Background:Activation of the ileal brake, by infusing lipid directly into the distal part of the small intestine, alters gastrointestinal motility and inhibits food intake. The ileal brake effect on eating behavior of the other macronutrients is currently unknown.Objective:The objective of this study was to investigate the effects of ileal infusion of sucrose and casein on food intake, release of gastrointestinal peptides, gastric emptying rate and small bowel transit time with safflower oil as positive control.Design:This randomized, single-blind, crossover study was performed in 13 healthy subjects (6 male; mean age 26.4+/-2.9 years; mean BMI 22.8+/-0.4 kg/m2) who were intubated with a naso-ileal catheter. Thirty minutes after the intake of a standardized breakfast participants received an ileal infusion, containing control (saline[C]), safflower oil (51.7 kcal[HL]), low-dose casein (17.2 kcal[LP]) or high-dose casein (51.7 kcal[HP]), low-dose sucrose (17.2 kcal[LC]), high-dose sucrose (51.7 kcal[HC]), over a period of 90 min. Food intake was determined during an ad libitum meal. VAS questionnaires for hunger and satiety and blood samples were collected at regular intervals.Results:Ileal infusion of lipid, protein and carbohydrate resulted in a significant reduction in food intake compared to control (HL: 464.3+/-90.7 kcal P<0.001, HP: 458.0+/-78.6 kcal P<0.005, HC: 399.0+/-57.0 kcal P<0.0001 vs. control: 586.7+/-70,2 kcal respectively, P<0.001). A reduction in energy intake was still apparent when the caloric amount of infused nutrients was added to the amount eaten during the ad libitum meal. Secretion of CCK and PYY but not of GLP-1 (7-36) was increased during ileal perfusion of fat, carbohydrates and protein. During ileal perfusion of all macronutrients a delay in gastric emptying and intestinal transit was observed, but differences were not significant compared to control.Conclusion:Apart from lipids also sucrose and casein reduce food intake upon ileal infusion, thereby activating the ileal brake. In addition to food intake, also satiety and gastrointestinal peptide secretion were affected.International Journal of Obesity accepted article preview online, 24 June 2014; doi:10.1038/ijo.2014.112.