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Pathogenesis elucidation and treatment development for inflammatory bowel disease from a perspective of the gut ecosystem regulation by alpha-defensin

Research Project

Project/Area Number 21H02891
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, 名誉教授 (90301019)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2021: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Keywords炎症性腸疾患 / Paneth細胞 / 自然免疫 / αディフェンシン / 腸内細菌叢 / クローン病 / 小胞体ストレス / 腸内エコシステム / 腸内環境
Outline of Research at the Start

本研究は、Paneth細胞が産生し分泌するα-defensinが腸内細菌叢を制御して腸内環境の形成と維持さらには破綻に関与することに着眼し、クローン病と潰瘍性大腸炎をα-defensinの質と量の異常による腸内エコシステムの恒常性破綻と捉えて、それぞれの病態を解明するとともに新規治療法開発を目指す。Paneth細胞の小胞体ストレス、オートファジーや分泌シグナル関連分子群の発現と機能を解析することでα-defensin が担う自然免疫と腸内細菌との共生メカニズムを包括的に理解し、さらに獲得免疫とのリンクによって生じる粘膜免疫系の撹乱を解明して、その修復・正常化による治療戦略を確立する。

Outline of Final Research Achievements

From a perspective of homeostasis disruption in the gut ecosystem due to abnormalities in the quality and quantity of Paneth cell alpha-defensins, small intestinal Paneth cells in inflammatory bowel disease, Crohn's disease and ulcerative colitis, were investigated. We clarified that the mechanism by which symbiosis with the gut microbiota regulated by Paneth cell alpha-defensins is particularly disrupted in Crohn's disease due to several abnormalities in molecules related with endoplasmic reticulum stress, autophagy, and secretion signals. A new treatment strategy for inflammatory bowel disease by repairing abnormal Paneth cells and normalizing the amount or quality of alpha-defensins, targeting the regulation of gut ecosystem disruption was established from the Paneth cell function perspective.

Academic Significance and Societal Importance of the Research Achievements

本研究は小腸内腔に分泌されるαディフェンシンの選択的殺菌作用が腸内エコシステムの恒常性維持に重要であることを証明し、そのメカニズムの破綻がクローン病の発症や進展を規定する可能性を示した大きな学術的意義を有する。加えて、Paneth細胞αディフェンシンによる全腸管の腸内細菌叢制御機構制御という視点からクローン病と潰瘍性大腸炎の病態をはじめて示し、さらに非感染性疾患を含む様々な病態における自然免疫と獲得免疫をつなぐαディフェンシンの異常を明らかにした学術的意義がある。また、その異常を修復・正常化することによる炎症性腸疾患の新規治療戦略を樹立した大きな社会的意義を持つ。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (41 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (3 results) Journal Article (18 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 17 results,  Open Access: 17 results) Presentation (19 results) (of which Int'l Joint Research: 2 results,  Invited: 6 results) Book (1 results)

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

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Southern California(米国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Southern California(米国)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Effects of exposure to the neonicotinoid pesticide clothianidin on α-defensin secretion and gut microbiota in mice2024

    • Author(s)
      YONOICHI Sakura、HARA Yukako、ISHIDA Yuya、SHODA Asuka、KIMURA Mako、MURATA Midori、NUNOBIKI Sarika、ITO Makiko、YOSHIMOTO Ayano、MANTANI Youhei、YOKOYAMA Toshifumi、HIRANO Tetsushi、IKENAKA Yoshinori、YOKOI Yuki、AYABE Tokiyoshi、NAKAMURA Kiminori、HOSHI Nobuhiko
    • Journal Title

      Journal of Veterinary Medical Science

      Volume: 86 Issue: 3 Pages: 277-284

    • DOI

      10.1292/jvms.23-0514

    • ISSN
      0916-7250, 1347-7439
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Basic Study of the Effects of Mulberry Leaf Administration to Healthy C57BL/6 Mice on Gut Microbiota and Metabolites2023

    • Author(s)
      Gan Li、Inamura Yuga、Shimizu Yu、Yokoi Yuki、Ohnishi Yuki、Song Zihao、Kumaki Yasuhiro、Kikukawa Takashi、Demura Makoto、Ito Masaaki、Ayabe Tokiyoshi、Nakamura Kiminori、Aizawa Tomoyasu
    • Journal Title

      Metabolites

      Volume: 13 Issue: 9 Pages: 1003-1003

    • DOI

      10.3390/metabo13091003

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antimicrobial Properties and Mode of Action of Cryptdin-4, a Mouse α-Defensin Regulated by Peptide Redox Structures and Bacterial Cultivation Conditions2023

    • Author(s)
      Wang Yi、Song Yuchi、Yan Shaonan、Hiramine Rina、Ohnishi Yuki、Yokoi Yuki、Nakamura Kiminori、Kikukawa Takashi、Ayabe Tokiyoshi、Aizawa Tomoyasu
    • Journal Title

      Antibiotics

      Volume: 12 Issue: 6 Pages: 1047-1047

    • DOI

      10.3390/antibiotics12061047

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Application of Benchtop NMR for Metabolomics Study Using Feces of Mice with DSS-Induced Colitis2023

    • Author(s)
      Song Zihao、Ohnishi Yuki、Osada Seiji、Gan Li、Jiang Jiaxi、Hu Zhiyan、Kumeta Hiroyuki、Kumaki Yasuhiro、Yokoi Yuki、Nakamura Kiminori、Ayabe Tokiyoshi、Yamauchi Kazuo、Aizawa Tomoyasu
    • Journal Title

      Metabolites

      Volume: 13 Issue: 5 Pages: 611-611

    • DOI

      10.3390/metabo13050611

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Shorter sleep time relates to lower human defensin 5 secretion and compositional disturbance of the intestinal microbiota accompanied by decreased short-chain fatty acid production2023

    • Author(s)
      Shimizu Yu、Yamamura Ryodai、Yokoi Yuki、Ayabe Tokiyoshi、Ukawa Shigekazu、Nakamura Koshi、Okada Emiko、Imae Akihiro、Nakagawa Takafumi、Tamakoshi Akiko、Nakamura Kiminori
    • Journal Title

      Gut Microbes

      Volume: 15 Issue: 1 Pages: 2190306-2190306

    • DOI

      10.1080/19490976.2023.2190306

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 今だから聞きたい! Q&A.抗菌ペプチドとは?2023

    • Author(s)
      綾部時芳
    • Journal Title

      Microbiome Science

      Volume: 2 Pages: 55-56

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota2023

    • Author(s)
      Nakamura Shunta、Nakamura Kiminori、Yokoi Yuki、Shimizu Yu、Ohira Shuya、Hagiwara Mizu、Song Zihao、Gan Li、Aizawa Tomoyasu、Hashimoto Daigo、Teshima Takanori、Ouellette Andre J.、Ayabe Tokiyoshi
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 3953-3953

    • DOI

      10.1038/s41598-023-30997-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Associations between Maternal Diet, Human Milk Macronutrients, and Breast-Fed Infant Growth during the First Month of Life in the SMILE Iwamizawa in Japan2023

    • Author(s)
      Komatsu Yosuke、Wada Yasuaki、Tabata Fuka、Kawakami Satomi、Takeda Yasuhiro、Nakamura Kiminori、Ayabe Tokiyoshi、Nakamura Koshi、Kimura Takashi、Tamakoshi Akiko
    • Journal Title

      Nutrients

      Volume: 15 Issue: 3 Pages: 654-654

    • DOI

      10.3390/nu15030654

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficient recombinant production of mouse-derived cryptdin family peptides by a novel facilitation strategy for inclusion body formation2023

    • Author(s)
      Song Yuchi、Wang Yi、Yan Shaonan、Nakamura Kiminori、Kikukawa Takashi、Ayabe Tokiyoshi、Aizawa Tomoyasu
    • Journal Title

      Microbial Cell Factories

      Volume: 22 Issue: 1 Pages: 9-9

    • DOI

      10.1186/s12934-023-02016-2

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota2022

    • Author(s)
      Chen Xuanzhong、Hashimoto Daigo、Ebata Ko、Takahashi Shuichiro、Shimizu Yu、Shinozaki Ryuga、Hasegawa Yuta、Kikuchi Ryo、Senjo Hajime、Yoneda Kazuki、Zhang Zixuan、Harada Shinpei、Hayase Eiko、Ara Takahide、Ohigashi Hiroyuki、Iwakura Yoichiro、Nakamura Kiminori、Ayabe Tokiyoshi、Teshima Takanori
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 48 Pages: 1-10

    • DOI

      10.1073/pnas.2211230119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficient and simple genetic engineering of enteroids using mouse isolated crypts for investigating intestinal functions2022

    • Author(s)
      Ohira Shuya、Yokoi Yuki、Ayabe Tokiyoshi、Nakamura Kiminori
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 637 Pages: 153-160

    • DOI

      10.1016/j.bbrc.2022.11.008

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hemodynamic response to intestinal pH stimulation measured with spectroscopic video imaging2022

    • Author(s)
      Funane Tsukasa、Yokoi Yuki、Kikuchi Masashi、Shinozaki Ryuga、Ayabe Tokiyoshi、Atsumori Hirokazu、Nishimura Ayako、Nakamura Kiminori、Kandori Akihiko
    • Journal Title

      Biomedical Physics & Engineering Express

      Volume: 9 Issue: 1 Pages: 017001-017001

    • DOI

      10.1088/2057-1976/aca20a

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Oral frailty and carriage of oral Candida in community‐dwelling older adults (Check‐up to discover Health with Energy for senior Residents in Iwamizawa; CHEER Iwamizawa)2022

    • Author(s)
      Baba Haruhisa, Watanabe Yutaka, Miura Kazuhito, Ozaki Kimiya, Matsushita Takae, Kondoh Miyako, Okada Kazutaka, Hasebe Akira, Ayabe Tokiyoshi, Nakamura Kiminori, Nakaoka Shinji, Ogasawara Katsuhiko, Suzuki Teppei, Saito Hiroshi, Kimura Takashi, Tamakoshi Akiko, Yamazaki Yutaka
    • Journal Title

      Gerodontology

      Volume: 39 Issue: 1 Pages: 49-58

    • DOI

      10.1111/ger.12621

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intestinal commensal microbiota and cytokines regulate Fut2 <sup>+</sup> Paneth cells for gut defense2022

    • Author(s)
      Kamioka Mariko、Goto Yoshiyuki、Nakamura Kiminori、Yokoi Yuki、Sugimoto Rina、Ohira Shuya、Kurashima Yosuke、Umemoto Shingo、Sato Shintaro、Kunisawa Jun、Takahashi Yu、Domino Steven E.、Renauld Jean-Christophe、Nakae Susumu、Iwakura Yoichiro、Ernst Peter B.、Ayabe Tokiyoshi、Kiyono Hiroshi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 3 Pages: 1-10

    • DOI

      10.1073/pnas.2115230119

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ingestion of miso regulates immunological robustness in mice2022

    • Author(s)
      Kotake Kunihiko、Kumazawa Toshihiko、Nakamura Kiminori、Shimizu Yu、Ayabe Tokiyoshi、Adachi Takahiro
    • Journal Title

      PLOS ONE

      Volume: 17 Issue: 1 Pages: e0261680-e0261680

    • DOI

      10.1371/journal.pone.0261680

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Potent bactericidal activity of reduced cryptdin-4 derived from its hydrophobicity and mediated by bacterial membrane disruption2022

    • Author(s)
      Sato Yuji、Wang Yi、Song Yuchi、Geng Weiming、Yan Shaonan、Nakamura Kiminori、Kikukawa Takashi、Demura Makoto、Ayabe Tokiyoshi、Aizawa Tomoyasu
    • Journal Title

      Amino Acids

      Volume: 54 Issue: 2 Pages: 289-297

    • DOI

      10.1007/s00726-021-03115-3

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lower human defensin 5 in elderly people compared to middle-aged is associated with differences in the intestinal microbiota composition: the DOSANCO Health Study2021

    • Author(s)
      Shimizu Yu、Nakamura Kiminori、Kikuchi Mani、Ukawa Shigekazu、Nakamura Koshi、Okada Emiko、Imae Akihiro、Nakagawa Takafumi、Yamamura Ryodai、Tamakoshi Akiko、Ayabe Tokiyoshi
    • Journal Title

      GeroScience

      Volume: - Issue: 2 Pages: 997-1009

    • DOI

      10.1007/s11357-021-00398-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decrease of α-defensin impairs intestinal metabolite homeostasis via dysbiosis in mouse chronic social defeat stress model2021

    • Author(s)
      Suzuki Kosuke、Nakamura Kiminori、Shimizu Yu、Yokoi Yuki、Ohira Shuya、Hagiwara Mizu、Wang Yi、Song Yuchi、Aizawa Tomoyasu、Ayabe Tokiyoshi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 9915-9915

    • DOI

      10.1038/s41598-021-89308-y

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Selective Paneth cell granule secretion in response to pathogenic and commensal bacteria in enteric mucosal immunity2024

    • Author(s)
      Yuki Yokoi, Shuya Ohira, Haruto Matsuoka, Shota Takemi, Tokiyoshi Ayabe, Kiminori Nakamura
    • Organizer
      第52回日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Paneth細胞が担う免疫/共生の異常による腸内細菌叢の撹乱を介する疾患発症2024

    • Author(s)
      綾部時芳
    • Organizer
      GI Week2024 第51回日本潰瘍学会(シンポジウム)
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 短眠はPaneth細胞α-defensin分泌量の低値および短鎖脂肪酸の産生量低下を伴う腸内細菌叢組成の撹乱に関係する2023

    • Author(s)
      清水由宇、山村凌大、横井友樹、綾部時芳、鵜川重和、中村幸志、岡田恵美子、今江章宏、中川貴史、玉腰暁子、中村公則
    • Organizer
      第27回腸内細菌学会学術集会(ワークショップ)
    • Related Report
      2023 Annual Research Report
  • [Presentation] 共生メカニズムからみた腸内細菌と疾患2023

    • Author(s)
      綾部時芳
    • Organizer
      本消化器病学会北海道支部 第25回教育講演会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 高齢者におけるPaneth細胞α-defensin分泌量の低さは加齢に伴う腸内細菌叢の遷移に関連する2022

    • Author(s)
      清水由宇、中村公則、菊池摩仁、鵜川重和、中村幸志、岡田恵美子、今江章宏、中川貴史、山村凌大、玉腰暁子、綾部時芳
    • Organizer
      第26回腸内細菌学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Application of a bench-top NMR instrument for omics studies of gut microbiota metabolites2022

    • Author(s)
      Zihao Song, Yuki Ohnishi, Seiji Osada, Li Gan, Jiaxi Jiang, Zhiyan Hu, Hiroyuki Kumeta, Yasuhiro Kumaki, Kiminori Nakamura, Tokiyoshi Ayabe, Kazuo Yamauchi, Tomoyasu Aizawa
    • Organizer
      第60回日本生物物理学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 食品が誘導するPaneth細胞αディフェンシンによる免疫と共生2022

    • Author(s)
      綾部時芳、横井友樹、高桑暁子、中村公則
    • Organizer
      第18回日本食品免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ベンチトップ NMR による炎症性腸疾患モデルマウスのメタボロミクス研究2022

    • Author(s)
      宋子豪、大西裕季、長田誠司、甘莉、蒋佳稀、胡知彦、久米田博之、熊木康裕、中村公則、綾部時芳、山内一夫、相沢智康
    • Organizer
      第61回NMR討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Regulation of Paneth cell granule secretion by selective sensing of pathogenic and commensal bacteria in intestinal homeostasis2022

    • Author(s)
      Yuki Yokoi, Shuya Ohira, Haruto Matsuoka, Yuito Kaibori, Ryuga Shinozaki, Tokiyoshi Ayabe, Kiminori Nakamura
    • Organizer
      第45回日本分子生物学会年会 ワークショップ
    • Related Report
      2022 Annual Research Report
  • [Presentation] High-efficient genetic engineering of enteroids using mouse isolated crypts revealing the intestinal function2022

    • Author(s)
      Shuya Ohira, Yuki Yokoi, Yuito Kaibori, Yu Shimizu, Tokiyoshi Ayabe, Kiminori Nakamura
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] αディフェンシンが担う腸内細菌叢制御と予防医療2022

    • Author(s)
      綾部時芳
    • Organizer
      第62回自然免疫賦活技術研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 腸内細菌との共生~その破綻による疾患2022

    • Author(s)
      綾部時芳
    • Organizer
      腸内フローラを考える会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 抗菌ペプチドαディフェンシンによる腸内細菌制御と健康2022

    • Author(s)
      綾部時芳、横井友樹、清水由宇、中村公則
    • Organizer
      日本食品・機械研究会 第17回腸内細菌をターゲットとした食品開発研究会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Dynamics of Paneth cell granule secretory responses to bacteria in innate enteric immunity2021

    • Author(s)
      Yuki Yokoi, Kiminori Nakamura, Shuya Ohira, Ryuga Shinozaki, Mani Kikuchi, Tokiyoshi Ayabe.
    • Organizer
      World Microbe Forum. Host-Microbe Biology
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ER Stress-Associated Misfolding of Paneth Cell α-Defensin Induces Dysbiosis and Ileitis in a Murine Model of Crohn’s Disease2021

    • Author(s)
      Yu Shimizu, Kiminori Nakamura, Aki Yoshii, Yuki Yokoi, Mani Kikuchi, Ryuga Shinozaki, Shunta Nakamura, Shuya Ohira, Rina Sugimoto, Tokiyoshi Ayabe
    • Organizer
      World Microbe Forum. Host-Microbe Biology
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 抗菌ペプチドから粘膜免疫を理解する2021

    • Author(s)
      綾部時芳、横井友樹、中村公則
    • Organizer
      第58回日本消化器免疫学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Paneth細胞顆粒分泌応答からみた食機能評価系の確立2021

    • Author(s)
      横井友樹、中村公則、高桑暁子、菊池摩仁、綾部時芳
    • Organizer
      第17回日本食品免疫学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 母親の高脂肪食摂取が子のPaneth細胞の発達に与える作用メカニズム2021

    • Author(s)
      八塚夏美、杉本理菜、大平修也、横井友樹、菊池摩仁、綾部時芳、中村公則
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Simple and efficient genetic engineering of enteroids by using mouse isolated crypts2021

    • Author(s)
      Shuya Ohira, Yuki Yokoi, Mani Kikuchi, Natsumi Yatsuzuka, Tokiyoshi Ayabe, Kiminori Nakamura
    • Organizer
      第44回日本分子生物学会年会 ワークショップ
    • Related Report
      2021 Annual Research Report
  • [Book] プレコンセプションケア2024

    • Author(s)
      綾部時芳
    • Total Pages
      447
    • Publisher
      株式会社メジカルビュー社
    • ISBN
      9784758321402
    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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