Mechanism of the Plasticity of Innate Immunity during Metabolic Re-compensation in Liver Cirrhosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17502
• 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: CHU Po-sung 慶應義塾大学, 医学部(信濃町), 講師 (80570689)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 自然免疫 / fibrolysis / 腸内細菌 / 胆汁酸 / acute-on-chronic肝不全

Outline of Final Research Achievements

Immune cells are key players in both fibrogenesis and fibrolysis. During carbon tetrachloride-induced liver fibrosis resolution. Significant retardation of liver fibrosis resolution was observed as TLR4-signaling was pharmacologically inhibited in vivo. Single-cell transcriptome analysis revealed the emergence of a Tlr4-expressing myeloid cell cluster with a restorative phenotype during resolution. Metagenomic predictive functional profiling demonstrated enrichment of multiple metabolic pathways linking to the significant increase in the proportion of family Erysipelotrichaceae during resolution. Quantitative dynamics of farnesoid X receptor (FXR)-stimulating secondary bile acids (BAs), namely 7-oxo-lithocholic acids, and inhibitory tauro-β-muricholic acids, were phenotypically correlated with resolution.
In addition, we also clarified that vulnerability to recurrent episodes of acute-on-chronic liver failure triggered by indeterminate precipitants in patients with liver cirrhosis.

Free Research Field

肝線維化

Academic Significance and Societal Importance of the Research Achievements

TLR4は肝星細胞におけるTGF-β径路を増強し肝線維化の線維化形成(fibrogenesis)を促進すると知られているが、線維化消退(fibrolysis)に対する影響は不明であった。本研究の結果によって、骨髄由来単球におけるTLR4のfibrolysisの役割が新たに解明されると同時に、生体内の腸内細菌または胆汁酸-FXRを介した制御機序が初めて明らかになり、抗線維化治療の開発に新たな突破点になり得る知見が得られた。
また、観察研究より、「急性誘因不明」は肝硬変患者における急性非代償化・ACLFの再発に寄与することが明らかになり、今後橋渡し研究の臨床マーカーになり得る。