Bile high-mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia

Area of Science:

• Gastroenterology
• Immunology
• Sepsis Pathophysiology

Background:

• Lipopolysaccharide (LPS) is a key factor in sepsis, known to induce intestinal hyperpermeability and bacterial translocation.
• LPS stimulates Kupffer cells to release TNF-alpha into bile, suggesting bile plays a role in endotoxemia.

Purpose of the Study:

• To investigate if hepatic Kupffer cells and macrophages release high-mobility group box 1 (HMGB1) into bile following LPS stimulation.
• To determine if bile containing HMGB1 contributes to gut barrier dysfunction in experimental endotoxemia.

Main Methods:

• Rats underwent bile duct catheterization and LPS administration, with bile flow and cytokine levels monitored.
• Neutralizing anti-HMGB1 antibody or sham IgG was administered into the duodenal lumen of endotoxemic rats.
• Normal mice were gavaged with normal or endotoxemic rat bile to assess its effects on gut barrier function.

Main Results:

• LPS challenge significantly decreased bile flow rate and increased bile TNF-alpha and HMGB1 levels.
• Anti-HMGB1 antibody administration reversed LPS-induced gut barrier dysfunction in rats.
• Endotoxemic rat bile increased gut mucosal permeability and bacterial translocation in normal mice, effects reversible by HMGB1 removal.

Conclusions:

• Bile HMGB1 is significantly elevated in experimental endotoxemia.
• Bile HMGB1 mediates gut barrier dysfunction, increasing intestinal permeability and bacterial translocation.
• Targeting bile HMGB1 represents a potential therapeutic strategy for sepsis-induced gut injury.