Mechanism of immune tolerance in the liver via gut-liver axis

• Project/Area Number: 18K15794
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Keio University
• Principal Investigator: TANIKI NOBUHITO 慶應義塾大学, 医学部(信濃町), 助教 (20627129)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 腸肝臓軸 / 免疫寛容 / マクロファージ / NNMT / 1-MNA / 腸肝相関

Outline of Final Research Achievements

The gut-liver axis is of clinical importance as a potential therapeutic target in a wide range of liver diseases. In this study, we demonstrated that IL-10-producing macrophages contribute to immune tolerance in the inflamed liver under intestinal barrier disruption in a murine tandem model of dextran sulfate sodium (DSS) colitis and concanavalin A (Con A) hepatitis. Intestinal barrier disruption protected mice from subsequent liver injury. The protective effect of DSS-Con A was canceled in gut-sterilized mice, suggesting that gut microbiota and their metabolites play a substantial role in this process. We identified 1-methylnicotinamide (1-MNA) as a candidate metabolite capable of suppressing liver injury with the potential to induce IL-10-producing macrophages and this effect was abrogated by gut sterilization. Collectively, our results provide a mechanistic insight into the regulation of immunological balance in the liver via the gut-liver axis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、まだ解明されていない肝臓特有の免疫応答・免疫寛容の誘導機序を腸肝相関の観点から明らかにすることを目的とし、LPSトレランス非依存的な肝臓内の免疫寛容の新たな機序に関して、IL-10産生マクロファージ、nicotinamide N-methyltransferase(NNMT)、1-methylnicotinamide(1-MNA)が関与する可能性を見出した。今後、これらをターゲットとした肝疾患の診断方法の開発や、治療薬の臨床応用への展開が期待され、学術的、社会的に大きな意義を有する成果と考えられる。

Research Products

• [Journal Article] Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. (2019)
  • Author(s): Koda Y, Nakamoto N, Chu P, Ugamura A, Teratani T, Shiba S, Taniki N, Sujino T, Miyamoto K, Mikami Y, Suzuki T, Yamaguchi A, Morikawa R, Sato K, Yoshimoto T, Kanai K.
  • Journal Title: J Clin Invest Volume: 129(8) Issue: 8 Pages: 3201-3213
  • DOI: 10.1172/jci125863
  • Peer Reviewed / Open Access
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intestinal barrier regulates immune responses in the liver via IL-10-producing macrophages. (2018)
  • Author(s): Taniki N, Nakamoto N, Chu PS, Mikami Y, Amiya T, Teratani T, Suzuki T, Tsukimi T, Fukuda S, Yamaguchi A, Shiba S, Miyake R, Katayama T, Ebinuma H, Kanai T.
  • Journal Title: JCI Insight. Volume: 3 Issue: 12
  • DOI: 10.1172/jci.insight.91980
  • Peer Reviewed / Open Access
• [Presentation] 腸肝臓軸を介した肝臓における免疫応答調整機序の解明 (2018)
  • Author(s): 谷木信仁、中本伸宏、金井隆典
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] 腸肝相関を介した肝臓免疫寛容誘導機序の解明 (2018)
  • Author(s): 谷木信仁、中本伸宏、金井隆典
  • Organizer: 第39回日本炎症・再生医学会
• [Presentation] 腸肝相関からみた肝臓免疫寛容誘導機序の解明 (2018)
  • Author(s): 谷木信仁、中本伸宏、金井隆典
  • Organizer: 第54回日本肝臓学会総会