OBJECTIVE: To investigate the effects of high-lipid enteral nutrition in a setting of developing inflammation and tissue damage. BACKGROUND: An excessive inflammatory response following severe trauma is associated with poor clinical outcome. Currently, therapies directed at attenuation of an ongoing inflammatory cascade are lacking. Administration of high-lipid enteral nutrition before hemorrhagic shock has been shown to effectively inhibit early and late proinflammatory cytokines by activation of the autonomic nervous system via cholecystokinin (CCK)-receptors. METHODS: A rat model of hemorrhagic shock was used in which animals were either fasted or treated with high-lipid or control low-lipid enteral nutrition. CCK-receptor antagonists were administered before feeding. Tissues and plasma were collected to assess inflammation and intestinal integrity. RESULTS: Administration of high-lipid enteral nutrition after shock reduced plasma interferon-gamma (IFN-gamma) significantly in comparison with those in low-lipid-treated and fasted animals (P < 0.01 and P < 0.001, respectively). Also, interleukin (IL)-10 levels in plasma were decreased in comparison with those in fasted animals (P < 0.001). Enterocyte damage, expressed as circulating ileal lipid-binding protein (ILBP), was prevented by early high-lipid nutrition in comparison with that in low-lipid-treated and fasted animals (P = 0.05 and P < 0.001, respectively). Furthermore, high-lipid feeding preserved intestinal integrity in comparison with that observed in low-lipid-treated and fasted animals, as assessed by bacterial translocation (BT) to distant organs (P < 0.05 and P < 0.001, respectively) and ileal permeability to horseradish peroxidase (HRP) (P = 0.05 and P < 0.001, respectively). The protective effects of high-lipid intervention were nullified by CCK-receptor antagonists (IFN-gamma; IL-10; BT; and HRP; P < 0.05). CONCLUSION: High-lipid enteral nutrition given postshock reduces inflammation and preserves tissue integrity via a CCK-receptor-dependent mechanism. These findings implicate that intervention with high-lipid enteral nutrition following events such as severe trauma is a potential therapy to attenuate the developing inflammatory response.