A key role of gut microbiota-vagus nerve axis and gut microbiota-spleen axis in sleep deprivation-mediated aggravation of systemic inflammation after LPS administration

Background: Sleep deprivation (SD) is shown to be correlated with exacerbated systemic inflammation after sepsis. However, the underlying mechanisms remain unclear. Methods: : In this study, mice were intraperitoneally injected with lipopolysaccharide (LPS) followed by 3 consecutive days of SD. The subdiaphragmatic vagotomy (SDV) was performed 2 weeks before LPS injection. The pseudo germ-free mouse model was created by administering antibiotics for 14 consecutive days, and then fecal microbiota transplant (FMT) was performed by gavaging supernatant from fecal suspension of septic mice with or without SD into pseudo germ-free mice with or without SDV or splenectomy. Splenectomy was performed 14 days prior to antibiotics administration. Results: : We found that SD after LPS administration increased the plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), reduced IL-10 plasma leve, increased spleen weight, and promoted pathological injury and IL-6 expression in lung, liver and kidney. Post-septic sleep deprivation had no effects on the diversity of gut microbiota. However, the relative abundance of Proteobacteria and its subgroups were increased in septic mice received SD. Pseudo germ-free mice transplanted with fecal bacteria from septic mice subjected to SD developed splenomegaly, systemic inflammation, organ inflammation and damage as their donors do. Intriguingly, SDV abolished the aggravated effects of SD on splenomegaly and inflammatory organ injury in septic mice received SD or in pseudo germ-free mice transplanted with fecal bacteria from septic mice subjected to SD. Furthermore, Splenectomy also abrogated the increase in IL-6 and TNF-α plasma levels and the decrease in IL-10 plasma level in pseudo germ-free mice transplanted with fecal bacteria from septic mice subjected to SD. Conclusions: : Taken together, our results suggest that gut microbiota-vagus nerve axis and gut microbiota-spleen axis could play key roles in modulating systemic inflammation induced by SD after LPS administration.