Exercise Preconditioning-Induced Modification of Gut Microbiota Increases Survival in Cecal Ligation and Perforation (CLP)-Induced Sepsis

Abstract

PURPOSE: To investigate whether exercise preconditioning-induced modification of gut microbiota increases survival in cecal ligation and puncture (CLP)-induced sepsis. METHODS: C57BL/6N male mice at age of 4 weeks were randomly assigned to either control (n=10) or exercise preconditioning (n=10). Mice in the exercise group were subjected to an 8-week-high-intensity treadmill running. Prior to sepsis, the effect of exercise preconditioning on gut microbiota was explored by 16S ribosomal RNA amplification sequencing. Survival probability, organ damage, and pro- and anti-inflammatory cytokines were assessed to investigate whether or not exercise preconditioning-induced changes in gut microbiota modulate host response to CLP-induced sepsis. RESULTS: Along with increased β diversity, exercise preconditioning induced the modification of gut microbiota at species level dominated by the phyla Bacteriodetes, Firmicutes, and Verrucomicrobia and to a less extent by the phylum Cyanobacteria. Preconditioned mice had higher survival (p<0.05) and less organ damage in sepsis compared to control mice. At 8-hr post-sepsis, the preconditioned mice had lower peritoneal interleukin (IL)-1β (p=0.020) and IL-6 (p<0.001) but higher peritoneal interferon (IFN)-γ (p=0.002), IL-10 (p<0.001), and transforming growth factor (TGF)-1β (p<0.001) compared to the control mice. In addition, the preconditioned mice has lower blood growth-regulated oncogene (GRO)-α (p=0.001), monocyte chemoattractant protein (MCP)-1 (p<0.001), macrophage inflammatory protein (MIP) 2 (p<0.001), and tumor necrosis factor (TNF)-α (p=0.003) compared to the control mice. At 20-hr post-sepsis, the preconditioned mice had lower peritoneal IL-1β (p<0.001) and Il-6 (p<0.001) but higher peritoneal TGF-1β (p<0.001) in conjunction with higher blood IL-17A (p=0.002) and TGF-1β (p=0.029) compared to the control mice. CONCLUSIONS: The current findings suggested that exercise preconditioning-induced modification of gut microbiota might contribute to increased survival in sepsis by modulating host response toward the establishment of a balance between pro- and anti-inflammation. Supported by the National Research Foundation funded by the Korean Government (NRF-2018R1D1A1B07048153 and NRF-2016R1A6A3A11932432).