Rifaximin Prevents T-Lymphocytes and Macrophages Infiltration in Cerebellum and Restores Motor Incoordination in Rats with Mild Liver Damage

Autores de CIPF

• Tiziano Balzano

  Autor

• Paola Leone

  Autor

• Gergana Mincheva Ganeva

  Autor

• M Carmen Castro Quero

  Autor

• Lestteriel Ignacio Reyes Castillo

  Autor

• Chusé Manuel Ramón Valero

  Autor

• Michele Malaguarnera

  Autor

• 

  Marta Llansola Gil

  Autor

• 

  Vicente Felipo Orts

  Autor

Grupos de Investigación

• Laboratorio de Neurobiología

  

  Jefe/a de Grupo

  Vicente Felipo Orts

Abstract

In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCI4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis.

Keywords

• liver disease; minimal hepatic encephalopathy; chemokines; neuroinflammation; neurotransmission; cerebellum