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Role of gut microbiota in the pathogenesis of primly sclerosing cholangitis

Research Project

Project/Area Number 16K09374
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionKeio University

Principal Investigator

NAKAMOTO NOBUHIRO  慶應義塾大学, 医学部(信濃町), 講師 (40383749)

Co-Investigator(Kenkyū-buntansha) 須田 亙  国立研究開発法人理化学研究所, 生命医科学研究センター, 副チームリーダー (20590847)
福田 真嗣  慶應義塾大学, 政策・メディア研究科(藤沢), 特任准教授 (80435677)
Research Collaborator CHU Po-Sung  
TANIKI Nobuhito  
TERATANI Toshiaki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords原発性硬化性胆管炎 / 腸内細菌 / IL-17 / 腸肝相関 / 免疫学
Outline of Final Research Achievements

Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of PSC patients and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper (Th)17 cell responses in the live . Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis, and Enterococcus gallinarum, which were prevalently detected in PSC patients. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.

Academic Significance and Societal Importance of the Research Achievements

原発性硬化性胆管炎(Primary Sclerosing Cholangitis; PSC)は肝臓内外の胆管に障害を認め胆汁うっ滞をきたす原因不明の自己免疫性疾患である。本邦における総患者数は約2,000名と推計され今後患者数の増加が予想される。高率に肝硬変への進展、胆管癌の合併を認め、肝移植以外に根本的な治療法が存在せず新規治療法の開発が待たれている。本研究課題の成果により、PSC患者に効率に存在する腸内細菌が病態の発症、および進展に寄与する可能性が示唆された。また、PSCの新規バイオマーカー、また治療標的としての有用性も期待され、学術的、社会的に大きな意義を有する成果と考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (7 results)

All 2019 2018 2017 2016 Other

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 3 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis.2019

    • Author(s)
      Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, Suzuki T, Koda Y, Chu PS, Taniki N, Yamaguchi A, Kanamori M, Kamada N, Hattori M, Ashida H, Sakamoto M, Atarashi K, Narushima S, Yoshimura A, Honda K, Sato T, Kanai T.
    • Journal Title

      Nat Microbiol.

      Volume: 4 Issue: 3 Pages: 492-503

    • DOI

      10.1038/s41564-018-0333-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Gut pathobionts underlie intestinal barrier dysfunction and liver Th17 immune responses in primary sclerosing cholangitis2019

    • Author(s)
      Nobuhiro Nakamoto
    • Organizer
      EASL annual meeting
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 原発性硬化性胆管炎の病態における腸内細菌の関与2017

    • Author(s)
      中本伸宏
    • Organizer
      日本消化器病学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Collaboration of intestinal microbiota induces bacterial translocation and Th17 immune response in primary sclerosing cholangitis2017

    • Author(s)
      中本伸宏
    • Organizer
      米国肝臓学会
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] The gut-liver axis plays a crucial role in murine immune tolerance in the liver2016

    • Author(s)
      中本伸宏
    • Organizer
      The Ameriac association for immunologists 2016 annual meeting
    • Place of Presentation
      Seattle, USA
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 原発性硬化性胆管炎の病態に関与する腸内細菌を発見-腸内細菌を標的とした新たな治療法の開発に期待-

    • URL

      https://www.keio.ac.jp/ja/press-releases/2019/1/15/28-50637/

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] Pore-forming Klebsiella pneumoniae strains enriched in primary sclerosing cholangitis trigger bacterial translocation and pathogenic Th17 priming in the liver2018

    • Inventor(s)
      中本伸宏
    • Industrial Property Rights Holder
      中本伸宏
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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