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

Area of Science:

• Gastroenterology
• Endocrinology
• Pharmacology

Background:

• Circulating endotoxin (lipopolysaccharide, LPS) is known to increase intestinal paracellular permeability.
• Glucagon-like peptide-2 (GLP-2) is investigated for its potential to counteract LPS-induced gut barrier dysfunction.
• The hypothesis posits that GLP-2 acutely reduces LPS-related intestinal permeability via a mechanism independent of its intestinotrophic effects.

Purpose of the Study:

• To investigate the acute effect of GLP-2 on LPS-induced increases in intestinal paracellular permeability.
• To determine if GLP-2's protective mechanism is related to its intestinotrophic properties.
• To establish the therapeutic window for exogenous GLP-2 administration in endotoxemia.

Main Methods:

• Assessed small intestinal paracellular permeability in vivo using FITC-dextran 4000 (FD4) in rats post-LPS treatment.
• Measured FD4 appearance in the portal vein (PV) at various time points (1-24 hours) after LPS administration.
• Evaluated the efficacy of a GLP-2 analog (teduglutide, TDG) and receptor antagonists.

Main Results:

• LPS treatment increased FD4 movement into the PV at 6 hours, accompanied by elevated endogenous GLP-2 levels and pro-inflammatory cytokine expression.
• Exogenous GLP-2 treatment administered 6 or 12 hours after LPS significantly reduced PV FD4 concentrations.
• Teduglutide (TDG) reduced FD4 uptake, an effect reversed by VPAC1 antagonist or L-NAME, but not EGF or IGF1 inhibitors.

Conclusions:

• Systemic LPS triggers endogenous GLP-2 release, which mitigates LPS-induced increases in gut permeability.
• Exogenous GLP-2 administration is therapeutically beneficial within 6-12 hours post-LPS exposure.
• GLP-2 treatment shows promise in preventing increased paracellular permeability during endotoxemia.