OBJECTIVE:: Early gut wall integrity loss and local intestinal inflammation are associated with the development of inflammatory complications in surgical and trauma patients. Prevention of these intestinal events is a potential target for therapies aimed to control systemic inflammation. Previously, we demonstrated in a rodent shock model that lipid-rich enteral nutrition attenuated systemic inflammation and prevented organ damage through a cholecystokinin receptor-dependent vagal pathway. Influence of lipid-rich nutrition on very early intestinal compromise as seen after shock is investigated. Next, the involvement of cholecystokinin receptor on the nutritional modulation of immediate gut integrity loss and intestinal inflammation is studied. DESIGN:: Randomized controlled in vivo study. SETTING:: University research unit. SUBJECTS:: Male Sprague-Dawley rats. INTERVENTIONS:: Liquid lipid-rich nutrition or control low-lipid feeding was administered per gavage before hemorrhagic shock. Cholecystokinin receptor antagonists were used to investigate involvement of the vagal antiinflammatory pathway. MEASUREMENTS AND MAIN RESULTS:: Gut permeability to horseradish peroxidase increased as soon as 30 mins postshock and was prevented by lipid-rich nutrition compared with low-lipid (p < .01) and fasted controls (p < .001). Furthermore, lipid-rich nutrition reduced plasma levels of enterocyte damage marker ileal lipid binding protein at 60 mins (p < .05). Early gut barrier dysfunction correlated with rat mast cell protease plasma concentrations at 30 mins (rs = 0.67; p < .001) and intestinal myeloperoxidase levels at 60 mins (rs = 0.58; p < .05). Lipid-rich nutrition significantly reduced plasma rat mast cell protease (p < .01) and myeloperoxidase (p < .05) before systemic inflammation was detectable. Protective effects of lipid-rich nutrition were abrogated by cholecystokinin receptor antagonists (horseradish peroxidase; p < .05 and rat mast cell protease; p < .05). CONCLUSIONS:: Lipid-rich enteral nutrition prevents early gut barrier loss, enterocyte damage, and local intestinal inflammation before systemic inflammation in a cholecystokinin receptor-dependent manner. This study identifies activation of the vagal antiinflammatory pathway with lipid-rich nutrition as a potential therapy in patients prone to develop a compromised gut.