JP2016508368A - 腸疾患の予防および治療のための、微生物の使用 - Google Patents
腸疾患の予防および治療のための、微生物の使用 Download PDFInfo
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Abstract
Description
1.1)サワードウおよびブレッド
サワードウ(Vollsauer)を、乳酸菌DSM26024株、DSM23090株、DSM23091株、DSM23200株、DSM23092株、DSM23093株、DSM23201株、DSM23174株およびDSM23121株を含む、I型サワードウライ麦スターターの伝統的な増殖により調製した。サワードウおよびサワードウブレッドの組成は:71%ライ麦粉、25%小麦粉、1.8%塩および2%パン粉(pH4.5、酸性度9〜10)である。生地を298℃で1.5時間焼いた。類似ブレッドは、2.5%炭酸水素ナトリウム、0.13%酢酸および1.2%乳酸でサワードウスターターを置き換えて、サワードウブレッドと同一であった。
サワードウ、サワードウブレッドおよび類似ブレッドの水抽出物(<10kDa)、ならびに、乳酸菌のMRS増殖培地を、代謝産物の定量化のために、LC−MS/MS分析に供した。分析前に、MRS培地を、10kDa Vivaspin 500フィルター(Sartorius Stedim biotech,Goettingen,Germany)を用いて濾過した。
Dionex Ultra High Performance Liquid Chromatography UltiMate(登録商標)3000(Dionex,Idstein,Germany)
−ポンプ−HPG−3400SD
−脱ガス装置−SRD−3400
−オートサンプラー−WPS−3000TSL
−カラムオーブン−TCC−3000SD
API 4000 QTRAP、線形イオントラップ四重極質量分析計(AB Sciex,Darmstadt,Germany):
−イオン化型−エレクトロスプレーイオン化(ESI)
−機器制御−Analyst software(AbSciex,Darmstadt,Germany)
−固定相:TSKgel Amide−80 3μm(150×2mm,Tosoh Bioscience,Stuttgart,Germany)
−固定相温度:40℃
−移動相:
サワードウ、サワードウブレッドおよび類似ブレッドを、凍結乾燥し、粉末にすり砕いた。100gの粉末化されたブレッドまたはサワードウを、500mLの蒸留水中に可溶化し、50℃で3時間、常時撹拌して抽出した。懸濁液を9000rpmで20分遠心分離した。上清を回収して4℃に保持した。ペレットを再度500mLの蒸留水中に再懸濁し、3時間抽出を繰り返した。遠心分離後、ペレットを再度500mLの蒸留水中に再懸濁し、一晩抽出した。3回の抽出ステップ後の上清(合計容量は約1.5L)を一緒にプールし、0.2μm、除外閾値100kDaおよび10kDaの、Vivaflow 200カセット(Sartorius,Goettingen,Germany)を用いて、段階的に濾過した。除外閾値100kDaおよび10kDaの濾液を凍結乾燥し、インビトロ分析のために、蒸留水中で25%に再懸濁した。10gの<10kDa画分を、100gの凍結乾燥したブレッドおよびサワードウから抽出した。
サワードウ、サワードウブレッドおよび類似ブレッド由来の水抽出物中の、エンドトキシン濃度の測定を、Limulus Amebocyte Lysate(LAL)Chromogenic Endpoint Assay(Hycult biotech,Uden,Netherlands)を用いて決定した。アッセイは、製造業者の説明書に従って行なった。溶液からパイロジェンを結合して除去する、固定化ポリミキシンBを有する樹脂を含む、Detoxi−GelTM Endotoxin Removing Columns(Thermo Scientific,Rockford,USA)を用いて、サワードウ、サワードウブレッドおよび類似ブレッド由来の水抽出物中の、エンドトキシン混入を除去した。エンドトキシンの除去は、製造業者の説明書に従って行なった。
細胞培養上清中の、インターフェロン誘導タンパク質(IP−10)(ミューリン/ヒト)および(ミューリン)濃度を、適切なELISAキット(R&D Europe,Abington,England)を用いて製造業者の説明書に従って決定した。ELISAは、Nunc MaxiSorp(登録商標)平底96ウェルプレート(Greiner Bio−One GmbH,Frickenhausen,Germany)を用いて行なった。手短には、96ウェルプレートを、一晩室温で、適切な捕捉抗体を用いてコーティングした。リン酸緩衝生理食塩水(PBS)を用いてプレートを3回洗浄し、PBS中1%のウシ血清アルブミンでブロッキングし、細胞培養上清とともに室温で1.5時間インキュベートした。プレートを洗浄し、適切な検出抗体とともに室温で1.5時間インキュベートした。プレートを洗浄し、検出酵素とともにインキュベートした。プレートを洗浄し、基質溶液とともにインキュベートした。基質と検出酵素の反応の測光分析により、タンパク質濃度を決定した。
サワードウから分離したL.rossiae(DSM26024)およびL.sanfranciscensis株(DSM23090、DSM23091、DSM23092、DSM23093、DSM23174、DSM23200、DSM23201)、L.sanfranciscensis基準株DSM20451(DSMZ GmbH,Braunschweig,Germany)、L.plantarum FUA 3038、および、L.brevis 3113(カナダ・アルバータ大学のGanzle教授より提供)、L.paracasei VSL#3(イタリア・L’AquilaのDeSimone博士より提供)を、30℃にて、Anaerogen packages(Anaerogen,Basingstoke,Oxoid,UK)を用いて、嫌気的条件下で、新しく添加した0.15%のL−システインを含むMRSブロス(pH5.4)中で増殖させた。固定化細菌(5%ホルムアルデヒド、4時間、4℃)を、使用前に滅菌PBSを用いて3回洗浄した。一晩(anovernight)の培養からの細菌(5×107cfu/ml)を、DMEM(1%グルタミン、20mM HEPES)および嫌気的(anerobical)培養に30℃で一晩移行させることにより、濃縮された馴化培地(CM)を作製した。細菌および細菌上清(CM)を、遠心分離(4500g、10分、室温)の後に分離した。CMをpH7.4に調節し、フィルター滅菌し(0.22μm)、そして、100kDaの排除サイズを有するVivacellフィルターシステム(Satorius Stedim Biotech,Goettingen,Germany)を用いて濃縮した(100×)。濃縮馴化培地を、細胞培養刺激実験において、1×希釈した。上述のそれぞれの培地に1.5%の寒天を添加することにより、寒天プレートを得た。
Dunkin Hardleyモルモット(Sulzfeld and Harlan Winkelmann GmbH,Borchen,Germany)由来のコーパス環状筋調製物を用いて、運動性測定を行なった。LabChart 5ソフトウェア(ADInstruments,Spechbach,Germany)を用いて、浴槽(organ bath)中で、力変換器を用いて筋肉の収縮力を測定した。手短には、胃の筋組織を粘膜層から切断して、続いて、氷冷調製Krebs溶液(pH7.4)(MgCl2×6H2O 1.2mM、CaCl2×2H2O 2.5mM、NaH2PO4 1.2mM、NaCl 117mM、NaHCO3 25mM、C6H12O6 11mM、KCl 4.7mM)を灌流した。コーパス環状筋の1.5cm2片を切り取り、37℃で、2つの電極間に、ポリアミドスレッドを用いて、両端から、20mLの実験用Krebs溶液(NaHCO3が20mMである点を除き調製Krebsと同一)中の浴槽中へ載せて、カルボゲン(95%O2および5%CO2)を用いて連続的に通気した。45分の平衡期間後、筋肉調製物を電場刺激(EFS)により刺激し、バイタリティを試験した。実験的処理と同様にEFSの間の収縮力の変化を力変換器により測定した。任意の処理間のタイムラプスは常に20分であった。
腸管上皮を横切るイオンの動きを、ウッシングチャンバー技術(Easy mount chambers,Physiologic instruments,San Diego,USA)および、LabChart 5ソフトウェア(ADInstruments,Spechbach,Germany)を用いて測定した。手短には、Dunkin Hardley モルモット(Sulzfeld and Harlan Winkelmann GmbH,Borchen,Germany)の遠位結腸片を切断し、筋肉層を除去し、粘膜/粘膜下組織の調製物を、記録領域0.5cm2を有するスライダーに載せた。頂端側および基底側を、5mLのKrebs溶液中に別々に浸した。実験手順の間、浴槽は37℃に維持し、カルボゲン(95%O2および5%CO2)を用いて連続的に通気した。45分の平衡期間後、組織を電気刺激して(パラメータ:刺激強度6V、持続時間10秒、周波数10Hz、単一パルス持続時間0.5ms)、組織バイタリティを評価した。能動イオン輸送の評価のために、短絡電流(ISC)を適用することにより、組織を横切る受動イオン輸送によって形成される自然発生の経上皮電圧(VTE)を0mVに設定した。能動的な(active)塩化物イオン分泌が誘導されると、VTEを0mVに維持するためにISCの増加が必要であることが分かる。ISCの変化は、アニオン分泌またはカチオン吸引により生じる電流に等しい。各実験の最初および最後に組織の経上皮抵抗性(TER=VTE/ISC×1000/2)を測定して、組織の完全性を評価した。
データを平均値±標準偏差(SD)として示す。全ての統計的計算は、処理群と、対応するコントロール群とを比較する、Statistical programming platform Rを用いて行ない、独立t検定を用いて分析した。様々な処理群と、対応するコントロール群とを比較するデータを、One−Way ANOVAを用いて分析し、その後、適切な多重比較の手順を行なった。データが正規分布に従わない、または不連続なデータを含む場合は、ノンパラメトリック検定(Mann−Whitney/順位和検定、順序に基づく(on ranks)ANOVA)を用いた。p値が0.05未満(*)または0.01未満(**)である場合に、有意差とみなした。主成分分析(PCA)をピアソン,K(On Lines and Planes of Closest Fit to Systems of Points in Space,Philosophical Magazine(1901),2(11),559−572、および、Theodoridis,G.,Gika,H.G.,Wilson,I.D.;LC−MS−based methodology for global metabolite profiling in metabonomics/metabolomics,TrAC Trends in Analytical Chemistry(2008),27(3),251−260)で記載する。
2.1)サワードウ、サワードウブレッドおよび類似ブレッド由来の抽出物中の、代謝産物のLC−MS/MS分析
サワードウおよび生のサワードウ(raw sourdough)のサワードウブレッドの水可溶性抽出物(<10kDa、トリプリケート)に対する発酵の効果を比較するために、3つの異なるバッチから調製したサワードウブレッドおよび類似ブレッドをLC−MS/MS分析に供した。抽出物中の代謝産物濃度は、公知濃度の代謝産物を有する標準溶液に対する比較により決定した。
アセチルコリン(ACH)は神経伝達物質であり、筋細胞上のムスカリン性(mACHR)またはニコチン性ACH受容体(nACHR)のいずれかを刺激することにより胃腸管内の運動性を活性化するのに関与する。サワードウ由来のアセチルコリンが、この活性を模倣するかどうか判定するために、モルモットの分離したコーパス筋を、サワードウ、サワードウブレッドおよび類似ブレッドの抽出物を用いて刺激し、収縮刺激を測定した。サワードウおよびサワードウ抽出物の両方とも、アセチルコリンと同様に、同等の濃度で筋収縮を誘導したが、類似ブレッド抽出物では誘導しなかった(図2)。アトロピン(mACHR特異的アンタゴニスト)を用いて、ムスカリン性またはニコチン性ACHRを活性化することにより抽出物が収縮を刺激するかどうか判定した。アトロピンを用いた筋条片の事前処理は、ACHならびにサワードウおよびサワードウブレッドの抽出物による刺激を完全に無効にし、サワードウ由来のアセチルコリンがmACHRを介して作用していることを示した。
腸神経により腸壁の漿膜側へ放出されるアセチルコリン(ACH)は、粘膜による塩化物イオンの分泌を刺激し、続いて、管腔中への水の受動輸送を行なう。この作用は、アセチルコリンエステラーゼによるアセチルコリンの迅速な分解のため一過的である。腸の分泌機能に対するサワードウ由来のACHの効果を、モルモット結腸において試験した。サワードウ、サワードウブレッド、類似ブレッドの抽出物、ならびに、(純粋な)ACHを、モルモット遠位結腸由来の腸粘膜/粘膜下組織調製物の、管腔(粘膜)側または漿膜側のいずれかに適用した。実験はウッシングチャンバー内で行ない、短絡電流(ISC)の変化を測定した。このシステムでは、能動イオン輸送のみが測定されるように、調製物にわたって電気的で浸透性の流体静力学的および化学的勾配のバランスを取ることにより、組織または上皮細胞層を横切るイオンの受動流動を除外する。ウッシングチャンバー中で、組織の各側付近に電極を置き、能動イオン輸送の結果として産生される、上皮にわたる自然発生の電位差(PD)の検出を可能にする(Hirota,C.L.and McKay D.M.,Cholinergic regulation of epithelial ion transport in the mammalian intestine,Br.J.Pharmacol.,2006,149(5):p.463−79)。驚くことに、粘膜側および漿膜側からの両方とも、ACHおよびACH含有抽出物(類似ブレッド抽出物は効果がなかった)により調製物を刺激すると、ISCの増加が見られ(図4)、サワードウおよびサワードウブレッド中のアセチルコリンは、刺激に適切であることが示された。
サワードウから単離したL.rossiae(DSM26024)およびL.sanfranciscensisの7株(DSM23090〜DSM23201)、別のサワードウから単離したL.brevis 3113およびL.plantarum FUA 3038、および、L.paracasei(VSL#3)を、MRS培地中で24時間増殖させた。増殖培地を回収して濾過し、LC−MS/MSを用いて分析した。
Lactocepin PrtP(L.paracasei(VSL#3)で発現されるセリンプロテアーゼ)は、炎症促進性ケモカインインターフェロン誘導タンパク質10(IP−10)を選択的に分解する。PrtPが本発明の乳酸菌中にも存在するかどうか調べるために、サワードウ8株:L.sanfranciscensis(DSM23090、DSM23091、DSM23092、DSM23093、DSM23174、DSM23200、DSM23201)およびL.rossiae(DSM26024)、ならびに、陽性コントロールとしてL.paracaseiから、全ての細菌DNAを分離した。Lactocepin PrtP特異的なプライマーを用いてDNAを増幅し、アガロースゲル上で可視化した。サワードウから単離した乳酸菌中には、検出可能な量のlactocepin PrtP遺伝子は存在しなかった。サワードウ乳酸菌8株およびL.paracaseiを、無刺激およびTNF活性化Mode−K細胞による、炎症促進性ケモカインIP−10の分泌に対するそれらの効果に関して試験した。興味深いことに、Lactocepin PrtP遺伝子は検出されなかったという事実にもかかわらず、馴化培地(図9)および固定化乳酸菌(図10)の両方とも、IP−10阻害活性を示した。このことは、サワードウ乳酸菌により産生される、炎症促進性ケモカインIP−10の分泌を阻害するのに適切な分泌型および細胞表面結合型の両方の因子が存在することを示唆する。この結果は、IBD患者において再度押し寄せる腸炎症にIP−10が関与しているので、IBDの潜在的な治療およびそれらの症状の軽減の基礎を提供する。
Claims (16)
- 腸疾患の予防および/または治療、および/または、腸疾患のリスク低減における、医療的使用のための、
アセチルコリン産生微生物。 - 請求項1に記載の使用のためのアセチルコリン産生微生物であって、
健康な腸管内菌叢を維持および/または促進するため、および/または、消化プロセスの毒性作用を低減するため、および/または、消化器系を刺激するため、および/または、腸調節を改善するための、
アセチルコリン産生微生物。 - 請求項1または2に記載の使用のためのアセチルコリン産生微生物であって、
前記腸疾患は、機能性腸疾患および/または腸神経系により制御される腸壁の分泌と関連する疾患であり、
具体的には、機能性便秘、機能性下痢および/または過敏性腸症候群(IBS)であり、
より具体的には、便秘が主であるIBS、交互のIBS、または下痢が主であるIBSである、
アセチルコリン産生微生物。 - 請求項1または2に記載の使用のためのアセチルコリン産生微生物であって、
前記腸疾患は炎症性腸疾患であり、
具体的には、潰瘍性大腸炎および/またはクローン病である、
アセチルコリン産生微生物。 - 請求項1から4のいずれか一項に記載の使用のためのアセチルコリン産生微生物であって、
前記微生物は、適切な培養条件下で、30mg/kg以上のアセチルコリンを産生する、
アセチルコリン産生微生物。 - 請求項1から5のいずれか一項に記載の使用のためのアセチルコリン産生微生物であって、
前記微生物が細菌である、
アセチルコリン産生微生物。 - 請求項1から6のいずれか一項に記載の使用のためのアセチルコリン産生微生物であって、
前記微生物は乳酸菌株であり、
具体的には、Lactobacillus sanfranciscensis株、Lactobacillus rossiae株、Lactobacillus brevis株、または、Lactobacillus plantarum株であり、
より具体的には、DSM23090株またはDSM23093株である、
アセチルコリン産生微生物。 - 請求項1から7のいずれか一項に記載の使用のためのアセチルコリン産生微生物であって、
前記乳酸菌は、DSM26024株、DSM23090株、DSM23091株、DSM23200株、DSM23092株、DSM23093株、DSM23201株、DSM23174株およびDSM23121株、またはそれらから培養される株の、いずれか1つから選択される、
アセチルコリン産生微生物。 - 請求項1から8のいずれか一項に記載の使用のためのアセチルコリン産生微生物であって、
製剤の剤形、機能性食品または機能性飲料中の、
アセチルコリン産生微生物。 - 請求項9に記載の使用のためのアセチルコリン産生微生物であって、
前記機能性食品がサワードウブレッドである、
アセチルコリン産生微生物。 - 請求項9または10に記載の使用のためのアセチルコリン産生微生物であって、
好ましい腸管内菌叢を維持および/または回復するための少なくとも1つのさらなる細菌をさらに含む、
アセチルコリン産生微生物。 - 請求項9または10に記載の使用のためのアセチルコリン産生微生物であって、
腸疾患の治療のための少なくとも1つのさらなる薬剤をさらに含む、
アセチルコリン産生微生物。 - 乳酸菌の使用による、アセチルコリンを産生する方法であって、
具体的には、Lactobacillus sanfranciscensis株およびLactobacillus rossiae株から選択される乳酸菌の使用による、
アセチルコリンを産生する方法。 - 腸疾患の治療および/または予防における使用のための、微生物によって産生されるアセチルコリンであって、
前記アセチルコリンは経口投与される、
微生物によって産生されるアセチルコリン。 - 腸内健康の維持および/または改善のための、アセチルコリン産生微生物の非医療的使用。
- 請求項2から11のいずれか一項に定義される、
請求項15の非医療的使用。
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WO2023068279A1 (ja) * | 2021-10-18 | 2023-04-27 | 国立研究開発法人医薬基盤・健康・栄養研究所 | ブラウチア(Blautia)属細菌のスクリーニング方法 |
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RU2675110C1 (ru) * | 2018-04-09 | 2018-12-17 | Федеральное государственное бюджетное учреждение науки Институт общей генетики им. Н.И. Вавилова Российской академии наук (ИОГЕН РАН) | Фармацевтическая композиция для терапии воспалительных заболеваний слизистых оболочек кишечника на основе штамма Lactobacillus brevis 47f, проявляющая местную противовоспалительную активность |
CN109337836B (zh) * | 2018-10-26 | 2021-11-26 | 贵州茅台酒股份有限公司 | 一种乳酸菌分离培养基及其制备方法及乳酸菌筛选方法 |
CN112870188A (zh) * | 2019-11-29 | 2021-06-01 | 复旦大学附属华山医院 | 一种缓解炎症的乙酰胆碱免疫调节剂及其制备方法和应用 |
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