Glp-2 Acutely Diminishes Lps-Related Intestinal Permeability in Rats

Circulating lipopolysaccharide (LPS; endotoxin) increases the permeability of the gut mucosal barrier, increasing LPS translocation into the circulation, augmenting endotoxemia with consequent systemic inflammation. Although daily treatment for 1 week with glucagon‐like peptide‐2 (GLP‐2) prevents the observed LPS‐related intestinal permeability increase, presumably due to its intestinotrophic effects, we hypothesized that acute administration of GLP‐2 reduces LPS‐related increased intestinal permeability by a mechanism unlikely related to hypertrophy. We thus examined the effect of GLP‐2 on intestinal permeability dynamics in vivo and in Ussing‐chambered intestinal mucosa in vitro . We assessed intestinal permeability in vivo by measuring the appearance of intraduodenally perfused FITC‐dextran 4000 (FD4) into the portal vein (PV) in rats every 15 min for 90 min at 6 or 24 hr after LPS treatment (5 mg/kg, ip). We also examined FD4 movement from mucosal to serosal solution (m‐to‐s) in Ussing‐chambered muscle‐stripped intestinal tissues of vehicle‐ or LPS‐treated animals. 6 hr after LPS treatment, PV FD4 concentrations gradually increased following bolus intraduodenal infusion of FD4 (0.1 mM). Co‐treatment with the GLP‐2 receptor antagonist GLP‐2(3–33) (1 mg/kg, ip) with LPS enhanced PV FD4 concentrations. In Ussing‐chambered ileum obtained from rats 6 hr after LPS treatment, m‐to‐s movement of FD4 was unchanged compared with controls, whereas FD4 movement was increased in the ileum of GLP‐2(3–33) co‐treated animals. Furthermore, PV GLP‐2 concentrations and proglucagon mRNA expression in ileal mucosa were increased 6 hr after LPS treatment. 24 hr after LPS treatment, PV FD4 concentrations were further increased compared to FD4 concentrations at 6 hr. Exogenous GLP‐2 treatment (100 nmol/kg, ip) 6 hr after LPS treatment reduced FD4 permeability measured 24 hr after LPS treatment. Increased intestinal permeability 6 hr after LPS administration was aggravated by GLP‐2 receptor antagonism. Systemic LPS releases endogenous GLP‐2, acutely protecting against LPS‐related loss of barrier function due to endotoxemia, followed by increased mRNA expression for the GLP‐2 precursor proglucagon. GLP‐2 treatment 6 hr after LPS administration prevented further increased intestinal permeability measured 24 hr after LPS, suggesting that the anti‐permeabilizing effects of GLP‐2 last longer than the t 1/2 of the hormone. Exogenous GLP‐2 treatment may be of value in the prevention of systemic inflammation associated with endotoxemia due to a “leaky gut”. Support or Funding Information Supported by VA Merit Review, NIH R01 DK54221, Shire Pharmaceuticals