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Regulation of intestinal environment by Paneth cells and new therapeutic strategy for inflammatory bowel disease

Research Project

Project/Area Number 18H02788
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionHokkaido University

Principal Investigator

Ayabe Tokiyoshi  北海道大学, 先端生命科学研究院, 教授 (90301019)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Keywords炎症性腸疾患 / Paneth細胞 / 自然免疫 / 腸内細菌 / αディフェンシン / 腸内環境 / クローン病 / 小胞体ストレス / α-defensin
Outline of Final Research Achievements

Focusing on the regulation of the intestinal microbiota by antimicrobial peptide alpha-defensin secreted by Paneth cells in the small intestine, secretory responses of Paneth cells were visualized and revealed the site-selective granule secretory stimulation, i.e., lumen side or basal side, and the granule replenishment after secretion. This study clarified for the first time the correlation between abnormalities in quality and quantity of alpha-defensin and disruption of the intestinal microbiota, dysbiosis, associated with disease progression in Crohn's disease model mice, and further presented novel therapeutic strategy for inflammatory bowel disease in the light of regulating the intestinal environment.

Academic Significance and Societal Importance of the Research Achievements

Paneth細胞の顆粒分泌評価系を確立し、コリン作動性刺激や細菌刺激でαディフェンシンを分泌することが示されて以来長年ディベートが続いていたPaneth細胞分泌応答の重要な課題を解決した学術的意義を有する。また、クローン病モデルマウスでPaneth細胞の過剰な小胞体ストレスがαディフェンシンの質的異常を生じ、還元型αディフェンシン分泌が腸内細菌叢破綻と腸炎進展を起こすことを示し、クローン病の病態理解と新規治療開発に新しい方向性を与えた学術的・社会的意義が大きい。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (53 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 13 results) Presentation (38 results) (of which Int'l Joint Research: 7 results,  Invited: 12 results)

  • [Int'l Joint Research] University of Southern California(米国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Simultaneous real-time analysis of Paneth cell and intestinal stem cell response to interferon-γ by a novel stem cell niche tracking method2021

    • Author(s)
      Yokoi Y, Adachi T, Sugimoto R, Kikuchi M, Ayabe T, Nakamura K
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 545 Pages: 14-19

    • DOI

      10.1016/j.bbrc.2021.01.050

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Analysis of Serotonin in Human Feces Using Solid Phase Extraction and Column-Switching LC-MS/MS2020

    • Author(s)
      Hirabayashi Y, Nakamura K, Sonehara T, Suzuki D, Hanzawa S, Shimizu Y, Aizawa T, Nakamura K, Tamakoshi A, Ayabe T
    • Journal Title

      Mass Spectrometry

      Volume: 9 Issue: 1 Pages: A0081-A0081

    • DOI

      10.5702/massspectrometry.A0081

    • NAID

      130007823248

    • ISSN
      2186-5116, 2187-137X
    • Year and Date
      2020-03-31
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression and localization of Paneth cells and their alpha-defensins in the small intestine of adult mouse2020

    • Author(s)
      Nakamura K, Yokoi Y, Fukaya R, Ohira S, Shinozaki R, Nishida T, Kikuchi M, Ayabe T
    • Journal Title

      Front Immunol

      Volume: 11 Pages: 570296-570296

    • DOI

      10.3389/fimmu.2020.570296

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mycotoxin deoxynivalenol has different impacts on intestinal barrier and stem cells by its route of exposure2020

    • Author(s)
      Hanyu H, Yokoi Y, Nakamura K, Ayabe T, Tanaka K, Uno K, Miyajima K, Saito Y, Iwatsuki K, Shimizu M, Tadaishi M, Kobayashi-Hattori K
    • Journal Title

      Toxins

      Volume: 12 Issue: 10 Pages: 610-610

    • DOI

      10.3390/toxins12100610

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Paneth cell alpha-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice2020

    • Author(s)
      Shimizu Y, Nakamura K, Yoshii A, Yokoi Y, Kikuchi M, Shinozaki R, Nakamura S, Ohira S, Sugimoto R, Ayabe T
    • Journal Title

      Life Science Alliance

      Volume: 3 Issue: 6 Pages: e201900592-e201900592

    • DOI

      10.26508/lsa.201900592

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disease progression-associated alterations in fecal metabololies in SAMP1/YitFc mice, a Crohn’s disease model2020

    • Author(s)
      Komatsu Y, Shimizu Y, Yamano M, Kikuchi M, Nakamura K, Ayabe T, Aizawa T
    • Journal Title

      Metabolomics

      Volume: 16 Issue: 4 Pages: 48-48

    • DOI

      10.1007/s11306-020-01671-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Associations of gut microbiota, dietary intake, and serum short-chain fatty acids with fecal short-chain fatty acids2020

    • Author(s)
      Yamamura R, Nakamura K, Kitada N, Aizawa T, Shimizu Y, Nakamura K, Ayabe T, Kimura T, Tamakoshi A
    • Journal Title

      Bioscience of Microbiota, Food and Health

      Volume: 39 Issue: 1 Pages: 11-17

    • DOI

      10.12938/bmfh.19-010

    • NAID

      130007788976

    • ISSN
      2186-3342
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Butyric Acid and Leucine Induce α-Defensin Secretion from Small Intestinal Paneth Cells2019

    • Author(s)
      Takakuwa Akiko、Nakamura Kiminori、Kikuchi Mani、Sugimoto Rina、Ohira Shuya、Yokoi Yuki、Ayabe Tokiyoshi
    • Journal Title

      Nutrients

      Volume: 11 Issue: 11 Pages: 2817-2817

    • DOI

      10.3390/nu11112817

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A simple culture method for liver and intestinal tissue-resident macrophages from neonatal mice2019

    • Author(s)
      Shimizu Y, Sakuragi N, Nakamura K, Taira T, Ayabe T, Fukui A
    • Journal Title

      In Vitro Cell Dev Biol - Animal

      Volume: 55 Issue: 6 Pages: 436-444

    • DOI

      10.1007/s11626-019-00359-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Paneth cell granule dynamics on secretory responses to bacterial stimuli in enteroids2019

    • Author(s)
      Yokoi Yuki、Nakamura Kiminori、Yoneda Tsukasa、Kikuchi Mani、Sugimoto Rina、Shimizu Yu、Ayabe Tokiyoshi
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s41598-019-39610-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Myc-induced nuclear antigen constrains a latent intestinal epithelial cell-intrinsic anthelmintic pathway.2019

    • Author(s)
      Pillai MR, Mihi B, Ishiwata K, Nakamura K, Sakuragi N, Finkelstein DB, McGargill MA, Nakayama T, Ayabe T, Coleman ML, Bix M
    • Journal Title

      PLoS One

      Volume: 26;14(2):e0211244 Issue: 2 Pages: 1-21

    • DOI

      10.1371/journal.pone.0211244

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential role of IFN-γ in T cell?associated intestinal inflammation2018

    • Author(s)
      Eriguchi Yoshihiro、Nakamura Kiminori、Yokoi Yuki、Sugimoto Rina、Takahashi Shuichiro、Hashimoto Daigo、Teshima Takanori、Ayabe Tokiyoshi、Selsted Michael E.、Ouellette Andre J.
    • Journal Title

      JCI Insight

      Volume: 3 Issue: 18 Pages: 1-18

    • DOI

      10.1172/jci.insight.121886

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ploidy-dependent change in cyclin D2 expression and sensitization to cdk4/6 inhibition in human somatic haploid cells.2018

    • Author(s)
      Yaguchi K, Yamamoto T, Shimada M, Sugimoto R, Nakamura K, Ayabe T, Uehara R.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 504 Issue: 1 Pages: 231-231

    • DOI

      10.1016/j.bbrc.2018.08.160

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Entamoeba histolytica Alters Ileal Paneth Cell Functions in Intact and Muc2 Mucin Deficiency2018

    • Author(s)
      Cobo Eduardo R.、Holani Ravi、Moreau France、Nakamura Kiminori、Ayabe Tokiyoshi、Mastroianni Jennifer R.、Ouellette Andre、Chadee Kris
    • Journal Title

      Infection and Immunity

      Volume: 86 Issue: 7

    • DOI

      10.1128/iai.00208-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 食を介したPaneth細胞の機能異常に基づくNASH発症メカニズムの解明2021

    • Author(s)
      萩原瑞、中村公則、中村駿太、八塚夏美、杉本理菜、横井友樹、綾部時芳
    • Organizer
      令和2年度北大細胞生物研究集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 霊長類T1R1およびT1R2抗体の作製2021

    • Author(s)
      小松さゆり、中安亜希、大島永心、新藤壮剛、今井啓雄、伯川美穂、杉山宗太郎、綾部時芳、中村公則、山根拓実、大石祐一、岩槻 健
    • Organizer
      日本農芸化学会2021年度大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Paneth細胞が担う腸内細菌叢の形成からみた疾患リスク上昇メカニズムの理解2020

    • Author(s)
      中村公則、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会.シンポジウムI
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 腸内環境がalpha-defensin isoformの殺菌活性に及ぼす影響2020

    • Author(s)
      篠崎竜我、中村公則、清水由宇、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 出生早期からのPaneth細胞発達により制御される腸内細菌定着機構2020

    • Author(s)
      西田琢人、中村公則、横井友樹、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Paneth細胞の機能異常は腸内細菌叢の破綻を介してNASH発症に関与する2020

    • Author(s)
      中村駿太、中村公則、菊池摩仁、横井友樹、大平修也、清水由宇、西田琢人、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 桑葉摂取によるα-defensinと腸内細菌叢の経時変化に対する統計解析2020

    • Author(s)
      子安惟、中岡慎、菊池摩仁、中村公則、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 膵癌初期発生における膵腸相関2020

    • Author(s)
      小野裕介、中村公則、清水由宇、横井友樹、杉本理菜、早川祐子、佐藤裕基、水上裕輔、綾部時芳、奥村利勝
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] クローン病モデルマウスSAMP1/YitFcの慢性回腸炎の免疫病態2020

    • Author(s)
      村山綾菜、中村公則、菊池摩仁、横井友樹、綾部時芳
    • Organizer
      第43回日本分子生物学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Paneth細胞が担う腸内細菌との共生と生体恒常性2020

    • Author(s)
      綾部時芳
    • Organizer
      第57回日本消化器免疫学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Alpha-defensin異常による腸内細菌叢の破綻とIBD2020

    • Author(s)
      綾部時芳、清水由宇、中村公則
    • Organizer
      第127回日本消化器病学会北海道支部例会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 腸内細菌はなぜ大切か? 自然免疫と腸内細菌から病気を紐解く2020

    • Author(s)
      綾部時芳
    • Organizer
      第45回札幌市医師会医学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 腸内環境と炎症性腸疾患・非感染性疾患―どこまでわかったか2020

    • Author(s)
      綾部時芳
    • Organizer
      第6回旭川IBD研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 母子の健康・腸内の環境2020

    • Author(s)
      綾部時芳
    • Organizer
      Society 5.0北海道の地方創生と未来
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Paneth cell in health and disease - an overview from intestinal homeostasis and inter organ network2019

    • Author(s)
      Ayabe T
    • Organizer
      Hokudai-USC Research Workshop “Gut-Organ Crosstalk”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Dynamics and mechanisms of Paneth cell granule secretory responses in enteroids2019

    • Author(s)
      Yokoi Y, Nakamura K, Sugimoto R, Ohira S, Kikuchi M, Ayabe T
    • Organizer
      Hokudai-USC Research Workshop “Gut-Organ Crosstalk”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Paneth cell alpha-defensin misfolding leads to dysbiosis and subsequent ileitis in a murine model of Crohn's disease2019

    • Author(s)
      Shimizu Y, Nakamura K, Kikuchi M, Ayabe T
    • Organizer
      Hokudai-USC Research Workshop “Gut-Organ Crosstalk”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Acetylcholine-induced Paneth cell granule secretion via muscarinic M3 receptor in mouse small intestine2019

    • Author(s)
      Yuki Yokoi, Kiminori Nakamura, Rina Sugimoto, Shuya Ohira, Mani Kikuchi and Tokiyoshi Ayabe
    • Organizer
      American Society for Cell Biology Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Paneth cell dysfunction in pathophysiology of nonalcoholic steatohepatitis2019

    • Author(s)
      Shunta Nakamura, Kiminori Nakamura, Mani Kikuchi, Yuki Yokoi, Shuya Ohira, Yu Shimizu, Takuto Nishida and Tokiyoshi Ayabe
    • Organizer
      American Society for Cell Biology Annual Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト糞便中セロトニンの分析2019

    • Author(s)
      平林由紀子、中村公則、曽根原剛志、鈴木大介、半澤悟、清水由宇、相沢智康、中村幸志、玉腰暁子、綾部時芳
    • Organizer
      日本質量分析学会 第67回質量分析総合討論会
    • Related Report
      2019 Annual Research Report
  • [Presentation] クローン病マウスモデルSAMP1/YitFcの病態形成におけるPaneth細胞α-defensin misfoldingの関与2019

    • Author(s)
      清水由宇、中村公則、菊池摩仁、綾部時芳
    • Organizer
      第23回腸内細菌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Paneth細胞の発達により制御される腸管恒常性の機構解明2019

    • Author(s)
      西田琢人、中村公則、横井友樹、綾部時芳
    • Organizer
      第9回オルソオルガノゲネシス検討会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 母親の高脂肪食摂取が子のPaneth細胞による腸内環境制御に与える影響の解明2019

    • Author(s)
      杉本理菜、中村公則、嶋 七海、清水由宇、横井友樹、綾部時芳
    • Organizer
      第9回オルソオルガノゲネシス検討会
    • Related Report
      2019 Annual Research Report
  • [Presentation] クローン病自然発症モデルSAMP1/YitFcマウスの病状進行に伴う腸内細菌叢および糞便メタボライトの変動2019

    • Author(s)
      小松陽介、清水由宇、山野めぐみ、中村公則、綾部時芳、相沢智康
    • Organizer
      第71回日本生物工学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 桑葉のα-defensin分泌促進効果と腸内細菌叢制御2019

    • Author(s)
      菊池摩仁、中村公則、綾部時芳
    • Organizer
      第15回日本食品免疫学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 母親の高脂肪食摂取が子の腸管上皮幹細胞ニッシェに与える影響2019

    • Author(s)
      嶋七海、中村公則、杉本理菜、横井友樹、綾部時芳
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 多様なα-defensin isoformに対するin vitroにおける効率的なS-S結合導入法の確立2019

    • Author(s)
      篠崎竜我、中村公則、清水由宇、綾部時芳
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 腸から健康になる話-腸内環境を整えて元気でいよう2019

    • Author(s)
      綾部時芳
    • Organizer
      岩見沢市幌向地域ふれあい健康講座
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Visualization of Paneth cell secretory response to bacterial stimuli using enteroids2019

    • Author(s)
      Yokoi Y, Nakamura K, Yoneda T, Nakamura S, Kikuchi M, Ayabe T
    • Organizer
      American Society for Cell Biology Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Relationship between morphological alteration of Paneth cells and dysbiosis in patients with inflammatory bowel disease2019

    • Author(s)
      Nagashima K, Nakamura K, Katsurada T, Shimizu Y, Yokoi Y, Otagiri S, Yamanashi K, Kinoshita K, Onishi R, Sakamoto N, Ayabe T
    • Organizer
      4th. Congress of European Crohn’s and Colitis Organisation Annual Meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 親の高脂肪食摂取が子のPaneth細胞α-defensinによる腸内環境制御に与える影響2019

    • Author(s)
      杉本理菜、中村公則、嶋七海、清水由宇、横井友樹、綾部時芳
    • Organizer
      日本農芸化学会2019年度大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] α-defensinによる腸内細菌叢の制御―共生と排除が疾病の鍵を握る2019

    • Author(s)
      綾部時芳
    • Organizer
      京滋腸内細菌研究会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 封入体共発現を利用した大量発現系において抗菌ペプチドcryptdin familyの生産性を決定する因子の解析2018

    • Author(s)
      保本美穂子、平峰里菜、宋 雨遅、佐藤優次、塚本 卓、菊川峰志、出村 誠、中村公則、綾部時芳、相沢智康
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Enteroidを用いたPaneth細胞顆粒の分泌と再形成の可視化2018

    • Author(s)
      横井友樹、中村公則、米田 司、菊池摩仁、綾部時芳
    • Organizer
      第8回オルソオルガノゲネシス検討会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ヒト糞便試料の保存条件がメタボロームに与える影響の検討2018

    • Author(s)
      包 克非,北田直也,稲村優雅,山野めぐみ,久米田博之,熊木康裕,大西裕季,塚本卓,菊川峰志,出村誠,中村公則,綾部時芳,山村凌大, 中村幸志,玉腰暁子,相沢智康
    • Organizer
      第57回NMR討論会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Analysisi of the regulation of Paneth cell differentiation in stem cell niche by using intestinal organoid2018

    • Author(s)
      大平修也、中村公則、菊池摩仁、横井友樹、杉本理菜、綾部時芳
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Involvement of Paneth cell α-defensin misfolding in disease progression of SAMP1/YitFc, a murine model of Crohn’s disease2018

    • Author(s)
      Shimizu Y, Nakamura K, Kikuchi M, Ayabe T
    • Organizer
      第47回日本免疫学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] α-defensinが担う腸内細菌の制御と疾病2018

    • Author(s)
      綾部時芳
    • Organizer
      北海道消化管疾患研究会
    • Related Report
      2018 Annual Research Report
    • Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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