Liver injury and intestinal permeability attenuation in antibiotics pretreatment following Concanavalin A administration in mice

Acute liver failure (ALF) is a syndrome, which result in a rapid loss of hepatic function. It develops from several conditions, including viral hepatitis, a toxin, chemical induced injury or autoimmunity. Intravenous... [ view full abstract ]

Acute liver failure (ALF) is a syndrome, which result in a rapid loss of hepatic function. It develops from several conditions, including viral hepatitis, a toxin, chemical induced injury or autoimmunity. Intravenous administration of Concanavalin(Con) A in mice provides a chemical ­induced experimental model for immune­ mediated liver injury in form of necrosis. In the present study, Con A-induced liver injury that activated through lipopolysaccharide (LPS)/Toll-like receptor-4 (TLR4) pathway of innate immune system is acutely abolished with antibiotics treatment to remove the source of LPS.

Treatment of male, LPS­ sensitive C3H/HeN mice with Con A(15 mg/kg i.v.) as control mice resulted in liver injury as evidenced by increased activity of plasma aminotransferases (ALT and AST), cytokines level (TNF-alpha, IFN-gamma, IL-6) and moderate hepatocellular necrosis (liver stereology and hepatic activity index(HAI) grading) in between 8 to 24 hours compared to significantly reduced of all results (p<0.001) in pretreated (5-6 days) with oral antibiotics (Polymyxin B (150mg/kg), Neomycin (450mg/kg)) mice. Furthermore, LPS-sensitive mice exhibited significantly reduced recovery levels of urine sucralose and lactulose/mannitol ratio using HPLC-MS/MS in antibiotics pretreated mice (p<0.001) in comparison to control mice.  Acute blockade of LPS/TLR4 pathway using antibiotics treatment to eliminate gram negative bacteria in the gut resulted in reduced liver injury and permeability at distal small intestine and colon in pretreated with antibiotics mice, indicating that this pathway is dependent when LPS sources was removed in the gut in the inflammatory response of the liver to Con A