O10: METFORMIN TREATMENT IMPROVES LYMPHOCYTE METABOLISM IN A MOUSE MODEL OF MAJOR SURGERY

Abstract

Abstract Introduction Lymphopaenia is common after major surgery and associated with poor outcome. T-lymphocytes restrain damaging innate inflammation. Major surgery impairs T-lymphocyte metabolism in humans, which promotes lymphopaenia. Metformin is known to improve mitochondrial bioenergetics in models of inflammation. Firstly, we hypothesised that a mouse model of major surgery would demonstrate impaired T-lymphocyte metabolism and secondly, that metformin treatment in vivo would reverse the phenotype. Method Male C57Bl/6 mice aged between 8 and 12 weeks were housed in a specific pathogen free environment with free access to food and water. Animals were dosed with either vehicle (phosphate buffered saline, 20 ml/kg) or metformin (250 mg/kg) daily via intraperitoneal injection for four days prior to and after surgery. A partial hepatectomy was performed under isofluorane anaesthesia. Naive littermates were used as controls. All experiments were performed according to the Animals (Scientific Procedures) Act 1986. Splenic T-lymphocytes were isolated by negative selection using magnetic beads. Mitochondrial bioenergetics were measured using a Seahorse Extracellular Flux analyser. Parametric statistical analysis was performed and a p-value < 0.05 was chosen to represent significance. Result T-lymphocytes demonstrated reduced spare respiratory capacity (SRC, 285 vs 497 %, p=0.004) after surgery compared to naive controls. Metformin treatment in vivo reversed this observation and SRC was comparable to naive (437 vs 497 %, p=0.34). Metformin treatment in vitro increased spare respiratory capacity in T-lymphocytes from mice after surgery compared to naive (change from untreated, 187 vs 91 %, p=0.03). Conclusion Perioperative metformin treatment improved T-lymphocyte metabolism in a mouse model of major surgery. Take-home message Metformin is a potential treatment for the lymphocyte metabolic dysfunction observed after surgery.