JP5905032B2 - 腸管内微生物叢の回復および再構成のためのシンバイオティクス組成物 - Google Patents
腸管内微生物叢の回復および再構成のためのシンバイオティクス組成物 Download PDFInfo
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Description
- 細菌株の少なくとも1種が、デンプンを分解することができ、
- 少なくとも1種のプレバイオティクス物質が、デンプンである
ことを特徴とするシンバイオティクス組成物に関する。
本発明において用いられている用語は、一般に、微生物学および生化学の技術分野の業者に受け入れられている標準定義に忠実であると予想される。下に挙げる数例の例外は、本発明の範囲内でさらに定義されてきた。
用いた株バンクから最も有望な株の主な選択判断基準は、コンゴーレッド結合(CRB)および塩凝集試験(Salt aggregation test)(SAT)により測定される、クロストリジウム・ディフィシル等、腸管病原体に対する抗菌活性(AMA)および腸壁に接着する能力であった。その次の判断基準は、少なくとも1種または複数のプレバイオティクス物質の発酵であった。被験株のスクリーニング結果をTable 1(表1)に提示する。
選択されたビフィズス菌およびLAB株の異なる組み合わせ(Table 2(表2))を試験して、これらの株相互の可能な相乗作用および適合性を決定した。特定の株によりバクテリオシン様物質が産生されるか決定するため、各株から得られる中和された抽出物の他の株に対するAMAを、MTPアッセイを用いて決定した。上に記す実験手順の通りにAMA抽出物を得た。
多株(multi-strain)プロバイオティクスまたはシンバイオティクスを開発するため、対象の腸管における有益微生物の腸管内微生物叢を回復させるための、高いプレバイオティクススコアおよび/またはプレバイオティクス指数を備える効率的な株を選択することが重要である。
上述の共培養実験において、選択された株は、互いに対してAMAを示さなかったため、互いに適合性であることが示された。同じ選択された株を、単一プレバイオティクス、プレバイオティクス組み合わせおよびプレバイオティクス組み合わせとSSの存在下で、pH制御されない条件下で共培養して、プロバイオティクス株間の相乗作用の可能性をさらに調査した。
非デンプン分解株LAB LU33とデンプン分解株Bif LU10の可能な同時供給および増殖増強を解明するため、1%(w/v)のSSを唯一の炭素源として含有するMRSCブロスにおいてこれらの株を共培養した。Bif LU10およびLAB LU33の共培養は、LAB LU33の増殖を増強した。デンプン分解の間に産生された中間代謝産物は、LAB LU33の増殖を支持した(Table 7(表7))。デンプン分解は、正常結腸環境の維持と、腸管内細菌叢を回復させるための他の有益微生物の増殖の増強に重要である。デンプン代謝におけるpHの減少は、LAB LU33を阻害しなかった。これらの株は両者共に互いに適合性であり、相乗的活性を示す。LAB 33およびBif LU10により示される相乗作用は、驚くべきことに、株特異的であることが判明した。同様に非デンプン分解株であるLAB LU28と、Bif LU10とをRSの存在下で増殖させた場合、LAB LU28の増殖は刺激されなかった。周知のプロバイオティクス株ラクトバチルス・ラムノサスGG非デンプン分解株を、SSの存在下でデンプン分解株Bif LU10と共培養した場合、同様の観察がなされた。ラクトバチルス・ラムノサスGG増殖は刺激されなかった。これらの2例は、栄養共生が、互いに組み合わせて用いた選択された株に特異的であることを示す。栄養共生は、明らかに同じ属の株間であっても明らかな特性ではない。
プレバイオティクスの異なる組み合わせと共培養した、選択された株(Table 2(表2))のうち2種以上の抽出物の、腸管病原体に対するAMAを決定した。プレバイオティクスの異なる組み合わせにより増殖した全てのCFSが、病原体ESBL大腸菌、黄色ブドウ球菌、クロストリジウム・ディフィシル2167およびNAP1/027に対しAMAを示したことが判明した(Table 8(表8))。共培養した抽出物のCFSを、毒素を含有するCD抽出物とインキュベートした場合、毒性効果の>70%が阻害され、これはCFSにおいて産生された酸が、抗毒素活性を示すことを示した。
上述の通り、クロストリジウム・ディフィシル、ESBL大腸菌、黄色ブドウ球菌、ネズミチフス菌は、ヒト病原体である。従って、このような病原体が、シンバイオティクス混合物に存在するプレバイオティクスを分解・利用することができるかスクリーニングすることが必須である。試験は、ヒト病原体;LUHospitalから入手した高病原性株NAP1/027等のクロストリジウム・ディフィシルの5種の臨床分離株、黄色ブドウ球菌、ESBL大腸菌、およびネズミチフス菌のいずれも、FOS、GOS、IMOS、XOS、イヌリン、RS、SS、ペクチンまたはキシランを利用できなかったことを示した。従って、ヒト病原体は、プレバイオティクス分解能力を示さなかった。この結果は、腸管感染症と闘うためのプロバイオティクスおよびプレバイオティクスのカクテルの開発を大いに促すものである。
単純かつ信頼できるin vitro方法を開発して、in vivoの胃の通過条件をシミュレートした。これは、選択されたプロバイオティクス株を、組み合わせた酸(30分間)および胆汁ストレスパルスに4時間曝露し、in vivoの胃腸通過(GITS)を37℃で好気的(LAB)および嫌気的(ビフィズス菌)に模倣することにより行った。先ず、細胞を、pH2.5のMRSC/MRS培地において酸ストレスに付した。30分後、細胞をPBSで洗浄し、ブタ胆汁5%(v/v)を含むMRSC/MRSにより4時間ストレスを加えた。30分および4時間後に株の生存率を決定した。酸または胆汁ストレスなしのMRSCブロスを対照として用いた。ストレスパルスを与えた細胞のプレバイオティクス分解能力を試験するため、同様にこの細胞を洗浄し、異なるプレバイオティクスまたはグルコースを含有するMRSCブロスに接種した。ストレス無負荷細胞を対照として用いた。
GITSは、PCと連結し、培養プログラム「BioXpert」により制御される1L「Biobundle」発酵槽、バイオコントローラー(biocontroller)ADI 1030および天秤(balance)からなる。液体(即ち、HCl、NaHCO3、胆汁塩、栄養培地)の温度、pH、培養容量、撹拌、酸素含量および速度率は、該プログラムにより制御される。GITSは、胃腸管をシミュレートする数個の容器(P1〜P5)を備える発酵槽である(図1)。
本発明の組成物は、対象の腸粘膜のコロニー形成と、(特に)対象における感染症の予防および治療、抗生物質関連下痢(AAD)および/または胃腸病原体に起因する感染症の症状の寛解および再発の予防に有利に用いることができる。
プロバイオティクス株LAB LU28、LAB LU30、Bif LU10およびBif LU30と、プレバイオティクスGOS、IMOSおよびRSを含有するシンバイオティクスサプリメント給餌の効果を、C57/BL/6マウスモデルにおいて調査した。給餌後の異なる時点の糞便と、実験終了時の盲腸におけるプロバイオティクスミックスの繁殖を調べた。
LAB LU28、LAB LU33、Bif LU10およびBif LU30と、GOSおよびRSを含む組成物の安全性は、免疫無防備状態のC57/BL/6マウスモデルにおいて確立された。癌化学療法において広く用いられるジヒドロ葉酸還元酵素およびDNA合成の阻害剤であるメトトレキサートを用いて、マウスを免疫無防備状態にした。メトトレキサート(3.5mg/Kg)を、マウスに経口により3日間与えた。2日後に、シンバイオティクス群に、水における4×1010cfu/mlと5%GOSを与えた。RSを飼料と混合し、マウスに6日間毎日与えた。プレート計数方法を用いた生存率調査および肝臓の病理組織診断のため、7日目にマウスを殺傷し、肝臓、脾臓、血液および腎臓を収集した。
Claims (17)
- ラクトバチルス属およびビフィドバクテリウム属からなる群から選択される少なくとも2種の細菌株と、1種または複数のプレバイオティクス物質とを含むシンバイオティクス組成物において、
- 前記細菌株の少なくとも1種が、ビフィドバクテリウム・ブレーベ種のBif LU10 (寄託番号LMG P-26117)であって、デンプンを分解することができ、
- 少なくとも1種のプレバイオティクス物質が、デンプンである
ことを特徴とするシンバイオティクス組成物。 - デンプンが、難消化性デンプン(RS)および/または可溶性デンプン(SS)である、請求項1に記載のシンバイオティクス組成物。
- 前記細菌株の1種が、非デンプン分解株である、請求項1または2に記載のシンバイオティクス組成物。
- 非デンプン分解細菌株が、ラクトバチルス・パラカゼイ種のものである、請求項3に記載のシンバイオティクス組成物。
- 非デンプン分解細菌株が、LAB LU33(寄託番号LMG P-26118)である、請求項3に記載のシンバイオティクス組成物。
- 株LAB LU23(寄託番号LMG P-26119)、LAB LU28(寄託番号LMG P-26120)、BIF LU29(寄託番号LMG P-26115)、および/またはBIF LU30(寄託番号LMG P-26116)のうち1種または複数をさらに含む、請求項1から5のいずれか一項に記載のシンバイオティクス組成物。
- 少なくともLAB LU33(寄託番号LMG P-26118)、およびBIF LU30(寄託番号LMG P-26116)を含む、請求項6に記載のシンバイオティクス組成物。
- 少なくともLAB LU33(寄託番号LMG P-26118)、BIF LU30(寄託番号LMG P-26116)、およびLAB LU28(寄託番号LMG P-26120)を含む、請求項6に記載のシンバイオティクス組成物。
- 前記細菌株のうち1種または複数が、その生産の間に酸、胆汁および/またはムチンに曝露されている、請求項1から8のいずれか一項に記載のシンバイオティクス組成物。
- 二糖、オリゴ糖、および/または多糖からなる群のプレバイオティクス物質をさらに含む、請求項1から9のいずれか一項に記載のシンバイオティクス組成物。
- 対象の腸粘膜のコロニー形成において使用するための、請求項1から10のいずれか一項に記載のシンバイオティクス組成物。
- 対象における抗生物質関連下痢(AAD)および/または胃腸病原体に起因する感染症の予防、治療、症状の寛解、および/またはその再発の予防において使用するための、請求項1から10のいずれか一項に記載のシンバイオティクス組成物。
- 抗生物質関連下痢(AAD)が、クロストリジウム・ディフィシルにより誘発される、請求項12に記載のシンバイオティクス組成物。
- 胃腸病原体による感染症が、サルモネラ属、カンピロバクター・ジェジュニ、広域スペクトルベータラクタマーゼ産生(ESBL)大腸菌に起因する、請求項12に記載のシンバイオティクス組成物。
- 対象が哺乳動物である、請求項11から14のいずれか一項に記載のシンバイオティクス組成物。
- 対象の腸粘膜のコロニー形成のための、請求項1から10のいずれか一項に記載のシンバイオティクス組成物を含む薬物。
- 抗生物質関連下痢(AAD)および/または胃腸病原体に起因する感染症を治療するための、請求項1から10のいずれか一項に記載のシンバイオティクス組成物を含む薬物。
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PCT/SE2012/050131 WO2012108830A1 (en) | 2011-02-09 | 2012-02-09 | Synbiotic compositions for restoration and reconstitution of gut microbiota |
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AP (1) | AP2013007097A0 (ja) |
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DK2672980T3 (en) | 2018-02-26 |
LT2672980T (lt) | 2018-03-12 |
AP2013007097A0 (en) | 2013-09-30 |
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