Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE). Hyperammonemia (HA) and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE. The cerebellum is one of the main cerebral regions affected in MHE. Rats with chronic HA show some motor and cognitive alterations reproducing neurological impairment in cirrhotic patients with MHE. Neuroinflammation and altered neurotransmission and signal transduction in the cerebellum from hyperammonemic (HA) rats are associated with motor and cognitive dysfunction, but underlying mechanisms are not completely known. The aim of this work was to use a multi-omic approach to study molecular alterations in the cerebellum from hyperammonemic rats to uncover new molecular mechanisms associated with hyperammonemia-induced cerebellar function impairment. We analyzed metabolomic, transcriptomic, and proteomic data from the same cerebellums from control and HA rats and performed a multi-omic integrative analysis of signaling pathway enrichment with the PaintOmics tool. The histaminergic system, corticotropin-releasing hormone, cyclic GMP-protein kinase G pathway, and intercellular communication in the cerebellar immune system were some of the most relevant enriched pathways in HA rats. In summary, this is a good approach to find altered pathways, which helps to describe the molecular mechanisms involved in the alteration of brain function in rats with chronic HA and to propose possible therapeutic targets to improve MHE symptoms.

肝硬化患者可能发展为隐匿性或轻度肝性脑病 (MHE)。高氨血症 (HA) 和外周炎症在诱导 MHE 的认知和运动改变中发挥协同作用。小脑是受 MHE 影响的主要大脑区域之一。患有慢性 HA 的大鼠表现出一些运动和认知改变，这些改变在患有 MHE 的肝硬化患者中再现了神经功能障碍。高氨血症 (HA) 大鼠小脑的神经炎症和改变的神经传递和信号转导与运动和认知功能障碍有关，但其潜在机制尚不完全清楚。这项工作的目的是使用多组学方法研究高氨血症大鼠小脑的分子变化，以揭示与高氨血症诱导的小脑功能障碍相关的新分子机制。我们分析了对照组和 HA 大鼠相同小脑的代谢组学、转录组学和蛋白质组学数据，并使用 PaintOmics 工具对信号通路富集进行了多组学综合分析。小脑免疫系统中的组胺能系统、促肾上腺皮质激素释放激素、环 GMP 蛋白激酶 G 通路和细胞间通讯是 HA 大鼠中最相关的一些富集通路。总而言之，这是找到改变的途径的好方法，