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

2019 Fiscal Year Final Research Report

• 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
• 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.

Free Research Field

消化器内科学関連

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。