JP6734472B2 - ラクトバチルス・アシドフィルスを含む更年期の予防または治療用組成物 - Google Patents
ラクトバチルス・アシドフィルスを含む更年期の予防または治療用組成物 Download PDFInfo
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- JP6734472B2 JP6734472B2 JP2019507317A JP2019507317A JP6734472B2 JP 6734472 B2 JP6734472 B2 JP 6734472B2 JP 2019507317 A JP2019507317 A JP 2019507317A JP 2019507317 A JP2019507317 A JP 2019507317A JP 6734472 B2 JP6734472 B2 JP 6734472B2
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Description
(1−1.実験動物および更年期動物モデルの作製)
更年期動物モデルを製作するために、Sprague−Dawley(SD)ラット(4週齢、100〜120g、メス)を株式会社Samtakoから分譲されて、実験動物用飼育箱に4週間適応させた後に実験に使用した。動物飼育は、温度22±1℃、湿度55±5%、明暗サイクルは昼夜周期(12時間昼間/12時間夜)、照度300Luxの条件下に行われ、飼料および飲水は、自由給餌した。また、すべての動物は、KFRI−IACUC(Korea Food Research Institute, Institutional Animal Care and Use Committee)の実験動物使用指針によって管理された。
前記実施例1−1の方法によってラットから卵巣摘出を実施した後、10週間毎週体重変化を測定し、糞便試料を採取し、手術後に12週以降からは、実験終了(手術後18週)まで2週に一回ずつ体重を測定し、糞便試料を採取して、以後に分析実験を進めた。
卵巣摘出手術後に長期間体重変化の観察と共に、骨密度の測定のために時期別に骨密度測定装備(pDEXATM,Norland)を利用して実験動物の大腿部の骨密度を測定して分析した。骨密度測定装備(pDEXATM,Norland)x−rayを利用して大腿部の測定Area(面積)、BMC(骨無機質量)、BMD(骨密度)等を測定して、OVXによる骨密度の変化と、候補腸内微生物処理群の骨密度の変化に対する影響を比較分析した。
卵巣摘出手術後に長期間体重変化の確認と共に、糞便試料の採取後に実験動物の機械的異痛の程度を測定するために、手術後4、12、16、18週にvon Freyフィラメントテストを実施した。実験動物を金網実験台が設置されたアクリル箱に入れ、15分以上適応させた後、実験動物の動き等が静かになってから、連続した太さのvon Freyフィラメント(Stoelting,USA)を使用して機械逃避閾値(mechanical withdrawal threshold)(g)を評価した。フィラメントを左側の患部の足裏に垂直に接触させ、5〜6秒間維持させて、実験動物が迅速な回避反応を示したり、またはフィラメントを剥離すると直ちにぎくりとしたり、足裏をなめると、陽性反応を示したものと見なした。中央部のvon Freyフィラメントから刺激して陽性反応を示した場合は弱いフィラメントで刺激し、陽性反応がない場合は強いフィラメントで刺激して進めた。陽性反応を示す最小の刺激の大きさを閾値とし、15g以上でも反応がない場合を上限線として、これ以上適用しなかった。
実験動物を卵巣摘出手術18週後に強制水泳試験(Forced swim test:FST)を実施した。このために、高さ50cm、直径25cmの透明なアクリル円筒形水槽に水(23〜25℃)を満たして、ラットの尻尾が底につかないほどの高さの水に強制的に落とした後、15分間強制水泳をさせた。24時間後に6分間同じ環境で強制水泳をさせ、録画した後、Smart 3.0プログラムを使用して登り(Climbing)、水泳(Swimming)、無動(Immobility)の時間を比較分析した。ここで、登りは、最も激烈な運動状態であって、前足を積極的に使用してアクリル円筒上に上がってこようと四肢を全部使用する状態を言い、水泳は、水面上を回って動いて、時々水底に潜水したりする状態を言う。また、不動とは、頭を含む上体の一部分だけ水面上に露出したまま動きがない状態であるが、これは、生存放棄による急激なうつ病状態を意味する。それぞれに該当する状態の時間を測定することによって、卵巣摘出手術の前後の行動変化をFSTを通じて比較分析した。
更年期動物モデルの腸内微生物メタゲノム分析のために、まず、Sham群およびOVX(卵巣摘出)群のラットの糞便試料を0.5gずつを回収してメタゲノムを抽出した。より具体的に、0.5gの試料をLN2を利用して均質化し、STESバッファーを添加した後、60℃で一晩培養して、細胞を溶解させた。細胞溶解後に、フェノール抽出(PCI:フェノール−クロロホルム−イソアミルアルコール)方法を利用してメタゲノムを抽出した。次に、クルードメタゲノム上に存在するRNAを除去するために10μl(100mg/ml)のRNaseを処理して1時間培養し、さらに、DNA精製カラムを利用して配列分析に利用可能な純度を有する精製されたメタゲノムを獲得した。
実験結果は、平均と標準誤差(mean±SEM)で示し、二つのグループ間の有意差は、スチューデントのt検定を通じて評価され、p<0.05を統計的に有意性があるものと見なし、p<0.05(*)、p<0.01(**)、p<0.001(***)で表示した。各群と対照群との統計的な比較は、各実験群間に分類して一元配置分散分析方法を使用し、統計的分析は、Statview(ver.5.01,The SAS Institute,CA)プログラムを利用した。
(2−1.体重の変化および骨密度の測定)
実施例1−1の方法によって卵巣摘出手術を実施した雌性ラットに対して実施例1−2の方法によって手術後1週から18週間体重を測定した。
卵巣摘出手術18週後にラットを犠牲にさせて、対照群(Sham)と卵巣摘出群(OVX)の臓器の重さおよび長さ変化の差異を調べてみるために、肝臓、脾臓、大腸等を摘出して、重さと長さを確認した。
卵巣摘出手術後に変化する血中生化学的指標を測定するために、卵巣摘出手術18週後にラットを犠牲にして、対照群(Sham)と卵巣摘出群(OVX)の腹部大動脈を通じて血液を採取した後、自動血液分析装備(FUJI DRY−CHEM 3500s)を通じて血中アルカリフォスファターゼ(ALP)、アスパラギン酸アミノトランスフェラーゼ(AST)、ガンマグルタミルトランスフェラーゼ(GGT)、グルコース(GLU)、総蛋白質(TP)、血液尿素窒素(BUN)、クレアチニン(CRE)濃度を比較測定した。
卵巣摘出手術後に変化する血中エストラジオール数値を測定するために、前記実施例2−3と同じ方法で卵巣摘出手術18週後にラットを犠牲にさせて、対照群(Sham)と卵巣摘出群(OVX)の血液を採取した後、Estradiol RIA kit(ES180S−100,SIEMENS,Calbiotech Inc)を利用して測定した。
卵巣摘出手術18週後、対照群(Sham)と卵巣摘出群(OVX)の解剖時にラットで脾臓とパイエル板を分離して単細胞化した後、72時間培養して、その上澄み液を取ってサイトカインの分析に使用した。細胞培養時には、コンカナバリンA(2μg/ml)を処理してT細胞を活性化した。サイトカイン分析は、Multi−Analyte LISArray for Rat Kit(Cat.336161,QIAGEN)を使用し、IL−1α、1β、2、4、6、10、12、13、INF−γ、TNF−α、GM、RANTESの数値を測定した。また、サイトカイン濃度の測定後、その発色程度を比較して、対照群と差異を示すサイトカインを再分析した。
前記実施例1−1の方法によって卵巣摘出手術後から0週、1週、3週、6週、10週、14週、および18週の当該期間に収集した対照群(Sham)と卵巣摘出群(OVX)の糞便サンプルを利用して前記実施例1−6の方法によってOVX手術によるエストロゲン減少による腸内微生物の変化の分析に使用した。
前記実施例3の結果に基づいて、対照群(sham)より卵巣摘出群(OVX)で有意に分布が減少した微生物のうち乳酸菌として最も大きい差異(腸内3%以上存在、二つの群間に2倍以上の量的差異)を示す微生物、すなわちラクトバチルス・アシドフィルスをターゲットに設定し、MRS/Rogosa培地、pH5/6.4、嫌気/好気性等の培養条件を異にして当該微生物の分離を試みた。Sham群およびOVX群の腸内微生物の変化確認サンプルの18週目の糞便を利用して当該微生物の分離を進め、101個の微生物コロニーを単一分離し、これらの16S rDNA塩基配列分析を通じて当該微生物の同定を進めた。
前記実施例4を通じて分離したターゲット候補腸内微生物であるラクトバチルス・アシドフィルスYT1菌株および従来に公知となったさらに他のラクトバチルス・アシドフィルス(KCTC 3164)を利用してラクトバチルス・アシドフィルスによる更年期症状の改善効果を調べてみるために、実施例1−1の方法によって作製した更年期動物モデルを利用して下記のような方法で実験を実施した。
前記方法によって各実験群のラットに対して卵巣摘出手術1週間後から16週間エストラジオールまたは各ラクトバチルス・アシドフィルス菌株を投与し、一週間の間隔で体重を測定した。
更年期動物モデルでラクトバチルス・アシドフィルスの投与による摂食行動変化を評価するために、卵巣摘出手術後1週から16週間飼料と飲水の摂取量を確認した。
前記実施例の結果に加えて、ラクトバチルス・アシドフィルスの投与により大腿部の骨密度が増加するかを調べてみようとした。このために、卵巣摘出後、各群のラットに対して手術8、12、および16週にラットを吸入麻酔し、骨密度測定装備(pDEXATM,Norland)を利用して大腿部の骨密度(BMD)を測定した。
従来に研究された報告によれば、卵巣摘出手術後に機械逃避閾値(mechanical withdrawal threshold)(g)、すなわち痛覚感受性が高くなると知られている。したがって、更年期動物モデルでラクトバチルス・アシドフィルスの投与による痛覚感受性の変化を確認するために、卵巣摘出手術4、8、12、および16週に前記実施例1−4の方法によってvon Freyフィラメントテストを実施して痛覚感受性を測定した。
更年期の症状で現れるうつ病がラクトバチルス・アシドフィルスの投与により改善され得るかを調べてみるために、卵巣摘出手術16週後にうつ病と類似した行動が現れるかを実施例1−5の方法によって強制水泳試験を実施した。
実施例5を通じて検証されたラクトバチルス・アシドフィルス菌株の効能とラクトバチルス属の他の種の菌株(ラクトバチルス・ロイテリ(L.Reuteri))との効能比較のために、更年期動物モデルを利用して下記のような方法で実験を実施した。
更年期動物モデルでラクトバチルス・アシドフィルス菌株の効能とラクトバチルス属の他の種の菌株(ラクトバチルス・ロイテリ(L.Reuteri))との効能比較のために、卵巣摘出手術後、試料投与12週のラットを吸入麻酔し、骨密度測定装備(pDEXATM,Norland)を利用して大腿部の骨密度(BMD)を測定した。
更年期動物モデルでラクトバチルス・アシドフィルス菌株の効能とラクトバチルス属の他の種の菌株(ラクトバチルス・ロイテリ(L.Reuteri))との痛覚感受性の変化効能を比較するために、卵巣摘出手術後、試料投与12週のラットに対して前記実施例1−4の方法によってvon Freyフィラメントテストを実施して、痛覚感受性を測定した。
受託番号:KCCM11808P
受託日付:20160120
Claims (5)
- 更年期症状の予防または治療効果を有するラクトバチルス・アシドフィルス(Lactobacillus acidophilus)YT1菌株(受託番号:KCCM11808P)であって、前記更年期症状は、更年期による体脂肪の増加、更年期による骨密度の減少、更年期による痛覚感受性増加又は更年期によるうつ病である、ラクトバチルス・アシドフィルスYT1菌株。
- 請求項1に記載の菌株を含むラクトバチルス・アシドフィルス(Lactobacillus acidophilus)を有効成分として含む、更年期症状の予防または治療用薬学的組成物であって、
更年期による体脂肪増加を抑制すること、更年期による骨密度減少を抑制すること、更年期による骨密度減少を抑制すること、更年期による痛覚感受性増加を抑制すること、又は更年期によるうつ病を緩和させることを特徴とする、薬学的組成物。 - 請求項1に記載の菌株を含むラクトバチルス・アシドフィルス(Lactobacillus acidophilus)を有効成分として含む、更年期症状の改善用食品組成物であって、
更年期による体脂肪増加を抑制すること、更年期による骨密度減少を抑制すること、更年期による骨密度減少を抑制すること、更年期による痛覚感受性増加を抑制すること、又は更年期によるうつ病を緩和させることを特徴とする、食品組成物。 - 健康機能性食品組成物であることを特徴とする、請求項3に記載の食品組成物。
- 請求項1に記載の菌株を含むラクトバチルス・アシドフィルス(Lactobacillus acidophilus)を有効成分として含む、更年期症状の改善用化粧料組成物であって、
更年期による体脂肪増加を抑制すること、更年期による骨密度減少を抑制すること、更年期による骨密度減少を抑制すること、更年期による痛覚感受性増加を抑制すること、又は更年期によるうつ病を緩和させることを特徴とする、化粧料組成物。
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PCT/KR2017/008737 WO2018030837A1 (ko) | 2016-08-12 | 2017-08-11 | 락토바실러스 아시도필루스를 포함하는 갱년기 예방 또는 치료용 조성물 |
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