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

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 (CCl4) 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.

Rifaximin Improves Spatial Learning and Memory Impairment in Rats with Liver Damage-Associated Neuroinflammation

“…We show here that CCL2 is increased in the hippocampus of rats with mild liver damage. Moreover, we previously showed that these rats have increased plasma levels of CX3CL1 at 4 weeks of CCl 4 treatment [ 36 ]. This suggest that the increased levels of CCL2 in the hippocampus and of CX3CL1 in blood of these rats would contribute to the infiltration of monocytes in the hippocampus.…”

“…Male Wistar rats (Charles River) weighing 150–180 g were intraperitoneally injected 3 times/week during 4 weeks with 1 mL/kg body weight of carbon tetrachloride (CCl 4 ) to induce liver damage. CCl 4 was prepared 1:10 ( v : v ) in corn oil as previously described [ 36 , 41 ] Control rats were intraperitoneally injected with corn oil. Rifaximin (Sigma, St. Louis, MO, USA) was dissolved in 100% ethanol and administered orally (20 mg/kg body weight).…”

“…Control rats were orally treated with the same volume of 100% ethanol. At 4 weeks of CCl 4 injections, this animal model shows liver steatosis, inflammation and fibrosis, but not hyperammonemia [ 36 ], similar to mild steatohepatitis in humans. The experiments were approved by the Ethic Committee of Animal Experimentation of our Center and by the Conselleria de Agricultura of Generalitat Valenciana and were performed in accordance with guidelines of the Directive of the European Commission (2010/63/EU) for care and management of experimental animals.…”

“…We have recently shown that mild liver failure in rats, similar to steatohepatitis in human patients, induces infiltration of lymphocytes and macrophages in the cerebellum [ 36 ]. We have also now analyzed infiltration of immune cells in the hippocampus and its possible relationship with neuroinflammation and cognitive impairment.…”

Acute Cerebellar Inflammation and Related Ataxia: Mechanisms and Pathophysiology

“…Thus, the reagent could impose another therapeutic option for treating cerebellar inflammation. They also suggest that Rifampicin restored motor incoordination by peripheral inflammation in rats [228]. It is interesting that a tropical Southeast Asian fruit named noni (Morinda citrifolia L.) showed anti-inflammatory activity in microglial cells.…”