The purpose of this study was to determine whether or not nutrients in the colon influence pancreatic and biliary secretion in humans. In six healthy subjects, similar caloric loads (117 cals) of oleic acid, essential amino acids, and glucose in isomolar (280 mosmol/L), similar pH (7.4) solutions were infused into the right colon at 10 ml/min through a colonic tube passed by mouth. A background of submaximal pancreatic and biliary secretion was maintained by continuous intravenous infusion of the octapeptide of cholecystokinin. Biliary and pancreatic secretions were quantitated using the gastroduodenal intubation perfusion technique. Among the three nutrients tested, only oleic acid in the colon decreased pancreatic enzymes and bicarbonate outputs. The mean trypsin output decreased from 26.3 ± 2.6 kU/h to 12.3 ± 1.9 kU/h (46% ± 6% of control), while the lipase output decreased from 62 ± 6.6 kU/h to 36 ± 5.6 kU/h (58% ± 6% of control). Similarly, the output of bicarbonate in the duodenal aspirate decreased from 31 ± 7.2 mEq/h to 16.3 ± 3.1 mEq/h (61% ± 5% of control). Intracolonic perfusion of essential amino acids or glucose had no effect on pancreatic enzymes and bicarbonate secretion. In contrast, all three nutrients in the colon inhibited biliary secretion. The mean output of bilirubin decreased from 56 ± 6 mg/h to 19 ± 2 mg/h (35% ± 5% of control) during intracolonic perfusion of oleic acid. Essential amino acids lowered the output of bilirubin from 54 ± 12 mg/h to 31 ± 8.6 mg/h (65% ± 6% of control), whereas glucose lowered it from 53 ± 12 mg/h to 22 ± 4 mg/h (45% ± 5% of control). This differing response of pancreatic and biliary output to intracolonic perfusion of nutrients suggests differential sensitivity of the pancreas and gallbladder to these inhibitory influences. In malabsorption states, unabsorbed nutrients in the colon may inhibit pancreatic and biliary secretion, further contributing to the loss of nutrients from the gastrointestinal tract.