Abstract
BackgroundGut–microbiota–brain axis links the relationship between intestinal microbiota and sepsis-associated encephalopathy (SAE). However, the key mediators between them remain unclear.MethodsMemory test was determined by Water maze. Intestinal flora was measured by 16S RNA sequencing. Neurotransmitter was detected by high-performance liquid chromatography (HPLC). Histopathology was determined by H&E, immunofluorescence (IF), and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining. Flow cytometry was employed to determine the proportion of macrophages.ResultsFecal microbiota transplantation (FMT) relieved hippocampus impairment of SAE rats by inhibiting inflammation cytokine secretion, the expression of IBA-1 and neurotransmitter disturbance, and cell apoptosis and autophagy, accompanied by the reduced M1 polarization and M1 pro-inflammation factors produced by macrophages in mesenteric lymph nodes (MLNs). Actually, M1 polarization in SAE rats depended on intestinal epithelial cell (IEC)-derived exosome. GW4869-initiated inhibition of exosome secretion notably abolished M1 polarization and the secretion of IL-1β. However, GW4869-mediated improvement of hippocampus impairment was counteracted by the delivery of recombinant interleukin (IL)-1β to hippocampus. Mechanistically, IEC-derived exosome induced the excessive circulating IL-1β produced by CP-R048 macrophages, which subsequently induced damage and apoptosis of hippocampal neurons H19-7 in an autophagy-dependent manner. And reactivation of autophagy facilitates intestinal IL-1β-mediated hippocampal neuron injury.ConclusionCollectively, intestinal flora disturbance induced the exosome release of IECs, which subsequently caused M1 polarization in MLNs and the accumulation of circulating IL-1β. Circulating IL-1β promoted the damage and apoptosis of neurons in an autophagy-dependent manner. Possibly, targeting intestinal flora or IEC-derived exosome contributes to the treatment of SAE.
Highlights
Sepsis is a fatal organ dysfunction caused by host response imbalance induced by infection
Cecal ligation and puncture (CLP)-induced Sepsis-associated encephalopathy (SAE) rats appeared to have a robustly decreased neurologic deficit score at day 1 postoperatively compared to the sham-operated rats that became no difference between them at day 7 postoperatively (Figure 1A)
Based on the Morris water maze that was performed on day 9 after surgery, both the mobile distance and time percent during platform quadrant significantly reduced in SAE rats, while these were reversed in fecal microbiota transplantation (FMT)-challenged SAE rats (Figures 1B, C)
Summary
Sepsis is a fatal organ dysfunction caused by host response imbalance induced by infection. Sepsis and its related complications are the main cause of death in critically ill patients (Singer et al, 2016). Sepsis-associated encephalopathy (SAE) is one of the common complications and the most common encephalopathy in patients of sepsis relating to poor prognosis and long-term cognitive dysfunction (Gofton and Young, 2012). It is reported that many factors are involved in the pathogenesis of SAE, including inflammatory cytokines, blood–brain barrier breakdown, ischemic process, neurotransmitter changes, and mitochondrial dysfunction, but the specific mechanism has not been figured out (Adam et al, 2013). Future research needs to clarify the key points of pathophysiological damage such as brain inflammatory response, blood–brain barrier, and abnormal neurotransmitter transmission preventing permanent damage to the brain function of SAE patients.
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