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090214 腸管免疫

090214 腸管免疫

●腸内フローラと生体免疫 東大 伊藤喜久治

ねずみの実験

腸内フローラは、実母ではなく里親に似る

アレルギー → 乳酸菌が少なく、多様性が少ない

IN-10ノックアウトで潰瘍性大腸炎

バクテロイデスの多様性
 …多様性のkeyとなる株がいるが、それもほかの株があってこそ定着できる
バクテロイデス多様性あると、胆汁酸DCAも多様化する

腸内細菌の酵素によって、毒素が分解されうる

…腸内細菌の代謝はパチンコみたいなもの。めちゃくちゃに動くが、うまくいけばいいところに入る

ヨーロッパでは155億円かけて、腸、膣、口、鼻、皮膚の常在菌を調べている
→食品

中国 → 漢方薬を理解するために調べている

「何が、どうして、を理解してScienceとして腸内フローラを理解するべき」

・死菌 サブスタンス でもいいというデータもある。が、定着せず流れてしまう

・無菌マウスに特定の腸内常在菌を定着させると、免疫応答が変わる。で、定着する場、の違いで機能が違うことは起こるのか?

・抗生物質で腸内細菌めためたになる、が、ある程度の期間がたつと元に戻る
→完全に消えない。かなりしつこく残っている、はず。そうでないと説明できない。ハンパじゃない抗生物質で完全に消すことはできるが、周りに動物がいるとすぐもどってくる

・ゴードン先生たちのobesity
「バクテロイデスでやせる(poorでも生きる、有機酸にもってくのが少ない、糞便のエネルギーが多い)」「カンピュテスでふとる(多彩、糞便のエネルギーが少ない、吸収している)」という説
…実際やってみると、違う気がするけれど…
誰も追試していないから

・日本の腸内細菌の戦略は?
省庁の縦割りが邪魔
医療なのか食品なのか決まらず、それぞれ興味は持つが、動けない
…アメリカ・ヨーロッパは、ゲノムという新しい切り口でまとまった
ゲノムのひとたちは力技で調べちゃう

ヒューマンゲノムが終わってからターゲットがない…


Germ freeは運動が悪くなり、ものがたまる


●粘膜機能と腸内フローラ 松本 敏 ヤクルト中央研究所

腸内細菌定着により、小腸粘膜上皮細胞が成熟する
 粘膜免疫が成熟する IF-γが働く
 破綻すると、病気になるだろう

そのひとつの破綻が、IBDだろう inflammatory bowel disease

「粘膜接着性細菌」
Proteobacteriaが、腸内細菌層での割合よりも多い
Bacteroidesもちょっと多い

炎症・癌ではそういった粘膜細菌層が消失する
実際、粘膜層の細菌と腸内細菌の割合の差が消失する
 足場がなくなる mucin

IL-6
T・B・マクロファージの分化産生に重要
Crohnマウス 粘膜のIL-6が非常に強い

TNFα converting enzyme(TACE)が粘膜のIL-6を切り出し、sIL-6Raが出る→炎症
マクロファージにIR-6Rがある

・TACEと癌の関係は?
昔の報告では、変わってなかった

・粘膜接着性細菌
IBDモデルは回腸と大腸を見ている
パネトはマウスは人と違い活性化しない

・ただ、臨床的には大腸炎癌はなかなか少ない
日本は特にCAC少ない

●消化管運動と腸内フローラ 東大 堀 正敏

正常な腸内フローラには
正常な腸内フローラ構成が重要だろう

無菌動物の腸管内容物輸送速度は正常動物と比較して遅い

消化管運動は壁内神経叢が司る

今日の話
1)腸内フローラは生理的な消化管運動制御に関与するか?

研究 閉鎖系で 筋収縮の大きさ(収縮機能)、回数(神経の機能)、全移動量 を評価
GFとコンベンショナルの比較

生理学的なパラメーターは??
 電解質やコリンなどみてみると、平滑筋収縮力んいは差はない

→ 無菌マウスでも蠕動運動は保たれている

…in vivoでの科学的な差が関与している?


2)Germ freeマウスでは、自然免疫応答機構を解した制御はどう変わる?

LPSなどでマクロファージが活性化
蠕動回数もLPSで減少する

TLR4 コンベンショナルはLPSで刺激すると上昇する
   GFではそういったものは起こらない
 …長期の無菌状態は、TLRの機能に異常が生じてそう

さらに下流の平滑筋細胞は、NOが関係(収縮を抑える)
…GFは、NOの感受性が落ちていた

3)構成する腸内フローラの変化は消化管運動にどのような影響を与える?
   先天性イレウスモデル EDNRB
    Hirchsprung病

実際、壁内神経叢を見てみると、発達が悪い

→腸内フローラを解析してみた
普段は大腸に生息しているものが回腸にいた …大腸化

粘膜炎症が強く、バリアが破壊してそう
→血中LPSをはかってみたら高かった
染めてみると、マクロファージが小腸以下では粘膜に進入、十二指腸以上ではなかった

…運動の破壊で腸内細菌乱れ、筋にマクロファージ進入、炎症

・筋層間のマクロファージの役割は?
…はっきりとはわかっていない
生理的にはscilent

・善玉菌が産生する乳酸や酢酸がかかわるという仮説がある


●IBSと腸内フローラ 東北大学 福土 審

脳機能と腸管運動の関係を調べてきた
Stressorと腸の悪循環
…最初にHitするのがどこか、わかっていない?
 外部環境・内部環境 の研究がなされないといけない

「Post infectious IBS」
…Acute enterocolitisのひとが優位に多い

Prospective
スペインのサルモネラ罹患者はIBS罹患者が非常に多かった
…腸内細菌が関与している?

IBSのひとは
微小炎症がIBDにつながる?

IBSは、フラジリン抗体要請率が高い (ルミナルバクテリア)
  クローン > IBS > UC

IBSは健常に比べてマストセル、神経が多い
→健常者にはおきない 知覚過敏がありそう

IBS 10日間の完全絶食をすると、粘膜の改善が得られる Fasting Therapy


抗生剤で有害菌をたたけば…
プロバイオティクスでの治療
 Studyでてきている

Bifidobacterium

IBSは便に有機酸が多かった

Luminal environment

●漢方薬はなぜ効くのか 田代眞一 昭和薬科大
配糖体は腸内菌の助けを要するプロドラッグ

10年前に富山で調べ始めた
腸内細菌叢と漢方の関係、薬物代謝を兄弟子が調べ始めた

京都大学
漢方が保険に収載された1年後
富山大学卒だからって漢方に関する質問が山ほどきた…

そのとき、構成生薬の、既知の成分の、既知の薬効の中から、
都合のいいストーリーを組み立てて説明していた

ジレンマ
・丸ごとでどうだ?
・消化管でどうだ? 経口
・なんで個体差? 証

…もともと飲んだものがそのまま届いているとは思えないが、何かが血中に届いているはず

…当日は、ポカリ、カロリーメイトを3日間飲んで、400ml血をとって、1ヶ月飲んで、最後に同じことをして、差があるかどうかみた

…やってみると、2時間後に初めて血中濃度があがってきた… 西洋薬と比べて遅い
…もともとの漢方の成分はほとんど血中に入っていなかった

生薬の成分は、「配糖体」が非常に多い

天然物が効く理由
大事な系であるほど動物も植物も同じものを使う

「天然物は毒にも薬にもならない」?
→生理活性成分の宝庫

有効成分に糖をくっつけると水に溶けやすい

…ジギトキシンなんかは配糖体でも水に溶けにくい
 が、消化管運動を抑制すると吸収がよくなりすぎる
 裏返すと普段あまり吸収されていない

グリチルリチン
同じ成分が経口でも売られているが、吸収できない
が、それを糖を切る菌がいるから、吸収できる人がいる

例: 8時間たったら、5人中2人血中濃度あがってきた

なんで???
菌は盲腸以降で急増する

バクテロイデス、回腸では10^3、盲腸では10^8

少ない菌数で活発に流れているのが小腸
大量の水分、貯留と攪拌されている盲腸以降

そこまで8時間かかる…


漢方の直腸内投与
・小児のゴレイサン
・つわり ハンゲ

このときの導体をしらべてみた
グリチルリチンの座薬
糖がついたままはいった!!!

それが、胆汁に排泄されて、菌の代謝を受けて問うがとれて再吸収される

…直腸粘膜は配糖体を通す 粘膜がスカスカ

直腸への投与
吸収の個人差を乗り越えられる
即効性が発揮される
 例: 胆石発作に芍薬甘草湯 ブスコパンより効く
妊婦への投与は慎重でありたい


とにかく
経口投与では糖がとれないと吸収されない配糖体がほとんど
 脂溶性になってから吸収される

「資化菌」がいて初めて効果がある

めったに入ってこない漢方の配糖体を分離できる菌は、マイナーだろう
→それが有効性の個人差になるか

「証」と考えてきたものが腸内フローラとしてでてきているかもしれない

センノシド
ビフィズス菌に切られてはじめて効く

→センノシド代謝能の調査
糞便中の代謝能測定

例: ひどいのは、代謝が促進していた
  まったく代謝されていないのがいた

が、もっとも活性が強い人間がびくともしていなかった
…便秘で普段からセンノシドを利用していた

センノシドは使っているうちに感受性が落ちてくる

女性の便秘は黄体期に起こる
 定期的な月経がおこるようになってから便秘が進行する
→薬学部には便秘のベテランがいる

…市販のビフィズス菌で配糖体分解できれば!

大黄もビフィズス菌も
…そこにはオリゴ糖が投与されていた 定着させるために
 おいしいものがはいっているから、投与できなかった

が、それをやめたら一気に下痢がでた。オリゴ糖がなくなってから元気に分解されてしまった

→オリゴ糖含まないビフィズス菌を作って切れた

ちなみに、
センノシド → セニジン → レインアンスロン
となる レインアンスロンは脂溶性なので乳児に届いちゃう →下痢に

「資化菌」が糖を切り、利用する菌がいないと…

…じゃ、菌を増やせば効くだろう

鎮痛の芍薬甘草湯 を月経痛に
…半分しか効かなかった

きっと、菌数が少なくて、吸収が悪いのだろう
→月経予定1週間前から飲ませた

麻薬性の鎮痛剤を使っていた子が、
頓用では効かなかったが、
事前投与でなおった

おなかの菌をばら撒いてからのほうがいい

抗菌剤で菌を抑えるとうまくいかない
例: 風邪

新薬はぐずぐずする
抗生剤はいっていると、漢方薬効かない

抗生剤はスペクトラムが狭いほうがいい


で、漢方薬は 腸内細菌のバランスを崩しうる
軟便化することがある
マルチトール 消化されないから吸収されない
そのままいって浸透圧下げて便柔らかくする
が、一部の高齢者では菌層が変化して腹痛がでたりする

…もしかすると、漢方で育った菌が産生するものが効果あるかもしれない


口の中の細菌、
消化管への直接作用
なども興味ある


●粘膜免疫調整剤としての補剤の役割 清原寛章 北里大学

生体を調整することで腸内フローラ変わる可能性あり
腸内フローラかえることで生体調整できる可能性あり

パイエル板に漢方薬は直接効くのか?

・十全タイホトウ
皮膚のびらんをなおす力が強い

・補中益気湯
特異的なIgG・IgAを誘導する力が強い
 マウスを使った実験で

パイエル板に活性成分はいり、CD62L陽性Bリンパ球あがり
CCR6陽性リンパ球誘導
→抹消へのリンパ球の誘導があがる
→抗原特異的な抗体の粘膜誘導アップ

補中益気湯で
MTXでの腸管上皮細胞のダメージを回復させた実験
 特にモルモットで見えやすい
 マウスで実験してみた
つまり、上皮細胞にも作用している

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היי אני רוצה להמליץ לכם על חברה בתחום מכירת רכבים המתמחה בשרותי טרייד אין לחברות ליסינג ולקוחות פרטיים . באתר, מידע רב המלווה בתמונות מכירת הרכבים ורשימה המתעדכנת יום יום עם הרכבים הנמצאים במקום ומיועדים למכירה.

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I do agree with all the ideas you've presented in your post. They're very convincing and will certainly work. Still, the posts are too short for starters. Could you please extend them a little from next time? Thanks for the post.

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Can't wait for your next post. Thank you!

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wheres your own feed? most likely concealed in basic sight knowing me hehe.

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