクトバチルス・ロイテリー（Ｌａｃｔｏｂａｃｉｌｌｕｓ ｒｅｕｔｅｒｉ）種の1種もしくはそれらを複数種の菌体を混合したもの、または培養物を含む（１）に記載の記憶・学習能維持および/または向上用組成物。
（３）ラクトバチルス属のヘテロ発酵型乳酸桿菌が、ラクトバチルス・ハービネンシスＳＢＴ０７９６株、ラクトバチルス・ラムノーサスＳＢＴ２２９９株、ラクトバチルス・カゼイＳＢＴ２２３２株、ラクトバチルス・パラカゼイＳＢＴ０２２８株、ラクトバチルス・ファーメンタムＳＢＴ１８５９株、ラクトバチルス・ムコーサエＳＢＴ２９５８株、ラクトバチルス・ロイテリーＳＢＴ１００１０株の1株もしくはそれらを複数株の菌体を混合したもの、または培養物を含む（２）に記載の記憶・学習能維持および／または向上用組成物。
（４）（１）から（３）のいずれかに記載の記憶・学習能維持および／または向上用組成物を含むことを特徴とする記憶・学習能維持および／または向上用食品、記憶・学習能維持および／または向上用医薬品、記憶・学習能維持および／または向上用飼料。
（５）受託番号がＮＩＴＥ Ｐ−０２９９３であるラクトバチルス・ハービネンシスＳＢＴ０７９６株、受託番号がＮＩＴＥ Ｐ−０２９９４であるラクトバチルス・ラムノーサスＳＢＴ２２９９株、受託番号がＮＩＴＥ Ｐ−０２９９５であるラクトバチルス・カゼイＳＢＴ２２３２株、受託番号がＮＩＴＥ Ｐ−０２９９６であるラクトバチルス・ファーメンタムＳＢＴ１８５９株、又は受託番号がＮＩＴＥ Ｐ−０２９９７であるラクトバチルス・ロイテリーＳＢＴ１００１０株。
The present inventors have focused on the microorganisms used in foods and the components contained therein from the viewpoint of whether various functional abnormalities of the living body can be prevented or ameliorated by the food materials that can be ingested on a daily basis. As a result of intensive research to solve the problems, we have prevented the deterioration of memory and learning ability that occurs with aging (aging) in the cells or cultures of multiple heterofermentative lactic acid rods of the genus Lactobacillus. / Or found an action to improve, and completed the present invention. That is, the present invention has the following configuration.
(1) A composition for maintaining and / or improving memory / learning ability, which comprises cells or cultures of heterofermentative lactic acid bacilli of the genus Lactobacillus.
(2) Heterofermentative Lactobacillus of the genus Lactobacillus is Lactobacillus harbinensis (Lactobacillus harbinensis) species, Lactobacillus ramnosus species, Lactobacillus casei (Lactobacillus casei) Lactobacillus casei (Lactobacillus lactobacillus) One or more of Lactobacillus fermentum, Lactobacillus mucosae, Lactobacillus reuteri, a mixture of these, and Lactobacillus fermentum, Lactobacillus mucosae, and Lactobacillus reuteri. Alternatively, the composition for maintaining and / or improving memory / learning ability according to (1), which comprises a culture.
(3) Heterofermentative lactic acid rods of the genus Lactobacillus are Lactobacillus herbinensis SBT0796 strain, Lactobacillus ramnosus SBT2299 strain, Lactobacillus casei SBT2232 strain, Lactobacillus paracasei SBT0228 strain, Lactobacillus fermentum SBT1859 strain. For maintaining and / or improving the memory / learning ability according to (2), which comprises one strain of Lactobacillus mucosae SBT2958 strain, one strain of Lactobacillus reutery SBT10010 strain or a mixture of multiple strains of cells, or a culture. Composition.
(4) A food for maintaining and / or improving memory / learning ability, which comprises the composition for maintaining / / or improving memory / learning ability according to any one of (1) to (3). Drugs for maintaining and / or improving ability, feeds for maintaining and / or improving memory / learning ability.
(5) Lactobacillus harbinensis SBT0796 strain with a trust number of NITE P-02993, Lactobacillus ramnosus SBT2299 strain with a trust number of NITE P-02994, and Lactobacillus casei SBT2232 strain with a trust number of NITE P-02995. , Lactobacillus fermentum SBT1859 strain with accession number NITE P-02996, or Lactobacillus reutery SBT10010 strain with accession number NITE P-02997.
本発明によれば、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善することができる。本発明は、記憶・学習能の低下が気になる高齢者の、日常生活における生活の質（Ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ）の向上に有効である。 According to the present invention, it is possible to prevent and / or ameliorate the deterioration of memory / learning ability that occurs with aging (aging). INDUSTRIAL APPLICABILITY The present invention is effective in improving the quality of life of elderly people who are concerned about deterioration of memory / learning ability.
本明細書で「記憶・学習能維持および／または向上」というときは、好ましくは、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善することを意味し、より好ましくは、加齢（老化）に伴って発生する記憶能の低下を予防および／または改善することを意味する。更に、本明細書で「加齢（老化）に伴って発生する記憶・学習能の低下」あるいは「加齢（老化）に伴って発生する記憶能の低下」というときは、好ましくは、アルツハイマー病やハンチントン病などの認知症およびパーキンソン病などの大脳基底核疾患を含む脳疾患、並びに、健忘症、記憶喪失、およびコルサコフ症候群などの記憶障害、並びに、うつ病、不安症、双極性障害、統合失調症、睡眠異常、およびストレス障害などの精神疾患伴って発生する記憶・学習能の低下あるいは記憶能の低下を含まない。 In the present specification, the term "maintaining and / or improving memory / learning ability" preferably means preventing and / or ameliorating the deterioration of memory / learning ability that occurs with aging (aging). More preferably, it means preventing and / or ameliorating the deterioration of memory ability that occurs with aging (aging). Furthermore, in the present specification, when "decrease in memory / learning ability that occurs with aging (aging)" or "decrease in memory ability that occurs with aging (aging)" is preferably referred to as Alzheimer's disease. Dementia such as Huntington's disease and cerebral basal nucleus disease such as Parkinson's disease, and memory disorders such as amnesia, memory loss, and Korsakov syndrome, as well as depression, anxiety, bipolar disorder, integration. Does not include memory / learning or memory loss associated with mental disorders such as dementia, sleep abnormalities, and stress disorders.
本明細書で「組成物」というときは、好ましくは、医薬組成物、または、食品組成物を意味する。 The term "composition" as used herein preferably means a pharmaceutical composition or a food composition.
本発明における乳酸菌としては、ラクトバチルス属に属するヘテロ発酵型乳酸桿菌を用いることを特徴とする。ラクトバチルス属に属するヘテロ発酵型乳酸桿菌としては、ラクトバチルス・ハービネンシス種、ラクトバチルス・ラムノーサス種、ラクトバチルス・カゼイ種、ラクトバチルス・パラカゼイ種、ラクトバチルス・ファーメンタム種、ラクトバチルス・ムコーサエ種、ラクトバチルス・ロイテリー種が好ましい。更に好ましいのはラクトバチルス・ハービネンシスＳＢＴ０７９６株、ラクトバチルス・ラムノーサスＳＢＴ２２９９株、ラクトバチルス・カゼイＳＢＴ２２３２株、ラクトバチルス・パラカゼイＳＢＴ０２２８株、ラクトバチルス・ファーメンタムＳＢＴ１８５９株、ラクトバチルス・ムコーサエＳＢＴ２９５８株、ラクトバチルス・ロイテリーＳＢＴ１００１０株であるが、本発明の記憶・学習能を維持および／または向上する効果を有するヘテロ発酵型乳酸桿菌であれば特に限定されるものではない。 The lactic acid bacterium in the present invention is characterized by using a heterofermentative lactic acid bacillus belonging to the genus Lactobacillus. As heterofermentative lactic acid rod bacteria belonging to the genus Lactobacillus, Lactobacillus habinensis species, Lactobacillus ramnosus species, Lactobacillus casei species, Lactobacillus paracasei species, Lactobacillus fermentum species, Lactobacillus mucosae species Lactobacillus reutery species are preferred. More preferred are Lactobacillus harbinensis SBT0796, Lactobacillus ramnosus SBT2299, Lactobacillus casei SBT2232, Lactobacillus paracasei SBT0228, Lactobacillus fermentum SBT1859, Lactobacillus mucosae SBT2958. The Reutery SBT10010 strain is not particularly limited as long as it is a heterofermentative lactic acid rod bacterium having an effect of maintaining and / or improving the memory / learning ability of the present invention.
これらのヘテロ発酵型乳酸桿菌は、単独で用いる事もできるし、適宜２つ以上の乳酸菌を組み合わせて用いてもよい。また、これらのヘテロ発酵型乳酸桿菌は、乳酸菌培養の常法に従って培養することができる。培養培地には、乳培地又は乳成分を含む培地、これを含まない半合成培地など種々の培地を用いることができる。このような培地としては、還元脱脂乳培地やMRS培地などを例示することができる。 These heterofermentative lactic acid bacilli may be used alone or in combination of two or more lactic acid bacteria as appropriate. In addition, these heterofermentative lactic acid bacilli can be cultivated according to a conventional method for culturing lactic acid bacteria. As the culture medium, various media such as a milk medium, a medium containing a milk component, and a semi-synthetic medium not containing the milk component can be used. Examples of such a medium include a reduced skim milk medium and an MRS medium.
得られた培養物から遠心分離などの集菌手段によって分離された菌体をそのまま本発明の有効成分として用いることができる。濃縮、乾燥、凍結乾燥などした菌体を用いることもできるし、加熱乾燥などにより死菌体にしてもよい。菌体として純粋に分離されたものだけでなく、培養物、懸濁物、その他の菌体含有物や、菌体を酵素や物理的手段を用いて処理した細胞質や細胞壁画分も用いることができる。培養物などの形態としては、合成培地であるＭＲＳ培地（ＤＩＦＣＯ社製）、還元脱脂乳培地など一般的に乳酸菌の培養に用いられる培地を用いた培養物だけでなく、チーズ、発酵乳、乳製品乳酸菌飲料などの乳製品などを例示することができるが特に限定されるものではない。 The cells separated from the obtained culture by means of collecting bacteria such as centrifugation can be used as they are as the active ingredient of the present invention. Bacterial cells that have been concentrated, dried, freeze-dried, etc. can be used, or can be killed by heat-drying or the like. Not only purely isolated cells, but also cultures, suspensions, other cell-containing substances, and cytoplasm and cell wall fractions obtained by treating cells using enzymes or physical means can be used. it can. The form of the culture is not only a culture using a medium generally used for culturing lactic acid bacteria such as a synthetic medium MRS medium (manufactured by DIFCO) and a reduced defatted milk medium, but also cheese, fermented milk, and milk. Products Dairy products such as lactic acid bacteria beverages can be exemplified, but are not particularly limited.
本発明の記憶・学習能維持および／または向上剤の製剤化に際しては、製剤上許可されている賦型剤、安定剤、矯味剤などを適宜混合して濃縮、凍結乾燥するほか、加熱乾燥して死菌体にしてもよい。これらの乾燥物、濃縮物、ペースト状物も含有される。また、ラクトバチルス属に属するヘテロ発酵型乳酸桿菌の記憶・学習能維持および／または向上作用を妨げない範囲で、賦型剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、懸濁剤、コーティング剤、その他の任意の薬剤を混合して製剤化することもできる。剤形としては、錠剤、カプセル剤、顆粒剤、散剤、粉剤、シロップ剤などが可能であり、これらを経口的に投与することが望ましい。 In formulating the memory / learning ability maintaining and / or improving agent of the present invention, the excipients, stabilizers, flavoring agents, etc. permitted in the formulation are appropriately mixed, concentrated, freeze-dried, and heat-dried. It may be a dead cell. These dried products, concentrates and pastes are also contained. In addition, excipients, binders, disintegrants, lubricants, flavoring agents, suspension agents, as long as they do not interfere with the memory / learning ability maintenance and / or improving action of heterofermentative lactic acid bacilli belonging to the genus Lactobacillus. , Coating agents, and any other drug can be mixed and formulated. The dosage form can be tablets, capsules, granules, powders, powders, syrups, etc., and it is desirable to administer these orally.
本発明の記憶・学習能維持および／または向上用組成物はどのような飲食品に配合しても良く、飲食品の製造工程中に原料に添加しても良い。飲食品の例としては、チーズ、発酵乳、乳製品乳酸菌飲料、乳酸菌飲料、バター、マーガリンなどの乳製品、乳飲料、果汁飲料、清涼飲料などの飲料、ゼリー、キャンディー、プリン、マヨネーズなどの卵加工品、バターケーキなどの菓子・パン類、さらには、各種粉乳の他、乳幼児食品、栄養組成物などを挙げることができるが特に限定されるものではない。さらに、本発明の記憶・学習能維持および／または向上用組成物を飼料に配合することができる。前記飲食品と同様にどのような飼料に配合しても良く、飼料の製造工程中に原料に添加しても良い。 The composition for maintaining and / or improving the memory / learning ability of the present invention may be blended in any food or drink, or may be added to a raw material during the manufacturing process of the food or drink. Examples of foods and drinks include cheese, fermented milk, dairy products, lactic acid bacteria beverages, lactic acid bacteria beverages, butter, dairy products such as margarine, beverages such as dairy beverages, fruit juice beverages, and soft beverages, and eggs such as jelly, candy, pudding, and mayonnaise. Processed products, sweets and breads such as butter cakes, various milk powders, infant foods, nutritional compositions, etc. can be mentioned, but are not particularly limited. Further, the composition for maintaining and / or improving the memory / learning ability of the present invention can be added to the feed. Like the food and drink, it may be blended with any feed and may be added to the raw material during the feed manufacturing process.
ラクトバチルス属に属するヘテロ発酵型乳酸桿菌の菌体又は培養物を配合して、記憶・学習能維持および／または向上用組成物あるいは、記憶・学習能維持および／または向上用飲食品、栄養組成物、飼料などの素材又はそれら素材の加工品に配合させて使用する場合、ラクトバチルス属に属するヘテロ発酵型乳酸桿菌の菌体または培養物の配合割合は特に限定されず、製造の容易性や好ましい一日投与量にあわせて適宜調節すればよい。投与対象者の症状、年齢などを考慮してそれぞれ個別に決定されるが、通常成人の場合、例えば、ラクトバチルス・ラムノーサスの培養物などを１０〜２００ｇ、あるいはその菌体自体を０．１〜５，０００ｍｇ摂取できるように配合量などを調整すればよい。このようにして摂取することにより所望の効果を発揮することができる。 A composition for maintaining and / or improving memory / learning ability, or a food / drink for maintaining and / or improving memory / learning ability, and a nutritional composition by blending cells or cultures of heterofermentative lactic acid bacilli belonging to the genus Lactobacillus. When used by blending with materials such as products and feeds or processed products of those materials, the blending ratio of the cells or cultures of heterofermentative lactic acid bacilli belonging to the genus Lactobacillus is not particularly limited, and the ease of production and It may be appropriately adjusted according to a preferable daily dose. It is determined individually in consideration of the symptoms, age, etc. of the recipient, but in the case of adults, for example, 10 to 200 g of a culture of Lactobacillus ramnosus, or 0.1 to 200 g of the cells themselves. The blending amount may be adjusted so that 5,000 mg can be ingested. By ingesting in this way, a desired effect can be exhibited.
本発明における、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善する乳酸菌をスクリーニングする方法として、Ｃ．ｅｌｅｇａｎｓを用いた温度走性試験を用いた。一般的に、食成分や薬剤の生理機能を検証する際には、マウスやラット、イヌ、サルなどの高等動物が用いられるが、それには多大な労力や時間、費用を要する上に、倫理面に十分に配慮する必要がある。動物実験の代替法として、動物の組織から分離した培養細胞などを用いた試験も行われている。 In the present invention, as a method for screening for lactic acid bacteria that prevent and / or improve the deterioration of memory / learning ability that occurs with aging (aging), C.I. A temperature taxis test using elegans was used. Generally, higher animals such as mice, rats, dogs, and monkeys are used to verify the physiological functions of food components and drugs, but this requires a great deal of labor, time, and cost, and is ethical. It is necessary to give due consideration to. As an alternative method for animal experiments, tests using cultured cells isolated from animal tissues are also being conducted.
Ｃ．ｅｌｅｇａｎｓは土壌中に生息する非寄生性の多細胞生物であり、実験動物としての取り扱いが容易である点に加え、体を構成する約１０００個の体細胞の細胞系譜がすべて明らかになっている点や神経系を有するなどといった点から、モデル生物として様々な研究分野で広く利用されている。特に、細胞死、神経、発生、老化等の様々な研究分野において多大な貢献を果たしてきた。さらに、近年では、アルツハイマー病や筋委縮性側索硬化症（ＡＬＳ）、パーキンソン病、ハンチントン病など様々な神経変性疾患モデルのＣ．ｅｌｅｇａｎｓを用いて、これらの神経変性疾患の予防や改善に有効な医薬品や食成分の探索が進められている。 C. C. elegans is a non-parasitic multicellular organism that lives in soil, and in addition to being easy to handle as an experimental animal, the cell lineage of about 1000 somatic cells that make up the body has been clarified. It is widely used in various research fields as a model organism because it has points and a nervous system. In particular, he has made great contributions in various research fields such as cell death, neurogenesis, development, and aging. Furthermore, in recent years, C.I., a model of various neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease. Using elegans, the search for effective medicines and food components for the prevention and improvement of these neurodegenerative diseases is underway.
Ｃ．ｅｌｅｇａｎｓは単純な神経回路を有しながらも、食餌の有無とその際に置かれた環境における塩濃度や温度などの情報を関連付けて記憶・学習することが知られており、連合学習や記憶などの認知機能を評価するモデル系として活用することができる（Nature, 376, 344-348 (1995)）。 C. Although elegans has a simple neural circuit, it is known to memorize and learn by associating information such as the presence or absence of food with the salt concentration and temperature in the environment placed at that time, such as associative learning and memory. It can be used as a model system for evaluating the cognitive function of (Nature, 376, 344-348 (1995)).
以下、本発明について実施例をもとにさらに詳細に説明するが、本発明は係る実施例に限定して解釈されるものではない。 Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not construed as being limited to such examples.
［試験例１］加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善する乳酸菌の評価
本明細書で用いるＣ．ｅｌｅｇａｎｓは野生型であるＮ２株を用い、「線虫ラボマニュアル」に従って飼育した。
１．試験方法
（１）供試菌
表１に示したラクトバチルス属に属するヘテロ発酵型乳酸桿菌の菌株をスクリーニングに供した。
[Test Example 1] Evaluation of lactic acid bacteria that prevent and / or improve the deterioration of memory / learning ability that occurs with aging (aging) C.I. Elegans used a wild-type N2 strain and was bred according to the "Nematode Lab Manual".
1. 1. Test Method (1) Test Bacteria Strains of heterofermentative lactic acid bacilli belonging to the genus Lactobacillus shown in Table 1 were subjected to screening.
（２）試験手順
(i) 評価サンプルの準備
上記（１）の各供試菌をMRS培地に植菌し、３７℃にて１６時間静置培養を行った。培養菌体を遠心分離（７，０００×ｇ、４℃、１５分）し、上清を廃棄した。菌体は生理食塩水で洗浄した後、菌体の湿重量を求め、０．０５ｇ／ｍｌになるようにＮＧバッファー（０．３％ ＮａＣｌ、１ｍＭ ＣａＣｌ２、１ｍＭ ＭｇＳＯ４、２５ｍＭリン酸緩衝液［ｐＨ６．０］）に再懸濁し、Ｃ．ｅｌｅｇａｎｓ飼育用プレート（ＮＧＭプレート）に２００μｌずつ播種したものをサンプルプレートとした。コントロールとして、Ｃ．ｅｌｅｇａｎｓの食餌として一般的に用いられている大腸菌ＯＰ５０株を用いた。
(2) Test procedure
(i) Preparation of evaluation sample Each test bacterium of (1) above was inoculated into MRS medium and statically cultured at 37 ° C. for 16 hours. The cultured cells were centrifuged (7,000 × g, 4 ° C., 15 minutes), and the supernatant was discarded. After washing the cells with physiological saline, the wet weight of the cells was determined, and NG buffer (0.3% NaCl, 1 mM CaCl 2 , 1 mM sulfonyl 4 , 25 mM phosphate buffer) was adjusted to 0.05 g / ml. Resuspended in [pH 6.0]) and C.I. A sample plate was prepared by sowing 200 μl each on an elegans breeding plate (NGM plate). As a control, C.I. Escherichia coli OP50 strain, which is generally used as a diet for elegans, was used.
(ii) 乳酸菌を摂取した加齢成虫の準備
ブリーチ処理により回収したＣ．ｅｌｅｇａｎｓの卵を、ＯＰ５０を播種したプレートに播き、２３℃で３日間静置し、若齢成虫を得た。この成虫をＮＧバッファーで回収し、乳酸菌を播種したプレートもしくはＯＰ５０を播種したプレートに移し、２３℃で４日間飼育し、加齢成虫を得た。
(ii) Preparation of aging adults ingested with lactic acid bacteria C. recovered by bleaching. Eggs of elegans were sown on a plate in which OP50 was sown and allowed to stand at 23 ° C. for 3 days to obtain young adults. The adults were collected with NG buffer, transferred to a plate in which lactic acid bacteria were sown or a plate in which OP50 was sown, and bred at 23 ° C. for 4 days to obtain aging adults.
(iii) 温度走性試験によるスクリーニング
温度走性試験は、Ｉｔｏ Ｈ．ら（J. Neurosci. Methods, 154, 45-52 (2006)）に記載の方法に従い以下の通り実施した。二つの恒温槽を準備し、コの字型のアルミ台（２１．５ｃｍ×６０ｃｍ×１．５ｃｍ厚）の片方の足を低温側（５℃）に、もう片方を高温側（３５℃）の恒温槽に浸すことで、アルミ台におよそ５℃から３５℃までの直線状温度勾配を形成した。角型シャーレに入れた寒天プレートを２０℃が中心となるようにアルミ台の上に置き、上述した若齢成虫もしくは加齢成虫をプレートの中央に放ち、一時間後の温度勾配上のＣ．ｅｌｅｇａｎｓの分布を評価した。記憶・学習能は、プレートを温度勾配方向に８等分したときの飼育温度（２３℃）近辺の２区画に位置したＣ．ｅｌｅｇａｎｓの割合を記憶指数（Ｍｅｍｏｒｙ ｉｎｄｅｘ）として評価した（図１）。また、ダネット型多重検定により、ＯＰ５０を摂取した加齢成虫を対照としたときの有意差の有無を評価した（ｐ＜０．０５を有意差ありと判定した）。
(iii) Screening by temperature taxis test The temperature taxis test is performed by Ito H. Et al. (J. Neurosci. Methods, 154, 45-52 (2006)) and the following procedure. Prepare two constant temperature baths, one foot of the U-shaped aluminum stand (21.5 cm x 60 cm x 1.5 cm thick) on the low temperature side (5 ° C) and the other on the high temperature side (35 ° C). By immersing in a constant temperature bath, a linear temperature gradient from about 5 ° C. to 35 ° C. was formed on the aluminum table. Place the agar plate in a square petri dish on an aluminum table so that the temperature is centered at 20 ° C., and release the above-mentioned young or aged adults to the center of the plate, and one hour later, C. The distribution of elegans was evaluated. The memory / learning ability was determined by C.I., which was located in two compartments near the breeding temperature (23 ° C.) when the plate was divided into eight equal parts in the temperature gradient direction. The proportion of elegans was evaluated as a memory index (FIG. 1). In addition, the presence or absence of a significant difference when an aged adult who ingested OP50 was used as a control was evaluated by a Danette-type multiple test (p <0.05 was judged to be significant).
２．試験結果
図２にスクリーニング結果を示す。若齢成虫に比べて加齢成虫で記憶指数が低下した。ヘテロ発酵型乳酸桿菌であるラクトバチルス・ハービネンシスＳＢＴ０７９６株、ラクトバチルス・ラムノーサスＳＢＴ２２９９株、ラクトバチルス・カゼイＳＢＴ２２３２株、ラクトバチルス・パラカゼイＳＢＴ０２２８株、ラクトバチルス・ファーメンタムＳＢＴ１８５９株、ラクトバチルス・ムコーサエＳＢＴ２９５８株、ラクトバチルス・ロイテリーＳＢＴ１００１０株を摂取した加齢成虫ではＯＰ５０を摂取したものと比べて記憶指数が有意に増加した。すなわち、上記菌体を摂取することにより、加齢（老化）に伴って発生する記憶・学習能の低下を予防および／または改善させることができることがわかった
2. 2. Test results
FIG. 2 shows the screening results. The memory index decreased in the aged adults compared to the young adults. Lactobacillus harbinensis SBT0796 strain, Lactobacillus ramnosus SBT2299 strain, Lactobacillus casei SBT2232 strain, Lactobacillus paracasei SBT0228 strain, Lactobacillus fermentum SBT1859 strain, Lactobacillus fermentum SBT1859 strain Aged adults who ingested the Lactobacillus reutery SBT10010 strain had a significantly increased memory index compared to those who ingested OP50. That is, it was found that by ingesting the above-mentioned cells, it is possible to prevent and / or improve the deterioration of memory / learning ability that occurs with aging (aging).
乳酸菌を摂取した線虫の記憶指数の結果を乳酸菌の16s rRNA配列を基にして作成した系統樹に当てはめ、乳酸菌の系統と記憶指数との間に相関関係があるか否かを検証した。その結果、系統樹のクラスターで記憶指数の値の傾向が異なり、ラクトバチルス属に属するホモ発酵型の菌株並びにロイコノストック属やビフィドバクテリウム属に属する菌株と比べて、ラクトバチルス属に属するヘテロ発酵型の菌株で高値を示した（図３、４）。ヘテロ発酵型の乳酸菌が産生する成分が線虫の温度記憶を向上させる可能性が示された。 The results of the memory index of nematodes that ingested lactic acid bacteria were applied to a phylogenetic tree created based on the 16s rRNA sequence of lactic acid bacteria, and it was verified whether there was a correlation between the strain of lactic acid bacteria and the memory index. As a result, the tendency of the memory index value differs depending on the cluster of the phylogenetic tree, and it belongs to the genus Lactobacillus as compared with the homofermentative strain belonging to the genus Lactobacillus and the strains belonging to the genus Leuconostoc and the genus Bifidobacterium. Heterofermentative strains showed high values (Figs. 3 and 4). It was shown that the components produced by heterofermentative lactic acid bacteria may improve the temperature memory of C. elegans.
（実施例１）記憶・学習能維持および／または向上用剤（顆粒）の製造
ラクトバチルス・ロイテリーＳＢＴ１００１０株を食用可能な合成培地（０．５％酵母エキス、０．１％トリプチケースペプトン添加）に５重量％摂取し、３８℃で１５時間培養後、遠心分離で菌体を回収した。回収した菌体を凍結乾燥し、前期菌体の凍結乾燥粉末を得た。この凍結乾燥粉末１ｇを乳糖５ｇと混合し、顆粒状に成形して本発明の記憶・学習能維持および／または向上用剤を得た。
(Example 1) Production of agent (granule) for maintaining and / or improving memory / learning ability Lactobacillus reutery SBT10010 strain edible synthetic medium (0.5% yeast extract, 0.1% trypticase soybean peptone addition) ) Was ingested in an amount of 5% by weight, cultured at 38 ° C. for 15 hours, and then the cells were collected by centrifugation. The recovered cells were freeze-dried to obtain a freeze-dried powder of the early cells. 1 g of this freeze-dried powder was mixed with 5 g of lactose and molded into granules to obtain an agent for maintaining and / or improving the memory / learning ability of the present invention.
（実施例２）記憶・学習能維持および／または向上用剤（散剤）の製造
第１３改正日本薬局方解説書製剤総則「散剤」の規定に準拠し、上記実施例１で得られたラクトバチルス・ロイテリーＳＢＴ１００１０株の凍結乾燥粉末１０ｇに乳糖（日局）４００ｇ、バレイショデンプン（日局）６００ｇを加えて均一に混合し、本発明の記憶・学習能維持および／または向上用剤を製造した。
(Example 2) Manufacture of agent (powder) for maintaining and / or improving memory / learning ability The lactobacillus obtained in Example 1 above in accordance with the provisions of the 13th revised Japanese Pharmacopoeia Manual of Formulation "Powder". -400 g of lactose (Japanese Pharmacopoeia) and 600 g of potato starch (Japanese Pharmacopoeia) were added to 10 g of lyophilized powder of Reutery SBT10010 strain and mixed uniformly to produce an agent for maintaining and / or improving memory / learning ability of the present invention.
（実施例３）記憶・学習能維持および／または向上用栄養組成物の製造
ラクトバチルス・ロイテリーＳＢＴ１００１０株を食用可能な合成培地（０．５％酵母エキス、０．１％トリプチケースペプトン添加）に５重量％摂取し、３７℃で１５時間培養後、遠心分離で菌体を回収し、回収した菌体を凍結乾燥した。ビタミンＣ４０ｇまたはビタミンＣとクエン酸の等量混合物４０ｇ、グラニュー糖１００ｇ、コーンスターチと乳糖の等量混合物６０ｇに、この凍結乾燥粉末の凍結乾燥粉末４０ｇを加えて混合した。混合物を袋に詰め、本発明の記憶・学習能維持および／または向上用栄養組成物を製造した。
(Example 3) Production of nutritional composition for maintaining and / or improving memory / learning ability A synthetic medium in which Lactobacillus reutery SBT10010 strain is edible (0.5% yeast extract, 0.1% trypticase soybean peptone added) After ingesting 5% by weight and culturing at 37 ° C. for 15 hours, the cells were collected by centrifugation, and the collected cells were lyophilized. To 40 g of vitamin C or an equal amount mixture of vitamin C and citric acid, 100 g of granulated sugar, and 60 g of an equal amount mixture of cornstarch and lactose, 40 g of the freeze-dried powder of this freeze-dried powder was added and mixed. The mixture was packed in a bag to produce a nutritional composition for maintaining and / or improving memory / learning ability of the present invention.
（実施例４）記憶・学習能維持および／または向上用飲料の製造
上記実施例３で得られたラクトバチルス・ロイテリーＳＢＴ１００１０株１ｇを６９９ｇの脱イオン水に溶解した後、４０℃まで加熱後、ウルトラディスパーサー（ＵＬＴＲＡ−ＴＵＲＲＡＸ Ｔ−２５；ＩＫＡジャパン社製）にて、９，５００ｒｐｍで２０分間撹拌混合した。マルチトール１００ｇ、酸味料２ｇ、還元水飴２０ｇ、香料２ｇ、脱イオン水１７６ｇを添加した後、１００ｍｌのガラス瓶に充填し、９５℃、１５秒間殺菌後、密栓し、本発明の記憶・学習能維持および／または向上用飲料１０本（１００ｍｌ入り）を製造した。
(Example 4) Production of beverage for maintaining and / or improving memory / learning ability After 1 g of Lactobacillus reutery SBT10010 strain obtained in Example 3 above was dissolved in 699 g of deionized water and then heated to 40 ° C. The mixture was stirred and mixed at 9,500 rpm for 20 minutes with an ultra disperser (ULTRA-TURRAX T-25; manufactured by IKA Japan). After adding 100 g of maltitol, 2 g of acidulant, 20 g of reduced starch syrup, 2 g of flavor and 176 g of deionized water, the bottle is filled in a 100 ml glass bottle, sterilized at 95 ° C. for 15 seconds, and then sealed to maintain the memory / learning ability of the present invention. And / or 10 bottles of improving beverage (100 ml) were produced.
（実施例５）記憶・学習能維持および／または向上用飼料の製造
大豆粕１２ｋｇ、脱脂粉乳１４ｋｇ、大豆油４ｋｇ、コーン油２ｋｇ、パーム油２３．２ｋｇ、トウモロコシ澱粉１４ｋｇ、小麦粉９ｋｇ、ふすま２ｋｇ、ビタミン混合物５ｋｇ、セルロース２．８ｋｇ、ミネラル混合物２ｋｇを配合し、１２０℃、４分間殺菌して、実施例３で得られたラクトバチルス・ロイテリーＳＢＴ１００１０株１０ｋｇを配合して、本発明の記憶・学習能維持および／または向上用飼料を製造した。
(Example 5) Production of feed for maintaining and / or improving memory / learning ability Soybean meal 12 kg, skim milk powder 14 kg, soybean oil 4 kg, corn oil 2 kg, palm oil 23.2 kg, corn starch 14 kg, wheat flour 9 kg, bran 2 kg, 5 kg of vitamin mixture, 2.8 kg of cellulose, and 2 kg of mineral mixture were blended, sterilized at 120 ° C. for 4 minutes, and 10 kg of lactobacillus reutery SBT10010 strain obtained in Example 3 was blended to memorize and learn the present invention. A feed for maintaining and / or improving performance was produced.
（実施例６）記憶・学習能維持および／または向上用発酵乳の製造
ビフィドバクテリウム・ロイテリーＳＢＴ１００１０株を食用可能な合成培地（０．５％酵母エキス、０．１％トリプチケースペプトン添加）に５重量％摂取し、３７℃で１７時間培養後、遠心分離で菌体を回収し、凍結乾燥した。この凍結乾燥菌体５ｇ、脱脂粉乳１７００ｇ、グルコース３００ｇ、脱イオン水７６９５ｇを混合し、９５℃で２時間保持することで加熱殺菌した。これを３７℃まで冷却し、乳酸菌スターター（Ｌｂ．ｃａｓｅｉ）を３００ｇ植菌し、撹拌混合後、３７℃に保持したインキュベーター内でｐＨ４．０まで発酵させた。ｐＨ４．０到達後、１０℃以下まで冷却し、本発明の記憶・学習能維持および／または向上用発酵乳１０ｋｇを製造した。
(Example 6) Production of fermented milk for maintaining and / or improving memory / learning ability A synthetic medium in which Bifidobacterium reutery SBT10010 strain is edible (0.5% yeast extract, 0.1% trypticase soybean peptone addition) ) Was ingested in an amount of 5% by weight, cultured at 37 ° C. for 17 hours, and the cells were collected by centrifugation and lyophilized. 5 g of the freeze-dried cells, 1700 g of skim milk powder, 300 g of glucose, and 7695 g of deionized water were mixed and sterilized by heating by holding at 95 ° C. for 2 hours. This was cooled to 37 ° C., 300 g of a lactic acid bacterium starter (Lb. Casei) was inoculated, stirred and mixed, and then fermented to pH 4.0 in an incubator maintained at 37 ° C. After reaching pH 4.0, the mixture was cooled to 10 ° C. or lower to produce 10 kg of fermented milk for maintaining and / or improving the memory / learning ability of the present invention.
（１）ラクトバチルス・ハービネンシスＳＢＴ０７９６株（受託番号：ＮＩＴＥ Ｐ−０２９９３、受託日：２０１９年６月２６日）、受託先：〒２９２−０８１８ 日本国千葉県木更津市かずさ鎌足２−５−８、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（ＮＰＭＤ）。
（２）ラクトバチルス・ラムノーサスＳＢＴ２２９９株（受託番号：ＮＩＴＥ Ｐ−０２９９４、受託日：２０１９年６月２６日）、受託先：〒２９２−０８１８ 日本国千葉県木更津市かずさ鎌足２−５−８、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（ＮＰＭＤ）。
（３）ラクトバチルス・カゼイＳＢＴ２２３２株（受託番号：ＮＩＴＥ Ｐ−０２９９５、受託日：２０１９年６月２６日）、受託先：〒２９２−０８１８ 日本国千葉県木更津市かずさ鎌足２−５−８、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（ＮＰＭＤ）。
（４）ラクトバチルス・ファーメンタムＳＢＴ１８５９株（受託番号：ＮＩＴＥ Ｐ−０２９９６、受託日：２０１９年６月２６日）、受託先：〒２９２−０８１８ 日本国千葉県木更津市かずさ鎌足２−５−８、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（ＮＰＭＤ）。
（５）ラクトバチルス・ロイテリーＳＢＴ１００１０株（受託番号：ＮＩＴＥ Ｐ−０２９９７、受託日：２０１９年６月２６日）、受託先：〒２９２−０８１８ 日本国千葉県木更津市かずさ鎌足２−５−８、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（ＮＰＭＤ）。
(1) Lactobacillus herbinensis SBT0796 strain (trust number: NITE P-02993, trust date: June 26, 2019), trustee: 2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 , National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (NPMD).
(2) Lactobacillus ramnosus SBT2299 shares (trust number: NITE P-02994, trust date: June 26, 2019), trustee: 2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 , National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (NPMD).
(3) Lactobacillus casei SBT2232 strain (trust number: NITE P-02995, trust date: June 26, 2019), trustee: 2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 , National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (NPMD).
(4) Lactobacillus fermentum SBT1859 shares (trust number: NITE P-02996, trust date: June 26, 2019), trustee: 2-5 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 8. National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (NPMD).
(5) Lactobacillus reutery SBT10010 shares (trust number: NITE P-02997, trust date: June 26, 2019), trustee: 2-5-8 Kazusakamatari, Kisarazu City, Chiba Prefecture, Japan 292-0818 , National Institute of Technology and Evaluation Patent Microorganisms Depositary Center (NPMD).
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