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The role of lifestyle-induced intestinal barrier dysfunction in the pathogenesis of autoimmune pancreatitis

Research Project

Project/Area Number 21K15987
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKindai University

Principal Investigator

Minaga Kosuke  近畿大学, 医学部, 講師 (30793814)

Project Period (FY) 2021-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords自己免疫性膵炎 / 生活習慣病 / 肥満 / 形質細胞様樹状細胞 / I型インターフェロン / 高脂肪食 / IgG4関連疾患 / タイトジャンクション蛋白質 / 腸内細菌 / Leaky Gut Syndrome / 腸内細菌叢 / 腸管バリア機能 / Dysbiosis / 自然免疫
Outline of Research at the Start

自己免疫性膵炎の発症には、腸内細菌叢の乱れ(Dysbiosis)により産生されるI型IFNやIL-33などの炎症性サイトカインが深く関与している。本疾患は高齢男性に好発することから、飲酒や高脂肪食などの生活習慣の乱れがその発症に影響を及ぼす可能性が考えられる。飲酒や高脂肪食は腸管バリア機能の低下やDysbiosis を来し、Leaky Gut Syndromeと呼ばれる病態を通して生活習慣病を誘導することが知られている。本研究では、自己免疫性膵炎の疫学的特徴と申請者らのこれまでの知見を踏まえ、生活習慣の乱れおよび腸管バリア機能の双方の視点から自己免疫性膵炎の病態解明と新規治療法の開発を目指す。

Outline of Final Research Achievements

Although autoimmune pancreatitis (AIP) predominantly occurs in middle-aged and elderly men, the roles of eating habits and lifestyle in the pathogenesis of AIP are poorly understood. In this study, we examined whether a high-fat diet (HFD), preferred by middle-aged and elderly men, increases sensitivity to experimental AIP. We modeled AIP in MRL/MpJ mice by repeated injections of polyinosinic:polycytidylic acid. HFD exacerbated AIP development and promoted pancreatic accumulation of interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs). Neutralization of type I IFN signaling pathways prevented the development of severe AIP induced by HFD. In contrast, leaky gut was less likely to be associated with the HFD-induced exacerbation of AIP, as was evidenced by the lack of significant alterations in the jejunal or ileal expression of tight junction proteins. These data suggest that HFD exacerbates experimental AIP through the activation of pDCs producing IFN-α.

Academic Significance and Societal Importance of the Research Achievements

自己免疫性膵炎(AIP)はIgG4関連疾患の膵特異的表現型である。AIPは中高年男性に多いという疫学的特徴を有しており、中高年男性が好む高脂肪食がAIPの発症に影響する可能性が考えられるが、高脂肪食による肥満とAIPの関係はこれまで解明されていなかった。そこで、本研究では高脂肪食による肥満が実験的AIPの発症に及ぼす影響を検討した結果、高脂肪食摂取が膵臓におけるpDCの活性化を誘導し、I型IFNの産生を亢進することによりAIPを悪化させることが判明した。今回の研究により高脂肪食摂取による肥満がAIPの危険因子として働く可能性が初めて示され、AIPの発症に生活習慣が関わっていることが示唆された。

Report

(3 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • Research Products

    (13 results)

All 2022 2021

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 10 results,  Open Access: 6 results) Presentation (3 results)

  • [Journal Article] High-fat diet aggravates experimental autoimmune pancreatitis through the activation of type I interferon signaling pathways2022

    • Author(s)
      Sekai Ikue、Minaga Kosuke、Hara Akane、Otsuka Yasuo、Kurimoto Masayuki、Omaru Naoya、Okai Natsuki、Masuta Yasuhiro、Takada Ryutaro、Yoshikawa Tomoe、Kamata Ken、Kudo Masatoshi、Watanabe Tomohiro
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 637 Pages: 189-195

    • DOI

      10.1016/j.bbrc.2022.11.030

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Disruption of the intestinal barrier exacerbates experimental autoimmune pancreatitis by promoting the translocation of <i>Staphylococcus sciuri</i> into the pancreas2022

    • Author(s)
      Yoshikawa Tomoe、Minaga Kosuke、Hara Akane、Sekai Ikue、Kurimoto Masayuki、Masuta Yasuhiro、Otsuka Yasuo、Takada Ryutaro、Kamata Ken、Park Ah-Mee、Takamura Shiki、Kudo Masatoshi、Watanabe Tomohiro
    • Journal Title

      International Immunology

      Volume: 34 Issue: 12 Pages: 621-634

    • DOI

      10.1093/intimm/dxac039

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pancreatic colonization of fungi in the development of severe acute pancreatitis2022

    • Author(s)
      Otsuka Yasuo、Kamata Ken、Minaga Kosuke、Watanabe Tomohiro、Kudo Masatoshi
    • Journal Title

      Frontiers in Cellular and Infection Microbiology

      Volume: 12 Pages: 1-7

    • DOI

      10.3389/fcimb.2022.940532

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Mouse Model of Acute and Chronic Pancreatitis2022

    • Author(s)
      Minaga Kosuke、Watanabe Tomohiro、Kamata Ken、Kudo Masatoshi、Strober Warren
    • Journal Title

      Current Protocols

      Volume: 2 Issue: 4

    • DOI

      10.1002/cpz1.422

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A Mouse Model of Acute and Chronic Pancreatitis2022

    • Author(s)
      Minaga Kosuke、Watanabe Tomohiro、Kamata Ken、Kudo Masatoshi、Strober Warren
    • Journal Title

      Current Protocols in Immunology

      Volume: -

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease2021

    • Author(s)
      Minaga Kosuke、Watanabe Tomohiro、Hara Akane、Yoshikawa Tomoe、Kamata Ken、Kudo Masatoshi
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 713779-713779

    • DOI

      10.3389/fimmu.2021.713779

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] IL-33 as a Critical Cytokine for Inflammation and Fibrosis in Inflammatory Bowel Diseases and Pancreatitis2021

    • Author(s)
      Kurimoto Masayuki、Watanabe Tomohiro、Kamata Ken、Minaga Kosuke、Kudo Masatoshi
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 781012-781012

    • DOI

      10.3389/fphys.2021.781012

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease2021

    • Author(s)
      Hara Akane、Watanabe Tomohiro、Minaga Kosuke、Yoshikawa Tomoe、Kamata Ken、Kudo Masatoshi
    • Journal Title

      World Journal of Gastroenterology

      Volume: 27 Issue: 19 Pages: 2257-2269

    • DOI

      10.3748/wjg.v27.i19.2257

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intestinal Dysbiosis and Autoimmune Pancreatitis2021

    • Author(s)
      Yoshikawa Tomoe、Watanabe Tomohiro、Kamata Ken、Hara Akane、Minaga Kosuke、Kudo Masatoshi
    • Journal Title

      Frontiers in Immunology

      Volume: 12 Pages: 621532-621532

    • DOI

      10.3389/fimmu.2021.621532

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A unique profile of serum cytokines in type 1 autoimmune pancreatitis and chronic rhinosinusitis2021

    • Author(s)
      Yoshikawa Tomoe、Minaga Kosuke、Hara Akane、Sekai Ikue、Otsuka Yasuo、Takada Ryutaro、Kamata Ken、Watanabe Tomohiro、Kudo Masatoshi
    • Journal Title

      Asian Pacific Journal of Allergy and Immunology

      Volume: -

    • DOI

      10.12932/ap-311020-0990

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] 形質細胞様樹状細胞の活性化に着目したIgG4関連疾患の新たな血清バイオマーカーの同定2022

    • Author(s)
      原茜、三長孝輔、鎌田研、渡邉智裕、工藤正俊
    • Organizer
      医学生・研修医の日本内科学会ことはじめ2022
    • Related Report
      2021 Research-status Report
  • [Presentation] 自己免疫性膵炎の発症に関わるサイトカイン・ケモカインネットワークの解明と新規バイオマーカーの同定2021

    • Author(s)
      原茜、吉川智恵、三長孝輔、鎌田研、渡邉智裕、工藤正俊
    • Organizer
      第29回 若手膵臓病研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 鎌田研、渡邉智裕、原茜、瀬海郁衣、大塚康生、三長孝輔、工藤正俊2021

    • Author(s)
      自己免疫性膵炎の発症に関わる腸内細菌叢の解析
    • Organizer
      第58回 日本消化器免疫学会総会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2024-01-30  

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