Lipid perfusion into the distal ileal lumen at supraphysiological loads inhibits pancreatic exocrine secretion and gastrointestinal motility in humans. In the present study, we sought to determine the effects of physiological postprandial intraileal lipid concentrations on endogenously stimulated pancreaticobiliary secretion, intestinal motility, and release of regulatory mediators. Eight healthy volunteers were intubated with an oroileal multilumen tube for continuous duodenal perfusion of essential amino acids (450 mumol/min), ileal perfusion of graded doses of lipids (0, 50 and 100 mg/min, each dose for 90-120 min), aspiration of duodenal and ileal chyme, and intestinal manometry. Venous blood samples were obtained for measurement of GLP-1 and PYY. Ileal lipid perfusion dose dependently decreased endogenously stimulated trypsin [262 +/- 59 vs. 154 +/- 42 vs. 92 +/- 20 U/min (P < 0.05)] and bile acid output [18.6 +/- 1.9 vs. 8.4 +/- 2.8 vs. 3.0 +/- 1.0 micromol/min (P < 0.05)]. Duodenal motor activity was not inhibited by either lipid dose. Trypsin and bile acid output correlated inversely with the release of GLP-1 and PYY (absolute value of R > 0.84; P < 0.05), whereas the motility index did not. Physiological postprandial ileal lipid concentrations dose dependently inhibited human digestive pancreatic protease and bile acid output, but not intestinal motor activity. Thus physiological postprandial ileal nutrient exposure may be of importance for the termination of digestive secretory responses. Ileocolonic release of GLP-1 and PYY appears to participate in mediating these effects.