Izquierdo-Altarejos Paula, Arenas Yaiza M, Montoliu Carmina, Pérez-Martínez Gaspar, Llansola Marta, Felipo Vicente
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Laboratory of Lactic Acid Bacteria and Probiotics, Department of Biotechnology, Instituto de Agroquímica y Tecnología de Alimentos (C.S.I.C.), Valencia, Spain; Departamento de Patología, Facultad de Medicina, Universidad Valencia, Valencia, Spain; INCLIVA Instituto de Investigación Sanitaria, Valencia, Spain.
Microbiol Res. 2025 May;294:128101. doi: 10.1016/j.micres.2025.128101. Epub 2025 Feb 13.
Cirrhotic patients may show minimal hepatic encephalopathy (MHE) which impairs life quality and span. There is a need of new safe treatments for MHE. Hyperammonemia is a main contributor to MHE. Hyperammonemic rats reproduce the cognitive impairment present in patients with MHE, which is mediated by neuroinflammation and altered glutamatergic neurotransmission in hippocampus. Probiotics induce positive effects in MHE patients, which could be mediated by bacterial extracellular vesicles (EVs). The aims of this work were to evaluate in hyperammonemic rats: 1) if intravenous administration of EVs from L. paracasei improves memory and learning and 2) reduces neuroinflammation in hippocampus and 3) to study the mechanisms involved using an ex vivo approach. It is shown that intravenous injection of EVs from L. paracasei reverses glial activation in hippocampus and cognitive impairment in hyperammonemic rats. Ex vivo studies in hippocampal slices show that hyperammonemia increases TNFα and TNFR1 and S1PR2 membrane expression and activation, leading to increased IL-1β content and activation of IL-1 receptor and of Src. This increases CCL2 and BDNF and TrkB activation. This leads to increased membrane expression of the NR2B subunit of the NMDA receptor and of the GluA2 subunit of AMPA receptors and reduced membrane expression of the GluA1 subunit, leading to cognitive impairment. EVs from L. paracasei reduce neuroinflammation in hyperammonemic rats and restore the function of the TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB pathway, glutamatergic neurotransmission and cognitive function in rats with hyperammonemia and MHE. This suggests that these EVs could also improve cognitive function in cirrhotic patients with MHE.
肝硬化患者可能会出现轻微肝性脑病（MHE），这会损害生活质量和寿命。需要针对MHE开发新的安全治疗方法。高氨血症是MHE的主要促成因素。高氨血症大鼠再现了MHE患者存在的认知障碍，这是由神经炎症和海马体中谷氨酸能神经传递改变介导的。益生菌对MHE患者有积极作用，这可能由细菌细胞外囊泡（EVs）介导。本研究的目的是在高氨血症大鼠中评估：1）静脉注射副干酪乳杆菌的EVs是否能改善记忆和学习能力；2）是否能减轻海马体中的神经炎症；3）使用体外方法研究其中涉及的机制。结果表明，静脉注射副干酪乳杆菌的EVs可逆转高氨血症大鼠海马体中的神经胶质细胞活化和认知障碍。海马体切片的体外研究表明，高氨血症会增加肿瘤坏死因子α（TNFα）、肿瘤坏死因子受体1（TNFR1）和鞘氨醇-1-磷酸受体2（S1PR2）的膜表达和活化，导致白细胞介素-1β（IL-1β）含量增加以及IL-1受体和Src的活化。这会增加趋化因子配体2（CCL2）、脑源性神经营养因子（BDNF）和酪氨酸激酶受体B（TrkB）的活化。这会导致N-甲基-D-天冬氨酸受体（NMDA受体）的NR2B亚基和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPA受体）的GluA2亚基的膜表达增加，而GluA1亚基的膜表达减少，从而导致认知障碍。副干酪乳杆菌的EVs可减轻高氨血症大鼠的神经炎症，并恢复高氨血症和MHE大鼠中TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB通路、谷氨酸能神经传递和认知功能。这表明这些EVs也可能改善患有MHE的肝硬化患者的认知功能。
