Alteration of Bile Acids and Omega-6 PUFAs Are Correlated With the Progression and Prognosis of Drug-Induced Liver Injury.

Background & Aims: Drug-induced liver injury (DILI) is one of the leading causes of liver failure with some of the patients progressed to chronic DILI. The mechanisms underlying the severity and chronicity of DILI are poorly elucidated and the biomarkers are limited. Metabolites and gut microbiota played a crucial role in the development of various liver diseases. Herein, a systematic analysis of serum metabolites and gut microbiota was performed in DILI patients, aiming to identify metabolites correlated with the progression and clinical prognosis of DILI. Methods: Various serum metabolites were quantitated using a metabolite array technology in this prospective study. Gut microbiome compositions and the expression profiles of liver genes were determined in patients with DILI and healthy controls. Results: Metabolomic analysis revealed that bile acids (BAs) and polyunsaturated fatty acids (PUFAs) were closely related to DILI severity and chronicity respectively. The ratios of serum primary/secondary BAs and omega-6/omega-3 PUFAs were elevated in DILI patients. A model established by adrenic acid (AdA) and aspartic acid (Asp) exerts good performance for predicting the chronicity of DLIL. Hepatic transcriptome revealed enhanced expression of PUFA peroxidation and supressed expression of BA synthesis related genes in DILI patients. In addition, Lactic acid bacteria and BA converting bacteria were increased in gut of DILI patients. Besides, elevated serum malondialdehyde (MDA) and fibroblast growth factor 19 (FGF19) was observed in DILI patients. Conclusion: BAs and PUFAs could be potent markers for the severity and chronicity of DILI respectively. The panel of AdA and Asp could be ideal predictive model for the risk of chronicity at the acute stage of DILI. Gut microbiota might act as a negative feedback mechanism to maintain the homeostasis of BAs and PUFAs via FGF19 signalling and PUFA saturation, respectively. Our study revealed novel biomarkers for severe and chronic DILI and provided new therapeutic targets for DILI.