Extracellular vesicles from Lacticaseibacillus paracasei reduce neuroinflammation in hippocampus and restore some cognitive functions in hyperammonemic rats.

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.