| Project/Area Number |
16K09374
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Keio University |
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Principal Investigator |
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| 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)
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| Research Collaborator |
CHU Po-Sung
TANIKI Nobuhito
TERATANI Toshiaki
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| 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)
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| Keywords | 原発性硬化性胆管炎 / 腸内細菌 / IL-17 / 腸肝相関 / 免疫学 |
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| 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.
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| 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。
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