GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats.

Abstract

Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect. We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1-24h after LPS treatment (5mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability. FD4 movement into the PV was increased 6h, but not 1 or 3h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24h after LPS were higher than FD4 concentrations 6h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12h after LPS treatment. FD4 uptake measured 6h after LPS was reduced by TDG 3 or 6h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors. Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6-12h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.