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

• Project/Area Number: 20H04098
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Hokkaido 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: ¥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)
• Keywords: Paneth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。

Research Products

• [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 production (2023)
  • 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
  • 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 microbiota (2023)
  • 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
  • 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 Japan (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Efficient recombinant production of mouse-derived cryptdin family peptides by a novel facilitation strategy for inclusion body formation (2023)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Efficient and simple genetic engineering of enteroids using mouse isolated crypts for investigating intestinal functions (2022)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota (2022)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Hemodynamic response to intestinal pH stimulation measured with spectroscopic video imaging (2022)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal commensal microbiota and cytokines regulate Fut2 ⁺ Paneth cells for gut defense (2022)
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ingestion of miso regulates immunological robustness in mice (2022)
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Potent bactericidal activity of reduced cryptdin-4 derived from its hydrophobicity and mediated by bacterial membrane disruption (2022)
  • 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
  • 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 method (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of Serotonin in Human Feces Using Solid Phase Extraction and Column-Switching LC-MS/MS (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Paneth cell alpha-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Expression and localization of Paneth cells and their alpha-defensins in the small intestine of adult mouse (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Disease progression-associated alterations in fecal metabololies in SAMP1/YitFc mice, a Crohn’s disease model (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Associations of gut microbiota, dietary intake, and serum short-chain fatty acids with fecal short-chain fatty acids (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Mycotoxin deoxynivalenol has different impacts on intestinal barrier and stem cells by its route of exposure (2020)
  • 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
  • Peer Reviewed / Open Access
• [Presentation] High-efficient genetic engineering of enteroids using mouse isolated crypts revealing the intestinal function (2022)
  • 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
• [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
• [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
• [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
• [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
• [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
  • 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
• [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
• [Presentation] Dynamics of Paneth Cell Granule Secretory Responses to Bacteria in Innate Enteric Immunity (2021)
  • Author(s): Yuki Yokoi, Kiminori Nakamura, Shuya Ohira, Ryuga Shinozaki, Mani Kikuchi, Tokiyoshi Ayabe
  • Organizer: World Microbe Forum
  • 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 Disease (2021)
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
• [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
• [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