JP5162243B2 - 胃腸の鎮痛作用を有するラクトバチルスアシドフィラスの菌株 - Google Patents
胃腸の鎮痛作用を有するラクトバチルスアシドフィラスの菌株 Download PDFInfo
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- JP5162243B2 JP5162243B2 JP2007531724A JP2007531724A JP5162243B2 JP 5162243 B2 JP5162243 B2 JP 5162243B2 JP 2007531724 A JP2007531724 A JP 2007531724A JP 2007531724 A JP2007531724 A JP 2007531724A JP 5162243 B2 JP5162243 B2 JP 5162243B2
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Description
i)試験微生物を準備し、少なくとも一つの上皮細胞と接触させる段階、及び
ii)少なくとも一つの上皮細胞のオピオイド受容体及び/又はカンナビノイド受容体の発現を検出する段階。
i)試験対象の微生物を準備し、少なくとも一つの上皮細胞と接触させ、
ii)少なくとも一つの上皮細胞におけるオピオイド受容体及び/又はカンナビノイド受容体の発現を検出する。
1/ 上皮細胞の調製:
リアルタイムPCR:
培養組織の上皮細胞の全RNAを、カラム抽出キット(Macherey−Nagel社製)を用いて分離した。端的には、細胞を1%のβ−メルカプトエタノールを含む溶解バッファーに懸濁し、その後第一のカラムを通過させ、全ての細胞残渣を除去した。DNAse処理後、RNAを相補DNAに逆転写し、更にμオピオイド受容体又はカンナビノイド受容体に特異的なプライマーを使用し、60℃のハイブリダイゼーション温度でリアルタイムPCR(ABPrism 7000、パーキン社)によって増幅した。
センス:ATgCCAgTgCTCATCATTAC;
アンチセンス:gATCCTTCgAAgATTCCTgTCCT;
−また、対照遺伝子として、β−アクチン
センス:TCACCCACACTgTgCCCATCTACgA;
アンチセンス:CAgCggAACCgCTCATTgCCAATg);
−カンナビノイド受容体
CB1センス:CCT AGA TGG CCT TGC AGA TAC C;
CB1アンチセンス:TGT CAT TTG AGC CCA CGT ACA G;
CB2センス:GCT AAG TGC CCT GGA GAA CGT;
CB2アンチセンス:TCA GCC CCA GCC AAG CT。
結果を、図1から3に示す。結果を、標的遺伝子(β−アクチン)/μオピオイド(MOR)受容体及び/又はカンナビノイド受容体(CB1、CB2)の比率で表した。μオピオイド受容体及び/又はカンナビノイド受容体は、ATCC HTB−38上皮細胞において発現していた(図1〜3)。
菌株
本発明のラクトバチルス アシドフィラスNCFM菌株を、37℃で一晩、deMan、Rogosa、Sharpe(MRS)培地(Becton Dickinson)で嫌気培養した。対数増殖期の細菌をインビトロ実験に使用した。培養液を動物に接種する前に、グラム染色により純度を解析した。
動物実験は、政府のガイドラインに従い、パスツール研究所(リール)の公認の機関において行った。Balb/cマウスをケージ当たり5匹収容し、12時間の光周期にて、標準のマウス餌料及び水道水を自由に摂取させた。一日に一度、14日間、109CFUのラクトバチルス アシドフィラス菌株(0.5%のCMC(カルボキシメチルセルロース、Sigma社)中に再懸濁)を強制的に動物の胃に供給した。動物を、頚椎脱臼によって屠殺した。全ての結腸を動物から切除し、2つのパーツに分割した。一つのパーツを一晩、4%のパラホルムアルデヒド酸で固定し、パラフィン包埋した。第二の結腸のパーツを、μオピオイド受容体(MOR)、カンナビノイド受容体(CB1及びCB2)、及び炎症性サイトカインTNFα、KC、及びIL−1βmRNAの定量化に用いた。
MORの発現が炎症により制御されるとの知見(Philippe Dら、JCI 2003;Pol Oら、Mol Pharmacol 2001;Pol Oら、Curr Top Med Chem 2004)より、TNBSによって誘導された結腸炎を陽性コントロールとして用いた。動物実験は、政府のガイドラインに従い、パスツール研究所(リール)の公認の機関において行った。動物をケージ当たり5匹収容し、標準のマウス餌料及び水道水を自由に摂取させた。結腸炎誘導の際、マウスを90〜120分間麻酔にかけ、0.9%のNaClと100%のエタノールの1:1混合液中に溶解させたTNBS(40μL、150mg/kg)を直腸内投与した。コントロールのマウスの場合、0.9%のNaClと100%のエタノールの1:1混合液又は生理食塩水を、同じ方法で投与した。動物をTNBS投与の4日後に屠殺した。
Rneasyキット(Macherey−Nagel社製、ウルト、フランス)を使用し、メーカーの指示に従い、全RNAを全結腸組織から単離した。分光光度法を用い、RNAを定量した。RNaseフリーのDNaseI(ロシュダイアグノスティック社、インディアナポリス、イリノイ、米国)20〜50ユニットを用い、30分間37℃処理の後、オリゴ−dTプライマー(ロシュダイアグノスティック社、インディアナポリス、イリノイ、米国)を用いて一本鎖cDNAを合成した。GeneAmp Abiprism 7000(Applera、Courtaboeuf、フランス)を用い、SYBR green Master Mix(Applera社製Courtaboeuf、フランス)を使用し、特異的なマウスオリゴヌクレオチド(表1を参照)によりmRNAを定量した。各アッセイにおいて、検量された、鋳型を含まないコントロールを含めた。各サンプルにつき、三回試験を行った。SYBR green色素の強度を、Abiprism 7000 SDSソフトウェア(Applera社製、Courtaboeuf、フランス)を使用して解析した。
全ての結果は、影響のないハウスキーピング遺伝子であるβ−アクチンにより標準化した。
ラクトバチルス アシドフィラス菌株を投与されたマウス結腸のパラフィン切片を作製し、免疫組織化学法を行った。無処置の動物をコントロールとして用いた。0.1%のTriton X−100を含むPBSにおいて4℃で5分間浸透処理を行った後、切片を1.5%のヤギ正常血清にて15分、及びブロッキングバッファー(ミルク中1%BSA)にて15分インキュベートし、抗体の非特異的吸着を最小化した。その後組織を室温で2〜12時間、CB1(1:200、Cayman Chemical社、アナーバー、米国)、又はCB2(1:10、Alpha Diagnostic社、サンアントニオ、米国)、又はMOR(1:500、Diasorin社、アントニー、フランス)と反応するウサギポリクローナル一次抗体とインキュベートした。その後切片を、Alexa 488 ヤギ抗ウサギIgGのFITC蛍光色素(1:100希釈、Dako Laboratories社、Trappes、フランス)とのコンジュゲートと、室温で1時間インキュベートした。各工程の間、切片を0.05%のTritonX−100を含むPBSにより5分間ずつ二回洗浄した。その後スライドをHoescht溶液(0.125mg/mL)で対比染色し、顕微鏡検査に供した。陰性コントロールの場合、特異抗体の代わりに正常ウサギ血清による染色を行った。蛍光顕微鏡(ライカ社、Bensheim、ドイツ)を用い、免疫蛍光を観察した。MOR、CB1及びCB2における免疫反応した上皮細胞の数を、5箇所の強拡大視野(HPF)において計数し、100個の上皮細胞当たりの個数として表した。
インビトロにて、結腸上皮細胞のHT−29又はCaco−2を、数種のプロバイオティクス又は細菌(L.acidophilus(NCFM)、L.salivarius(UCC118)、L.paracasei(LPC37)、共生大腸菌、付着性浸潤性大腸菌(LF82))(100細菌/細胞)と0〜6時間インキュベートした。プロバイオティクスによるμオピオイド受容体(MOR)及びカンナビノイド受容体(CB1及びCB2)の発現誘導におけるNFκB経路の役割を、特異的な抑制物質(カフェイン酸フェネチルエステル(CAPE))を用いてHT−29細胞を前処理することにより試験した。TNFα(10ng/mL、2時間)(G共役タンパク質の発現誘導源)を陽性コントロールに使用した。インビトロで受容体(MOR1、CB1及びCB2受容体)の発現誘導に最も効果的なプロバイオティクスを選別した後、プロバイオティクスを109CFUにて15日間Balb/cマウス(n=10)に経口投与し、インビボ試験を行った。マウスの上皮細胞及び結腸におけるMOR、CB1及びCB2の発現を、リアルタイムPCR及び免疫組織化学により解析した。炎症性サイトカイン(TNFα、KC及びIL−1β)のmRNAを、マウス結腸のリアルタイムPCRにより解析した。
Claims (9)
- 上皮細胞においてオピオイド受容体及び/又はカンナビノイド受容体の発現を誘導するラクトバチルス アシドフィラスの菌株の、上皮細胞におけるオピオイド受容体及び/又はカンナビノイド受容体の発現の誘導を介したヒト又は動物の胃腸の鎮痛の治療薬の製造における使用であって、前記ラクトバチルス アシドフィラスの菌株は他の乳酸菌との混合物の形態ではない使用。
- 前記ラクトバチルス アシドフィラスの菌株がATCC寄託番号:PTA−4797(Lactobacillus acidophilus NCFM菌株としても知られる)である、請求項1記載の使用。
- 前記鎮痛がオピオイド受容体及び/又はカンナビノイド受容体を経てなされる、請求項1又は2記載の使用。
- 前記菌株は、薬学的に許容できる担体中に製造される、請求項1乃至3のいずれか一項記載の使用。
- 前記菌株は、動物又は植物由来の乳製品中に製造される、請求項1乃至4のいずれか一項記載の使用。
- 以下の段階を含み、:
i) 少なくとも一つの上皮細胞を試験微生物と接触させる段階、
ii) 少なくとも一つの前記上皮細胞においてオピオイド受容体及び/又はカンナビノイド受容体の発現を検出する段階
前記試験微生物は、前記少なくとも一つの上皮細胞においてオピオイド受容体及び/又はカンナビノイド受容体の発現を誘導していた場合に選択される、
上皮細胞におけるオピオイド受容体及び/又はカンナビノイド受容体の発現の誘導を介したヒト又は動物の胃腸の鎮痛を目的としてヒト又は動物に投与するための単一の微生物を選別する方法。 - 工程i)又はii)における少なくとも一つの上皮細胞が、ATCC HTB−38細胞株又はCaco−2細胞株に由来する、請求項6記載の方法。
- 工程ii)が、μオピオイド受容体及び/又はCB1受容体及び/又はCB2受容体を検出することによって行われる、請求項6又は7記載の方法。
- 工程ii)が、オピオイド受容体及び/又はカンナビノイド受容体のメッセンジャーRNAの発現を検出することによって行われる、請求項6乃至8のいずれか一項記載の方法。
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JP2012246300A (ja) * | 2004-09-21 | 2012-12-13 | Dupont Nutrition Biosciences Aps | 胃腸の鎮痛作用を有するラクトバチルスアシドフィラスの菌株 |
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US7888062B1 (en) | 2010-02-01 | 2011-02-15 | Microbios, Inc. | Process and composition for the manufacture of a microbial-based product |
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RU2642306C2 (ru) | 2012-05-21 | 2018-01-24 | ДюПон НЬЮТРИШН БАЙОСАЙЕНСИЗ АпС | Штамм lactobacillus, обладающий ингибирующей активностью против дрожжей и плесневых грибов (варианты), и его применение |
RU2640255C2 (ru) | 2012-05-21 | 2017-12-27 | ДюПон НЬЮТРИШН БАЙОСАЙЕНСИЗ АпС | Штамм propionibacterium, обладающий ингибирующей активностью против дрожжей и плесневых грибов (варианты) и его применение |
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CN108102960B (zh) * | 2017-12-25 | 2020-12-25 | 齐鲁工业大学 | 一种嗜酸乳杆菌ncfm耐酸保护剂 |
CN108949643A (zh) * | 2018-08-31 | 2018-12-07 | 重庆子和杉农业发展有限公司 | 一种培育兔用乳酸菌的方法和无公害养兔的方法 |
WO2021156777A1 (en) * | 2020-02-06 | 2021-08-12 | Buzzelet Development And Technologies Ltd. | Microbial combinations and uses thereof |
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