Deletion of interleukin-22 binding protein increases gut permeability, dysbiosis, and mortality in sepsis

The gut is hypothesized to play a pivotal role in sepsis progression through increased intestinal permeability, dysbiosis, and immune dysregulation. Interleukin (IL)-22 maintains intestinal homeostasis and is negatively regulated by IL-22 binding protein (IL-22BP), yet the roles of IL-22 and IL-22BP in sepsis remain undetermined. Using a cecal ligation and puncture (CLP) model with a sham control, we measured IL-22 and IL-22BP at 24 h and compared IL-22-deficient (Il22-/-) and IL-22BP-deficient (Il22ra2-/-) mice with wild-type (WT) mice. Gut permeability, tight junction protein expression, histology, and cytokines were assessed at 24 and 48 h, and the microbiome at baseline and 24 h. Survival was monitored for 168 h; co-housed mice were also evaluated. Plasma and jejunal IL-22, along with plasma IL-22BP levels, were significantly higher in CLP than in sham mice. In Il22-/- mice, mortality and gut permeability showed no significant difference from those in WT mice. By contrast, Il22ra2-/- mice exhibited significantly higher mortality (85% vs. 40%) and increased gut permeability. These changes were associated with elevated claudin-4 and reduced claudin-15 expression, localized cytokine upregulation, and no histological differences. Fecal bacterial loads were comparable between WT and Il22ra2-/- mice, but microbiome composition differed at baseline and 24 h after CLP. Co-housing eliminated the survival difference between groups. In conclusion, whereas IL-22 deficiency had no impact on gut permeability or mortality, IL-22BP deficiency increased gut permeability and mortality with altered cytokine expression and gut dysbiosis, suggesting that IL-22BP plays a protective role in maintaining gut homeostasis in sepsis.