細胞膜有機イオン輸送体および接着分子による新規微生物認識機構の解明と腸炎への関与

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23590931
• Research Institution: Asahikawa Medical College
• Principal Investigator: 藤谷 幹浩 旭川医科大学, 医学部, 准教授 (80322915)
• Co-Investigator(Kenkyū-buntansha): 大竹 孝明 旭川医科大学, 医学部, 講師 (10359490)
• Keywords: 腸内細菌 / 炎症性腸疾患 / ポリリン酸 / トランスポーター / エンドサイトーシス / インテグリン

Research Abstract

１．腸内細菌由来の生理活性物質の同定とその認識機構に関係する細胞表面分子の解明
および細胞内環境の変化とそのメカニズムの解明．
新規麦芽乳酸菌の培養上清から腸管上皮バリア機能を増強する活性物質であるポリリン酸を同定することに成功した。さらに、インテグリンのshRNAおよび脂質ラフト抑制剤にてポリリン酸の作用が減弱することを明らかにした。さらに、このポリリン酸は腸上皮の細胞内に取り込まれることも明らかにした。以上から、インテグリンに結合した後、脂質ラフト誘導性エンドサイトーシスによって腸上皮に取り込まれ、作用を発揮することが示唆された。すなわち腸内細菌の中には、Toll様受容体などのパターン認識受容体を介さず、細胞内輸送機構にて宿主とのコミュニケーションをとっているものが存在すると考えられた。
２．腸管炎症モデルマウスおよびヒト腸管炎症において，これら新規の細菌認識機構の発現を調べ，腸管炎症の病態との関連性を明らかにする．
前年度は、慢性腸炎マウスモデルにおける、ポリリン酸の腸管障害改善作用や線維化改善効果を明らかにした。さらに今年度は、in vitro炎症モデルにおいて、ポリリン酸が腸上皮およびマクロファージからの炎症性サイトカインの産生を抑制すること、線維芽細胞に対する作用は無いことが明らかになった。以上からポリリン酸は腸上皮およびマクロファージを標的として抗炎症作用を発揮し、腸炎による腸管障害や線維化を改善していると考えられた。
これらの研究成果の一部は英文誌に公表した。また、一部は現在投稿中である。

Research Products

• [Journal Article] Probiotic treatments for induction and maintenance of remission in inflammatory bowel diseases: A meta-analysis of randomized controlled trials. (2014)
  • Author(s): Fujiya M, Ueno N, Kohgo Y.
  • Journal Title: Clin J Gastroenterol Volume: 7 Pages: 1-13
  • DOI: 10.1007/s12328-013-0440-8.
  • Peer Reviewed
• [Journal Article] Up-regulation of iron regulatory hormone hepcidin by interferon α. (2014)
  • Author(s): Ichiki K, Ikuta K, Addo L, Tanaka H, Sasaki Y, Shimonaka Y, Sasaki K, Ito S, Shindo M, Ohtake T, Fujiya M, Torimoto Y, Kohgo Y.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 29 Pages: 387-394
  • DOI: 10.1111/jgh.12348.
  • Peer Reviewed
• [Journal Article] Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of nonalcoholic fatty liver disease in mice. (2014)
  • Author(s): Sawada K, Ohtake T, Hasebe T, Abe M, Tanaka H, Ikuta K, Suzuki Y, Fujiya M, Hasebe C, Kohgo Y.
  • Journal Title: Hepatology Research Volume: in press Pages: in press
  • DOI: 10.1111/hepr.12199.
  • Peer Reviewed
• [Journal Article] microRNA-18a induces apoptosis in colon cancer cells via the autophagolysosomal degradation of oncogenic heterogeneous nuclear ribonucleoprotein A1. (2014)
  • Author(s): Fujiya M, Konishi H, Kamel M.K.M, Ueno N, Inaba Y, Moriichi K, Tanabe H, Ikuta K, Ohtake T, Kohgo Y.
  • Journal Title: Oncogene Volume: in press Pages: in press
  • DOI: 10.1038/onc.2013.429.
  • Peer Reviewed
• [Journal Article] Decreased vessel networks and irregular vessel on narrow band imaging are useful findings to distinguish intestinal lymphoma from lymphoid hyperplasia. (2014)
  • Author(s): Fujiya M, Kashima S, Ikuta K, Dokoshi T, Sakatani A, Tanaka K, Ando K, Ueno N, Tominaga M, Inaba Y, Ito T, Moriichi K, Tanabe H, Saitoh Y, Kohgo Y.
  • Journal Title: Gastrointestinal Endoscopy Volume: in press Pages: in press
  • DOI: 10.1016/j.gie.2014.03.030.
  • Peer Reviewed
• [Journal Article] Traffic control of bacteria-derived molecules- A new system of host-bacterial crosstalk. (2013)
  • Author(s): Konishi H, Fujiya M, Kohgo Y.
  • Journal Title: International Journal of Cell Biology Volume: 2013 Pages: 8
  • DOI: 10.1155/2013/757148.
  • Peer Reviewed
• [Journal Article] microRNA-146b improves intestinal injury in mouse colitis by activating NF-kB and improving epithelial barrier function. (2013)
  • Author(s): Nata T, Fujiya M, Ueno N, Moriichi K, Konishi H, Tanabe H, Ohtake T, Ikuta K, Kohgo Y.
  • Journal Title: Journal of Gene Medicine Volume: 15 Pages: 249-260
  • DOI: 10.1002/jgm.2717.
  • Peer Reviewed
• [Journal Article] Reduction of E-cadherin by Human Defensin-5 in Esophageal Squamous Cells. (2013)
  • Author(s): Nomura Y, Tanabe H, Moriichi K, Igawa S, Ando K, Ueno N, Kashima S, Tominaga M, Goto T, Inaba Y, Ito T, Ishida-Yamamoto A, Fujiya M, Kohgo Y.
  • Journal Title: Biochem Bioph Res Co Volume: 439 Pages: 71-77
  • DOI: 10.1016/j.bbrc.2013.08.026.
  • Peer Reviewed
• [Journal Article] Infliximab extends the duration until the first surgery in patients with Crohn’s disease. (2013)
  • Author(s): Sakatani A, Fujiya M, Ito T, Inaba Y, Ueno N, Kashima S, Tominaga M, Moriichi K, Okamoto K, Tanabe H, Ikuta K, Ohtake T, Kono T, Furukawa H, Ashida T, Kohgo Y.
  • Journal Title: Biomed Research International Volume: 2013 Pages: 879491
  • DOI: 10.1155/2013/879491.
  • Peer Reviewed
• [Journal Article] 潰瘍性大腸炎と粘膜治癒 (2013)
  • Author(s): 藤谷幹浩、高後 裕．
  • Journal Title: 日本消化器病学会雑誌 Volume: 110 Pages: 1900-1908
  • DOI: 10.11405/nisshoshi.110.1900
  • Peer Reviewed
• [Presentation] Long-term oral dietary administration of a new probiotic, Lactobacillus brevis SBC8803, alters gut the microbiota and ameliorates DSS-induced colitis in mice. (2014)
  • Author(s): Ueno N, Fujiya M, Segawa S, Konishi H, Sakatani A, Tanaka K, Dokoshi T, Ando K, Kashima S, Inaba Y, Ito T, Moriichi K, Shigyo T, Kohgo Y.
  • Organizer: DDW 2014 (AGA)
  • Place of Presentation: Chicago
  • Year and Date: 20140503-20140506
• [Presentation] 炎症性腸疾患における腸内環境の異常と新規治療開発 (2014)
  • Author(s): 藤谷幹浩
  • Organizer: 第42回名古屋クローン病研究会
  • Place of Presentation: 名古屋
  • Year and Date: 20140307-20140307
  • Invited
• [Presentation] 消化器がんの内視鏡治療 (2014)
  • Author(s): 藤谷幹浩
  • Organizer: 平成25年度がんプロフェッショナル養成基盤推進プラン市民公開講座「がん治療を学ぶ」
  • Place of Presentation: 札幌
  • Year and Date: 20140202-20140202
  • Invited
• [Presentation] 大腸腫瘍性病変に対する内視鏡診断 (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 第27回日本消化器内視鏡学会北海道セミナー
  • Place of Presentation: 札幌
  • Year and Date: 20131110-20131110
  • Invited
• [Presentation] Polypectpmy/EMR (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 第34回日本消化器内視鏡学会重点卒後教育セミナー
  • Place of Presentation: 東京
  • Year and Date: 20130929-20130929
  • Invited
• [Presentation] The operative time for endoscopic submucosal dissection can be estimated based on the size and endoscopically described area of the lesion. (2013)
  • Author(s): Fujiya M, Tominaga M, Moriichi K, Tanaka K, Dokoshi T, Sakatani A, Ando K, Ueno N, Kashima S, Inaba Y, Ito T, Tanabe H, Ikuta K, Kohgo Y.
  • Organizer: 1st International Conference of Federation of Asian Clinical Oncology (FACO)
  • Place of Presentation: Xiamen
  • Year and Date: 20130926-20130926
• [Presentation] 炎症性腸疾患－診療の基本と最新の知見― (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 旭川薬剤師会・旭川病院薬剤師会炎症性腸疾患アドヒアランスセミナー
  • Place of Presentation: 旭川
  • Year and Date: 20130829-20130829
  • Invited
• [Presentation] The novel probiotic function through activation of intestinal epithelial autophagy. (2013)
  • Author(s): Inaba Y, Fujiya M, Kohgo Y.
  • Organizer: 16th International Congress of Mucosal Immunology (ICMI 2013)
  • Place of Presentation: Vancouver
  • Year and Date: 20130717-20130717
• [Presentation] 大腸癌診断の現況と課題 (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 2013年度日本消化器がん検診学会北海道支部医師研修会
  • Place of Presentation: 札幌
  • Year and Date: 20130713-20130713
  • Invited
• [Presentation] A probiotic-derived polyphosphate improves chronic inflammation and fibrosis via caveolin-dependent endocytosis. (2013)
  • Author(s): Fujiya M, Segawa S, Ueno N, Inaba Y, Moriichi K, Kohgo Y.
  • Organizer: GI Research Academy 2013
  • Place of Presentation: Kyoto
  • Year and Date: 20130628-20130628
• [Presentation] 腸内細菌による新しい腸疾患治療の開発 (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 広島FD・IBD研究会
  • Place of Presentation: 広島
  • Year and Date: 20130627-20130627
  • Invited
• [Presentation] Treatment with the heat-killed body of Lactobacillus brevis SBC8803 ameliorates intestinal injury in a dextran sulfate sodium-induced chronic colitis model by enhancing the intestinal barrier function. (2013)
  • Author(s): Ueno N, Fujiya M, Segawa S, Dokoshi T, Ando K, Inaba Y, Moriichi K, Tanabe H, Kobayashi N, Shigyo T, Kohgo Y.
  • Organizer: 1st annual meeting of Asian Organization for Crohn's & Colitis (AOCC)
  • Place of Presentation: Ｔｏｋｙｏ
  • Year and Date: 20130613-20130613
• [Presentation] Infliximab for the Treatment of Crohn’s Disease: Infusion Reactions at a Single Center over a 10-year period. (2013)
  • Author(s): Inaba Y, Fujiya M, Kohgo Y.
  • Organizer: 1st annual meeting of Asian Organization for Crohn's & Colitis (AOCC)
  • Place of Presentation: Tokyo
  • Year and Date: 20130613-20130613
• [Presentation] A bamboo-like appearance is a characteristic finding of the upper GI in patients with Crohn’s disease. (2013)
  • Author(s): Sakatani A, Fujiya M, Kashima S, Tanabe H, Dokoshi T, Tanaka K, Ando K, Ueno N, Tominaga M, Inaba Y, Ito T, Moriichi K, Kohgo Y.
  • Organizer: DDW 2013 (ASGE)
  • Place of Presentation: Orland
  • Year and Date: 20130518-20130521
• [Presentation] Probiotic-derived polyphosphate inhibits colon cancer progression through the inactivation of the ERK pathway and the induction of cancer cell apoptosis. (2013)
  • Author(s): Sakatani A, Fujiya M, Konishi H, Segawa S, Kashima S, Ueno N, Tanaka K, Dokoshi T, Ando K, Tominaga M, Inaba Y, Ito T, Tanabe H, Moriichi K, Kohgo Y.
  • Organizer: DDW 2013 (AGA)
  • Place of Presentation: Orland
  • Year and Date: 20130518-20130521
• [Presentation] A probiotic-derived polyphosphate improves chronic inflammation and fibrosis via caveolin-dependent endocytosis. (2013)
  • Author(s): Konishi H, Fujiya M, Segawa S, Kashima S, Ueno N, Tanaka K, Sakatani A, Dokoshi T, Ando K, Tominaga M, Inaba Y, Ito T, Tanabe H, Moriichi K, Kohgo Y.
  • Organizer: DDW 2013 (AGA)
  • Place of Presentation: orland
  • Year and Date: 20130518-20130521
• [Presentation] A polyphosphate derived from Lactobacillus brevis improves the intestinal barrier function and injury in acute and chronic experimental colitis. (2013)
  • Author(s): Fujiya M, Konishi H, Ueno N, Inaba Y, Ito T, Moriichi K, Tanabe H, Segawa S, Shigyo T, Kohgo Y.
  • Organizer: 13th International Conference of FFC
  • Place of Presentation: Kyoto
  • Year and Date: 20130511-20130511
• [Presentation] エキスパートセミナー15「潰瘍性大腸炎における粘膜治癒の診断と臨床的意義」 (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 第85回日本消化器内視鏡学会総会
  • Place of Presentation: 京都
  • Year and Date: 20130510-20130512
  • Invited
• [Presentation] 潰瘍性大腸炎における粘膜治癒の診断と臨床的意義 (2013)
  • Author(s): 藤谷幹浩
  • Organizer: 北海道炎症性腸疾患学術講演会
  • Place of Presentation: 札幌
  • Year and Date: 20130420-20130420
  • Invited