Dynamic Changes and Diagnostic Value of Plasma Tryptophan and Its Metabolites in Different Stages of Hepatic Encephalopathy Detected by Ultra‐Performance Liquid Chromatography–Tandem Mass Spectrometry

ABSTRACT Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver disease. Early diagnosis remains challenging due to insidious onset and lack of stage‐specific biomarkers. Tryptophan (TRP) metabolism is closely linked to the gut–liver–brain axis and is dysregulated in HE. However, most prior studies only compared a single HE model with controls, failing to uncover stage‐to‐stage dynamic alterations. Here, we quantified plasma TRP metabolites across HE stages 1–4 in a rat model using UPLC‐MS/MS. Compared with the Sham group, ALT and AST peaked in HE2 and declined in HE3–HE4, reflecting massive acute hepatocyte necrosis followed by enzyme exhaustion, whereas histological liver injury and modified neurological severity score (mNSS) scores progressively worsened. TRP metabolites exhibited stage‐dependent shifts: TRP, kynurenine, and XA fell, whereas 5‐HT and IAA rose in HE1; TA increased in HE2‐HE3; KA and XA elevated, but IPA dropped in HE4. These results indicated that plasma TRP metabolic profiles are closely linked to liver injury and neurological dysfunction during HE progression and serve as candidate staging biomarkers in rat models, awaiting further clinical‐cohort validation. From a broader perspective, this study reveals dynamic reprogramming of TRP metabolism in HE, providing preclinical evidence for metabolomics‐oriented diagnosis and targeted therapy.