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Understanding mechanisms of disease development via disrupted Paneth cell development involving maturation and formation of intestinal microbiota

Research Project

Project/Area Number 20H04098
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 59040:Nutrition science and health science-related
Research InstitutionHokkaido University

Principal Investigator

Nakamura Kiminori  北海道大学, 先端生命科学研究院, 教授 (80381276)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2021: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
KeywordsPaneth細胞 / αディフェンシン / 腸内細菌 / 共生 / 先制医療
Outline of Research at the Start

本研究は、胎児期から乳幼児期におけるPaneth細胞の発達異常が腸内細菌叢形成の破綻を誘導し、疾患リスク上昇に関与するとの仮説を立て、そのメカニズムを栄養制御モデルマウスとαディフェンシン欠損マウスを用いて細胞・分子レベルで証明し、Paneth細胞機能の修復による腸内環境制御機構の正常化を標的とした疾患予防・治療戦略を提案することを目的とする。本研究によって、自然免疫による細菌叢との共生機構を標的とした、独創的な先制医療シーズの創出が期待できる。

Outline of Final Research Achievements

The living environment during pregnancy is increasingly known to influence the child's future health and disease risk (DOHaD). The involvement of the maternal gut microbiota, which is influenced by diet, as one of the environmental factors inducing DOHaD has increased concern, but the underlying mechanisms are unknown. This study showed that gut microbiota disruption via decreased α-defensin due to maternal high-fat diet intake prevents maturation of the child's gut microbiota by inducing abnormal Paneth cell development due to epigenetic modifications during the embryonic period. These findings contribute to the establishment of novel disease prevention methods that target α-defensin during the maternal gestation period to reduce the risk of developing a child's disease.

Academic Significance and Societal Importance of the Research Achievements

本研究は、いまだ十分に理解されていない腸内細菌叢形成機序の解明において、宿主因子であるPaneth細胞・α-defensinが個人の多様な腸内細菌叢の成熟・形成に大きく関与するという独自性の高い発想を基とした仮説を証明することにより、自然免疫による細菌叢との共生機構を標的とした疾患の予防・治療に直結する独創的で画期的な先制医療シーズを創出する基盤を構築したことから、学術的および社会的な要請において大きく意義がある。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (36 results)

All 2023 2022 2021 2020

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

  • [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
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] 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] 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] 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] 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] 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] 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] 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
      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] 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] 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
      2020 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
      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
  • [Presentation] High-efficient genetic engineering of enteroids using mouse isolated crypts revealing the intestinal function2022

    • Author(s)
      大平修也, 横井友樹, 海堀唯人, 清水由宇, 綾部時芳, 中村公則
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 腸管恒常性維持における病原菌と常在菌の選択的センシングによるPaneth細胞顆粒分泌調節2022

    • Author(s)
      横井友樹, 大平修也, 松岡温音, 海堀唯人, 篠崎竜我, 綾部時芳, 中村公則
    • Organizer
      第45回日本分子生物学会
    • 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大会
    • Related Report
      2022 Annual Research Report
  • [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] 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
    • Related Report
      2021 Annual Research Report
  • [Presentation] Paneth細胞αディフェンシンによる腸内細菌形成からみた健康と病気2021

    • Author(s)
      中村公則
    • Organizer
      東洋大学 ライフイノベーション研究所シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Simple and efficient genetic engineering of enteroids by using mouse isolated crypts.2021

    • 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
    • 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] 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
    • 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
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [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] 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年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Paneth細胞αディフェンシン による腸内細菌叢制御を介した生体恒常性の維持機構2020

    • Author(s)
      中村 公則、綾部 時芳
    • Organizer
      第75回日本体力医学会大会
    • 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
    • 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] 腸内環境がα-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] 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] 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、奥村利勝、綾部時芳
    • Organizer
      第24回腸内細菌学会学術集会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2024-01-30  

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