肝硬変は依然として「生命予後」のみならず人類の「生命の質」を脅かし続けている。四塩化炭素肝線維化回復マウスモデルを用いて、骨髄由来単球細胞の自然免疫を担うTLR4が蓄積された細胞外基質の消退に寄与するMMP12の発現増強に必須であることを明らかにし、その過程に腸内細菌、特にErysipelotrichaceae属の存在、FXR拮抗能を有する胆汁酸Tauro-βMCAの低下、MMP誘導能を有する胆汁酸7-oxo-LCAの増加に関連することを突き止めた。また、肝硬変患者の観察研究を用いでAcute-on-chronic肝不全「再発」と「誘因」に関連する臨床表現型の特徴を特定した。
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.

研究種目 : 若手研究
研究期間 : 2019～2020
課題番号 : 19K17502
研究分野 : 肝線維化