基于呼出气及血清代谢组学的DILI慢性化体质倾向及代谢紊乱机制研究

药物性肝损伤（DILI）在撤除药物因素后仍会出现慢性病程，甚则迅速进展至肝硬化，但其发生机制不清，风险无法预测，极大地限制了临床上对慢性DILI患者的早期发现和有效治疗。既往文献报道，体质差异很可能是DILI慢性化的重要原因。前期研究发现，急、慢性DILI患者的中医体质特征存在明显差异，且与其免疫代谢状态异常有关。为此，本项目建立DILI队列，收集中医体质信息，采集DILI患者的呼出气、血清标本，利用代谢组学分析DILI慢性化主要中医体质的代谢特征谱，筛查鉴定其差异性呼出气及血清代谢物；采用通路富集分析等方法，关联上述代谢物构成“全景”代谢组学筛选DILI慢性化主要中医体质的免疫代谢靶标通路及关键免疫调控代谢标志物；评价关键免疫调控代谢标志物对DILI慢性化主要中医体质的免疫细胞亚群的调控作用，初步阐明中医体质参与DILI慢性化的机制，为DILI慢性化的及早识别和有效防控提供新参考。

Some patients with drug-induced liver injury (DILI) after the drug withdrawal could develop the chronicity, or even cirrhosis rapidly. However, the early recognition and effective treatment for chronic DILI are very limited and difficult because of the unknown mechanism and unpredictable risks. According to previously published reports, host factor could be the main cause of the chronicity in patients with DILI. In a case-series study, the proportions of patients with Traditional Chinese Medicine (TCM) constitutions are markedly different between patients with acute DILI and chronic DILI. This is likely to be influenced by immunometabolic disorders in patients with chronic DILI. In this project, the main TCM constitution of patients with chronic DILI is evaluated and identified based on the clinical data and the information of TCM constitutions in a DILI cohort. Subsequently, exhaled breath condensate (EBC) and serum in patients with chronic and non-chronic DILI are collected. Using metabolomics, different characteristics of EBC and serum metabolites between patients with chronic and non-chronic DILI are described, and those in patients with chronic DILI accompanied by the main TCM constitution are analyzed. The relevant metabolic biomarkers of the main TCM constitution in patients with chronic DILI are identified and selected according to biological databases. For predicting the chronicity in patients with DILI, a prognostic model is constructed by a panel of EBC and serum selected and identified metabolites associated with immune. The identified biomarkers or the prognostic model are externally validated for the recognition and warning of the chronicity of DILI. Consequently, according to the present knowledge of metaflammation and immunometabolic disorders, the pathways and relevant mechanism for the main TCM constitution of chronic DILI were studied in metabolites related with the immune response and peripheral blood mononuclear cell (PBMC) samples of patients with chronic DILI. This study will contribute to improving the early recognition, diagnosis and prevention for the chronic DILI.