Related Experiment Video
Updated: May 27, 2025
Intracerebroventricular Delivery of Gut-Derived Microbial Metabolites in Freely Moving Mice
Published on: June 2, 2022
Extracellular vesicles from Lacticaseibacillus paracasei reduce neuroinflammation in hippocampus and restore some
Paula Izquierdo-Altarejos1, Yaiza M Arenas2, Carmina Montoliu3
1Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Abstract:
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.
Insights
Extracellular vesicles (EVs) from L. paracasei probiotics can reverse cognitive impairment and neuroinflammation in hyperammonemic rats. These EVs show potential for treating minimal hepatic encephalopathy (MHE) in cirrhotic patients.
Area of Science:
- Neuroscience
- Gastroenterology
- Microbiology
Background:
- Minimal hepatic encephalopathy (MHE) impairs quality of life in cirrhotic patients.
- Hyperammonemia, a key factor in MHE, causes cognitive deficits via neuroinflammation and altered hippocampal neurotransmission.
- Probiotics may offer therapeutic benefits for MHE, potentially through bacterial extracellular vesicles (EVs).
Purpose of the Study:
- To evaluate if intravenous L. paracasei EVs improve memory and learning in hyperammonemic rats.
- To determine if these EVs reduce neuroinflammation in the hippocampus.
- To elucidate the underlying mechanisms using ex vivo hippocampal slice studies.
Main Methods:
- Intravenous administration of L. paracasei EVs to hyperammonemic rats.
- Assessment of cognitive function (memory and learning) in treated rats.
- Ex vivo analysis of hippocampal slices to investigate molecular pathways, including glial activation, cytokine expression (TNFα, IL-1β), receptor activation (TNFR1, IL-1R, TrkB), and neurotransmitter receptor expression (NMDA, AMPA).
Main Results:
- Intravenous L. paracasei EVs reversed cognitive impairment and reduced glial activation in the hippocampus of hyperammonemic rats.
- Ex vivo studies revealed that hyperammonemia upregulates TNFα, TNFR1, S1PR2, IL-1β, CCL2, BDNF, and alters glutamatergic receptor expression (NR2B, GluA2, GluA1).
- L. paracasei EVs restored the TNFα-TNFR1-S1PR2-IL-1β-CCL2-BDNF-TrkB pathway, normalized glutamatergic neurotransmission, and improved cognitive function.
Conclusions:
- L. paracasei EVs effectively reduce neuroinflammation and cognitive deficits in a rat model of hyperammonemia and MHE.
- EVs from L. paracasei restore critical molecular pathways involved in neuroinflammation and synaptic plasticity.
- These findings suggest a potential therapeutic role for L. paracasei EVs in improving cognitive function in cirrhotic patients with MHE.
