ObjectiveTo determine the effect of chronic exposure to endotoxin (lipopolysaccharide) and Staphylococcal enterotoxin B on hepatic injury and function.DesignProspective, controlled trial.SettingResearch laboratory in a university hospital.SubjectsMale Sprague-Dawley rats weighing 325–350 g with chronic vascular and bile catheters.InterventionsChronically catheterized rats were treated daily with saline, 50 &mgr;g/kg Staphylococcal enterotoxin B alone, 1000 &mgr;g/kg lipopolysaccharide alone, 1000 &mgr;g/kg lipopolysaccharide with 50 &mgr;g/kg Staphylococcal enterotoxin B, or 100 &mgr;g/kg lipopolysaccharide with 50 &mgr;g/kg Staphylococcal enterotoxin B for 10 days. Serum and biliary measures of hepatic injury and dysfunction were measured before and then 6 hrs and 1, 2, 3, 7, and 10 days after the start of treatment. The animals were killed at 10 days and the livers examined histologically.Measurements and Main ResultsMean rates of bile flow, biliary indocyanine green excretion, and bile acid flux were significantly decreased immediately after treatment (6 hr, 1 and 2 days) and then at 10 days. Increases in biliary and serum &ggr;-glutamyltransferase and serum bile acids also occurred in a similar bimodal pattern. Animals treated with lipopolysaccharide or Staphylococcal enterotoxin B alone became tolerant and did not develop the bimodal pattern of hepatic dysfunction. Histologic examination of the liver at 10 days revealed periportal inflammation and fibrosis.ConclusionsThe combination of lipopolysaccharide and Staphylococcal enterotoxin B leads to late liver injury, whereas either toxin alone does not. These data may explain the frequent development of liver dysfunction in patients exposed to multiple bacterial toxins such as in sepsis, multiple-system organ failure, and other diseases with altered intestinal permeability.