Crosstalk between enteric neurons, immune cells and intestinal flora in the maintenance of intestinal homeostasis

• Project/Area Number: 18K06951
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Chiba University
• Principal Investigator: HATANO Masahiko 千葉大学, 大学院医学研究院, 教授 (20208523)
• Co-Investigator(Kenkyū-buntansha): 坂本 明美 千葉大学, バイオメディカル研究センター, 准教授 (90359597) ; 藤村 理紗 千葉大学, バイオメディカル研究センター, 助教 (30376363)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腸管神経 / 腸管免疫 / 腸内細菌 / Hirschsprung病類縁疾患 / Ncx KOマウス / 好酸球 / 腸内細菌叢 / 無菌マウス / Neuromedin U / IL5 / IL-5 / 腸内フローラ

Outline of Final Research Achievements

Enteric neurons play critical roles in the regulation of intestinal homeostasis. We demonstrated that Ncx KO mice which have a large number of enteric neurons have high susceptibility to DSS induced colitis due to epithelial hyperpermeability and dysbiosis. In this study, we investigated the mucosal immunity in Ncx KO mice. FACS analysis revealed that the percentage of eosinophils in lamina propria of small intestine (SI) in Ncx KO mice was significantly higher than that in wild type (WT) mice. IL5 and neuromedin U mRNAs were upregulated in SI of Ncx KO mice compared to those of WT mice. Furthermore, IL5 was upregulated in the ILC2 cell population, suggesting activation of Neuromedin U-ILC2-IL5 axis. In order to elucidate the role of eosinophils in Ncx KO mice, we deleted eosinophils by creating Ncx KO /dblGATA double KO (DKO) mice and induced DSS enterocolitis. The increased mortality in DKO mice suggested that eosinophils play a protective role in the intestine of Ncx KO mice.

Academic Significance and Societal Importance of the Research Achievements

本研究は腸管神経増加により腸管免疫系やバリア機構に異常をきたすことを明らにし、腸管神経の数はその発生・分化過程で厳密に制御される必要があることを示した。腸管神経増加状態にあるNcx KOマウスでは腸管粘膜固有層の好酸球増加が腸管炎症に対して保護的に機能することを示したものであり、これまで腸管好酸球が炎症促進的に機能するという報告が多かったが腸管好酸球の多様性を示したものである。今後炎症性腸疾患・好酸球性腸炎などの炎症疾患や腸管アレルギー疾患などの発症機序や病態が明らかできる可能性がありさらに腸管神経系をターゲットとした新たな治療、予防法が確立できその成果の臨床的・社会的意義は大きい。

Research Products

• [Journal Article] A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis (2022)
  • Author(s): Watanabe Eizo、Takasu Osamu、Teratake Youichi、Sakamoto Teruo、Ikeda Toshiaki、Kotani Joji、Kitamura Nobuya、Ohmori Masaaki、Teratani Ayako、Honda Goichi、Hatano Masahiko、Mayer Benjamin、Schneider E. Marion、Oda Shigeto
  • Journal Title: Frontiers in Medicine Volume: 8
  • DOI: 10.3389/fmed.2021.762198
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recombinant thrombomodulin attenuates hyper-inflammation and glycocalyx damage in a murine model of Streptococcus pneumoniae?induced sepsis (2022)
  • Author(s): Watanabe Eizo、Akamatsu Toshinobu、Ohmori Masaaki、Kato Mayu、Takeuchi Noriko、Ishiwada Naruhiko、Nishimura Rintaro、Hishiki Haruka、Fujimura Lisa、Ito Chizuru、Hatano Masahiko
  • Journal Title: Cytokine Volume: 149 Pages: 155723-155723
  • DOI: 10.1016/j.cyto.2021.155723
  • Peer Reviewed / Open Access
• [Journal Article] Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice. (2021)
  • Author(s): Ohara Y, Fujimura L, Sakamoto A, Teratake Y, Hiraoka S, Koseki H, Saito T, Terui K, Mitsunaga T, Nakata M, Yoshida H, Hatano M.
  • Journal Title: Sci Rep. Volume: 4;11(1) Issue: 1 Pages: 3191-3191
  • DOI: 10.1038/s41598-021-82785-1
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs (2020)
  • Author(s): Matsuda Shuichi、Kim Jun-Dal、Sugiyama Fumihiro、Matsuo Yuji、Ishida Junji、Murata Kazuya、Nakamura Kanako、Namiki Kana、Sudo Tatsuhiko、Kuwaki Tomoyuki、Hatano Masahiko、Tatsumi Koichiro、Fukamizu Akiyoshi、Kasuya Yoshitoshi
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 18 Pages: 6746-6746
  • DOI: 10.3390/ijms21186746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of the SET8 Pathway Ameliorates Lung Fibrosis Even Through Fibroblast Dedifferentiation (2020)
  • Author(s): Ugai Keita、Matsuda Shuichi、Mikami Hideki、Shimada Ayako、Misawa Tomoko、Nakamura Hiroyuki、Tatsumi Koichiro、Hatano Masahiko、Murayama Toshihiko、Kasuya Yoshitoshi
  • Journal Title: Frontiers in Molecular Biosciences Volume: 7
  • DOI: 10.3389/fmolb.2020.00192
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptomic changes involved in the dedifferentiation of myofibroblasts derived from the lung of a patient with idiopathic pulmonary fibrosis (2020)
  • Author(s): Suzuki Kenichi、Kim Jun-Dal、Ugai Keita、Matsuda Shuichi、Mikami Hideki、Yoshioka Kento、Ikari Jun、Hatano Masahiko、Fukamizu Akiyoshi、Tatsumi Koichiro、Kasuya Yoshitoshi
  • Journal Title: Molecular Medicine Reports Volume: 22 Issue: 2 Pages: 1518-1526
  • DOI: 10.3892/mmr.2020.11218
  • NAID: 120007168384
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1 (2020)
  • Author(s): Zhang Kai、Yang Chun、Chang Lijia、Sakamoto Akemi、Suzuki Toru、Fujita Yuko、Qu Youge、Wang Siming、Pu Yaoyu、Tan Yunfei、Wang Xingming、Ishima Tamaki、Shirayama Yukihiko、Hatano Masahiko、Tanaka Kenji F.、Hashimoto Kenji
  • Journal Title: Translational Psychiatry Volume: 10 Issue: 1 Pages: 32-32
  • DOI: 10.1038/s41398-020-0733-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression (2019)
  • Author(s): Kim Min-Kyeong、Song Ji-Yang、Koh Dong-In、Kim Jin Young、Hatano Masahiko、Jeon Bu-Nam、Kim Min-Young、Cho Su-Yeon、Kim Kyung-Sup、Hur Man-Wook
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 1 Pages: 299-313
  • DOI: 10.1074/jbc.ra118.004204
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cleavage of SPACA1 regulates assembly of sperm?egg membrane fusion machinery in mature spermatozoa† (2019)
  • Author(s): Yamatoya Kenji、Kousaka Marika、Ito Chizuru、Nakata Kazuya、Hatano Masahiko、Araki Yoshihiko、Toshimori Kiyotaka
  • Journal Title: Biology of Reproduction Volume: 102 Issue: 3 Pages: 750-757
  • DOI: 10.1093/biolre/ioz223
  • Peer Reviewed / Open Access
• [Journal Article] Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine (2019)
  • Author(s): Zhang K, Sakamoto A, Chang L, Qu Y, Wang S, Pu Y, Tan Y, Wang X, Fujita Y, Ishima T, Hatano M, Hashimoto K.
  • Journal Title: Eur Arch Psychiatry Clin Neurosci. Volume: 270 Issue: 3 Pages: 1-10
  • DOI: 10.1007/s00406-019-01092-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of Eqtn in mice reduces male fertility and sperm-egg adhesion (2018)
  • Author(s): Ito Chizuru、Yamatoya Kenji、Yoshida Keiichi、Fujimura Lisa、Sugiyama Hajime、Suganami Akiko、Tamura Yutaka、Hatano Masahiko、Miyado Kenji、Toshimori Kiyotaka
  • Journal Title: Reproduction Volume: 156 Issue: 6 Pages: 579-590
  • DOI: 10.1530/rep-18-0394
  • Peer Reviewed / Open Access
• [Journal Article] Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38 (2018)
  • Author(s): Kasuya Yoshitoshi、Umezawa Hiroki、Hatano Masahiko
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 3 Pages: 867-867
  • DOI: 10.3390/ijms19030867
  • Peer Reviewed / Open Access
• [Journal Article] Influence of autophagy on acute kidney injury in a murine cecal ligation and puncture sepsis model (2018)
  • Author(s): Sunahara Satoshi、Watanabe Eizo、Hatano Masahiko、Swanson Paul E.、Oami Takehiko、Fujimura Lisa、Teratake Youichi、Shimazui Takashi、Lee Chiwei、Oda Shigeto
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1050-1050
  • DOI: 10.1038/s41598-018-19350-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of Noninvasive In Vivo Approach to Assess Vascular Permeability in Inflammation Using Fluorescence Imaging. (2017)
  • Author(s): Shimazui T, Nakada TA, Fujimura L, Sakamoto A, Hatano M, Oda S.
  • Journal Title: Shock. Volume: - Issue: 6 Pages: 1-1
  • DOI: 10.1097/shk.0000000000001075
  • Peer Reviewed / Open Access
• [Presentation] Crosstalk between enteric neurons and immune cells in the maintenance of intestinal homeostasis (2021)
  • Author(s): Takashi Fumita, Lisa Fujimura, Akemi Sakamoto, Masahiko Hatano
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Bcl6 maintains germinal center B cells and regulates memory B cell function (2021)
  • Author(s): Qin Fan, Lasa Fujimura, Masahiko Hatano, Akemi Sakamoto
  • Organizer: 第50回日本免疫学会学術集会
• [Presentation] Roles of enteric neuron in eosinophil induction (2019)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Takashi Fumita, Masahiko Hatano
  • Organizer: 第48回日本免疫学会学術集会 浜松 2019.12.12.
• [Presentation] Ncx KOマウスを用いたプロポリスの腸管バリア機能改善に及ぼす効果の検討 (2019)
  • Author(s): 清宮航、藤村理紗、坂本明美、中嶋利典、文田貴志、幡野雅彦
  • Organizer: 第42回日本分子生物学会年会 博多 2019.12.3.
• [Presentation] 腸管炎症における制御性T細胞の役割とオートファジーの関与 (2019)
  • Author(s): 中嶋利典、坂本明美、藤村理紗、清宮航、文田貴志、大森智瑛、幡野雅彦
  • Organizer: 第42回日本分子生物学会年会 博多 2019.12.6.
• [Presentation] Analysis of the frequency and function of regulatory T-cell using human blood samples in biliary atresia. (2019)
  • Author(s): Satoru Oita, Takeshi Saito, Akemi Sakamoto, Keita Terui, Shugo Komatsu, Kazuaki Harada, Yoshitaka Shinno, Lisa Fujimura, Masahiko Hatano, Hideo Yoshida
  • Organizer: The Pacific Association of Pediatric Surgeons 52nd Annual Meeting Christchurch, New Zealand,11/03/2019
  • Int'l Joint Research
• [Presentation] Roles of enteric neurons in gut mucosal immunity (2018)
  • Author(s): Lisa Fujimura, Akemi Sakamoto, Masahiko Hatano
  • Organizer: 第47回日本免疫学会学術集会 博多 2018. 12.12
• [Presentation] Critical roles of enteric neurons in intestinal microbiota and barrier function (2018)
  • Author(s): Masahiko Hatano
  • Organizer: International conference on Bioinformatics, Biotechnology, and Biomedical Engineering, Yogyakarta Indonesia, 2018.10.19
  • Int'l Joint Research / Invited
• [Presentation] 胆道閉鎖症の病態形成における制御性T細胞の意義 (2018)
  • Author(s): 笈田 諭, 齋藤 武, 坂本 明美, 照井 慶太, 中田 光政, 小松 秀吾, 原田 和明, 秦 佳孝, 勝海 大輔, 古金 遼也, 藤村理紗, 幡野 雅彦, 吉田 英生
  • Organizer: 第45回日本胆道閉鎖症研究会 2018年11月3日 久留米
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学HP
  • URL: https://www.m.chiba-u.ac.jp/dept/shikkanseimei/
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学
  • URL: https://www.m.chiba-u.ac.jp/dept/shikkanseimei/
• [Remarks] 千葉大学大学院医学研究院 疾患生命医学 Webページ
  • URL: http://www.m.chiba-u.ac.jp/dept/shikkanseimei/
• [Patent(Industrial Property Rights)] 整腸用茶発酵組成物及びその製造方法 (2020)
  • Inventor(s): 幡野雅彦、横尾岳大、石田達也、木村勝紀
  • Industrial Property Rights Holder: 国立大学法人千葉大学、株式会社明治
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020