Metabolomics study of the effects of zinc sulfate in minimal hepatic encephalopathy

Abstract Minimal hepatic encephalopathy (MHE) is a cognitive, motor, and sleep-related disorder resulting from liver impairment, often linked to elevated ammonia levels. Zinc deficiency is common in patients with cirrhosis and has been associated with cognitive dysfunction. Zinc supplementation has shown promise in improving MHE, but the underlying metabolic mechanisms remain unclear. To investigate the therapeutic effects of zinc sulfate on metabolic changes in the striatum of MHE rats using 1H-NMR-based metabolomics. We established a rat model of MHE using partial portal vein ligation and administered zinc sulfate to a subset of rats. A control group was included for comparison. Behavioral assessments of spatial learning and memory were performed using the Morris water maze (MWM). Striatum metabolites were analyzed through 1H-NMR spectroscopy, and key metabolic pathways were identified using statistical analyzes. Zinc supplementation improved cognitive performance in the MHE rats, evidenced by reduced escape latency in the MWM. Metabolomics analysis identified 47 metabolites, with 10 key metabolites showing significant differences between MHE and control groups. Zinc supplementation normalized several disrupted pathways, including those related to glycolysis, glutamine metabolism, and BCAA metabolism. Key metabolites affected by zinc included lactate, alanine, glutamate, and branched-chain amino acids. Zinc sulfate supplementation alleviates cognitive impairments in MHE rats by restoring disrupted metabolic pathways, including nitrogen metabolism. The findings suggest that zinc plays a therapeutic role in improving brain function in MHE.