INTESTINAL EPITHELIAL-SPECIFIC OCCLUDIN DELETION WORSENS GUT PERMEABILITY AND SURVIVAL FOLLOWING SEPSIS

ABSTRACT: Sepsis induces intestinal hyperpermeability, which is associated with higher mortality. Occludin is a tight junction protein that plays a critical role in regulating disease-associated intestinal barrier loss. This study examined the role of intestinal occludin on gut barrier function and survival in a preclinical model of sepsis. Intestinal epithelial-specific occludin knockout (occludin KO IEC ) mice and wild type controls were subjected to intra-abdominal sepsis and sacrificed at predetermined endpoints for mechanistic studies or followed for survival. Occludin KO IEC mice had a significant increase in intestinal permeability, which was induced only in the setting of sepsis as knockout mice and control mice had similar baseline permeability. The worsened barrier was specific to the leak pathway of permeability, without changes in either the pore or unrestricted pathways. Increased sepsis-induced permeability was associated with increased levels of the tight junction ZO-1 in occludin KO IEC mice. Occludin KO IEC mice also had significant increases in systemic cytokines IL-6 and MCP-1 and increased bacteremia. Furthermore, occludin KO IEC mice had higher levels of jejunal IL-1β and MCP-1 as well as increased MCP-1 and IL-17A in the peritoneal fluid although peritoneal bacteria levels were unchanged. Notably, 7-day mortality was significantly higher in occludin KO IEC mice following sepsis. Occludin thus plays a critical role in preserving gut barrier function and mediating survival during sepsis, associated with alterations in inflammation and bacteremia. Agents that preserve occludin function may represent a new therapeutic strategy in the treatment of sepsis.