JP5951101B2 - 食品成分及び食品組成物のスクリーニング方法 - Google Patents
食品成分及び食品組成物のスクリーニング方法 Download PDFInfo
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Description
本発明者らは、肝がん及び肺がんが多発する発がんモデルを開発し、発がん機構について解析を行った。その結果、腸内細菌叢の変化によりグラム陽性菌率が上昇し、このグラム陽性菌により産生されるデオキシコール酸の血中濃度が上昇することを明らかにした。さらに、デオキシコール酸が肝星細胞に細胞老化を引き起こし、肝星細胞がSASP因子を分泌するようになることでその周囲の肝実質細胞の発がんが促進されるという機構を明らかにした。
本発明のスクリーニング方法は、前記細菌の生産物が、胆汁酸代謝物であるデオキシコール酸又はリトコール酸の少なくとも1種であることを特徴とする。
本発明者らは、肥満及び発がん物質により発がんを誘導したマウスモデルを用いて解析を行ったが、腸内細菌叢の変化が発がんを誘発するという発がん機構から、腸内細菌叢がグラム陽性菌優勢に変化する状態であれば、肥満に関わらず発がんリスクが高まるものと理解される。
本発明のスクリーニングにより選択される食品成分を含む食品は、いかなるがんの発症リスクを持つ個体に対しても有用である。
本発明者らが解明した、腸内細菌叢の変化からがん発症までの多段階にわたる機構を基に、以下に例示するスクリーニング方法によって、発がんリスクを低減する作用を有する化合物を選択することができる。
具体的なスクリーニング方法としては、腸内細菌叢を変化させた実験動物を用い、候補物質を一定期間投与する。ここで、腸内細菌叢を変化させた実験動物としては、例えば、実施例1の肥満モデル動物系を用いることができる。実施例1に記載のように、肥満によって、腸内細菌叢を変化させることができればマウスに限らず、一般的に用いられているラット、ウサギ等どのような動物を用いることもできる。
腸内細菌の培養系を用いることによって、実験動物を用いるよりも多くの候補物質を短時間にスクリーニングすることが可能である。
ここで、前述の実験動物を用いたスクリーニング方法、及び、培養細胞系によるスクリーニング方法において、腸内細菌叢の変化は、グラム染色剤、グラム陽性菌とグラム陰性菌を識別するPCRプライマー等、グラム陽性菌と陰性菌を識別可能な試薬を適宜用いて解析することができる。PCR法を用いる場合、検出用のプライマー、PCR条件等は当業者が設計及び設定することが可能であるが、例えば、クロストリジウム属クラスターXIに属する菌を検出する場合には、非特許文献9に記載のクロストリジウム属クラスターXIに特異的なプライマーを用いることもできる。
本発明のスクリーニング方法により選択された食品成分又は食品組成物は、発がんリスクを軽減するため、あるいは、発がん予防のための食品として使用することができる。
図2Aに本発明で用いた発がんモデルの作成方法を示す。野生型(C57BL/6)の新生仔マウスに、発がん物質であるDMBA(7,12-dimethylbenz [a] anthracene)を0.5%含むアセトン溶液を背部に1回塗布した。仔マウスは母マウスとともに、通常食(ND)又は高脂肪食(HFD)で4週目まで共に飼育した。高脂肪食は米国Research Diets社のD12492(Rodent Diet with 60% kcal%Fat)を用いている。生後4週で離乳させた後も、仔マウスは引き続き通常食又は高脂肪食で飼育した。30週で肝臓及び肺を摘出し、がん発生の有無を解析した。解剖時のマウスの平均体重は通常食飼育マウスでは平均33g、高脂肪食飼育マウスでは平均51gであり、高脂肪食飼育マウスは、通常食飼育マウスに比べて約1.5倍の体重であった。
最近、いくつかの分泌因子ががん発生リスクを増加することが示唆されており、それらの中にはSASP因子に分類されるものも含まれていた(非特許文献8)。
[実施例3:腸内細菌叢の改善による発がん抑制効果]
図4Aに実験系を示す。野生型マウス新生仔に対し、DMBA塗布を行い、高脂肪食飼育を行った。13週から抗生物質カクテル(4Abx、抗生物質カクテル投与群)又はバンコマイシン(VCM、バイコマイシン投与群)を飲み水に混ぜて投与し、飼育開始から30週目に肝臓を摘出し、肝がん発症の解析を行った。一方、コントロール群は、13週目までと同様に飼育を続けた。抗生物質カクテルには、アンピシリン(1g/l)、ネオマイシン(1g/l)、メトロニダゾール(1g/l)及びバンコマイシン(500mg/l)が含まれている。バンコマイシン単独投与の場合も500mg/lで投与した。
次に、実施例3で行った抗生物質投与による腸内細菌叢の変化を示す。図4Aに示した実験系で、通常食飼育、高脂肪食飼育、高脂肪食飼育で飼育するとともにバンコマイシンを与えた群の3群で、腸内細菌叢の解析を行った。
rRNAをコードする遺伝子をPCR増幅し、さらにV1‐V4の超可変領域を増幅し同定を行った。
高脂肪食飼育マウスに、飼育開始から13週目から抗生物質カクテルを投与して飼育し、このマウスに体重1gあたり40μgのデオキシコール酸(DCA)、又はコントロールとして溶媒(Vehicle)のみを週に3回経口投与した(図6A)。
実施例3、4に示すように、抗生物質投与によって、腸内細菌数を減少させることにより、肝発がんのリスクが減少することが示された。そこで、腸内細菌を保有しない無菌環境でマウスを飼育し、実施例1と同様に新生仔マウスにDMBA処理し、高脂肪食で飼育し、体重が45g以上になった肥満したマウスについて30週齢時に肝がん発症の有無を解析した。
Claims (4)
- 発がんリスクを軽減するための食品成分又は食品組成物を選定するために行うスクリーニング方法であって、
腸内細菌叢におけるグラム陰性菌に対するグラム陽性菌の減少を指標とすることを特徴とする方法。 - 発がんリスクを軽減するための食品成分又は食品組成物を選定するために行うスクリーニング方法であって、
腸内細菌叢におけるグラム陰性菌に対するクロストリジウム属に属する菌の減少を指標とすることを特徴とする方法。 - 発がんリスクを軽減するための食品成分又は食品組成物を選定するために行うスクリーニング方法であって、
腸内細菌叢を変化させたモデル動物に、候補物質を一定期間継続して投与し、
腸内細菌叢におけるグラム陰性菌に対するグラム陽性菌の減少を指標として選定することを特徴とする方法。 - 請求項3記載のスクリーニング方法であって、
前記腸内細菌叢を変化させたモデル動物が高脂肪食飼育マウスであることを特徴とするスクリーニング方法。
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