Extracellular vesicles from plasma of patients with minimal hepatic encephalopathy induce neuroinflammation and cognitive impairment in rats, which are prevented by treating the patients with rifaximin

Minimal hepatic encephalopathy (MHE) appearance is associated with a pro-inflammatory shift in peripheral inflammation. Treatment of MHE patients with rifaximin reverses this shift in and improves MHE. How peripheral alterations are transmitted to brain to induce MHE remains unclear. In rats with MHE, plasma extracellular vesicles (EV) induce cognitive impairment. We hypothesized that in cirrhotic patients, the shift in peripheral inflammation is associated with alterations in plasma EV which contribute to induce MHE in cirrhotic patients. We also hypothesized that rifaximin treatment reverses MHE by reversing changes in EV. The aims were: 1) assess if injecting rats with plasma EV from MHE patients (MHE-EV) induce cognitive impairment, 2) identify the underlying mechanisms, 3) assess if treating MHE patients with rifaximin reverses the pathological effects of their EV and, 4) if this is associated with reversal of changes in EV protein cargo. We isolated plasma EV from cirrhotic patients without and with MHE, treated or not with rifaximin, and controls and injected them to rats. We analysed cognitive function, neuroinflammation and glutamate receptors membrane expression in hippocampus. MHE-EV, but not EV from patients without MHE show increased TNFα content and trigger a strong cognitive impairment in rats. This is mediated by altered membrane expression of AMPA and NMDA glutamate receptors in hippocampus, due to increased neuroinflammation, with glial activation and enhanced activation of the TNFα-TNFR1-S1PR2-IL-1β-IL-1R pathway. The EV from MHE patients treated with rifaximin did not show increased TNFα levels and did not induce the above pathological effects. Rifaximin treatment reverses the changes in the cargo of the EV from plasma of MHE patients, including the increase in TNFα and eliminates the pathological effects of the EV. The data show that in cirrhotic patients the presence of MHE is associated with changes in their blood EV which transmit pathological effects to the brain, inducing neuroinflammation and altered glutamatergic neurotransmission in hippocampus which leads to cognitive impairment. Rifaximin treatment reduces TNFα and other altered proteins in the EV and reverses their pathological effects. EV could be a therapeutic target to improve MHE by modifying EV content or blocking the TNFα effects.