OBJECTIVES:: Controlling the inflammatory cascade during sepsis remains a major clinical challenge. Recently, it has become evident that the autonomic nervous system reduces inflammation through the vagus nerve. The current study investigates whether nutritional stimulation of the autonomic nervous system effectively attenuates the inflammatory response in murine Gram-negative sepsis. DESIGN:: Controlled in vivo and ex vivo experimental study. SETTINGS:: Research laboratory of a university hospital. SUBJECTS:: Male C57bl6 mice. INTERVENTIONS:: Mice were intraperitoneally challenged with lipopolysaccharide derived from Escherichia coli. Before lipopolysaccharide administration, mice were fasted or enterally fed either lipid-rich nutrition or low-lipid nutrition. Antagonists to cholecystokinin receptors or nicotinic receptors were administered before lipopolysaccharide administration. Blood and tissue samples were collected at 90 mins. Mesenteric afferent discharge was determined in ex vivo preparations in response to both nutritional compositions. MEASUREMENTS AND MAIN RESULTS:: Both lipid-rich and low-lipid nutrition dose-dependently reduced lipopolysaccharide-induced tumor necrosis factor-alpha release (high dose: both 1.4 +/- 0.4 ng/mL) compared with fasted mice (3.7 +/- 0.8 ng/mL; p < .01). The antiinflammatory effect of both nutritional compositions was mediated through cholecystokinin receptors (p < .01), activation of mesenteric vagal afferents (p < .05), and peripheral nicotinic receptors (p < .05). Lipid-rich nutrition attenuated the inflammatory response at lower dosages than low-lipid nutrition, indicating that enrichment of enteral nutrition with lipid augments the antiinflammatory potential. Administration of lipid-rich nutrition prevented endotoxin-induced small intestinal epithelium damage and reduced inflammation in the liver and spleen compared with fasted (all p < .01) and low-lipid nutrition controls (all p < .05). CONCLUSIONS:: The current study demonstrates that lipid-rich nutrition attenuates intestinal damage and systemic as well as organ-specific inflammation in murine Gram-negative sepsis through the nutritional vagal antiinflammatory pathway. These findings implicate enteral administration of lipid-enriched nutrition as a promising intervention to modulate the inflammatory response during septic conditions.