Intestinal Epithelial Cell Exosome Launches IL-1β-Mediated Neuron Injury in Sepsis-Associated Encephalopathy

Front Cell Infect Microbiol. 2022 Jan 17:11:783049. doi: 10.3389/fcimb.2021.783049. eCollection 2021.

Abstract

Background: Gut-microbiota-brain axis links the relationship between intestinal microbiota and sepsis-associated encephalopathy (SAE). However, the key mediators between them remain unclear.

Methods: Memory 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.

Results: Fecal 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.

Conclusion: Collectively, 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.

Keywords: IL-1β; exosome; fecal microbiota transplantation; intestinal epithelial cell; mesenteric lymph nodes; sepsis-associated encephalopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Cells
  • Exosomes*
  • Fecal Microbiota Transplantation
  • Neurons
  • Rats
  • Sepsis-Associated Encephalopathy*