There is evidence that the distal intestine participates in the regulation of gastric motor and secretory function. It was the aim of this study to examine in greater detail the effects of ileal nutrient exposure on human gastric acid secretion and to investigate potential intermediary mechanisms. Twelve normal subjects were intubated with an oroileal multilumen tube assembly for gastric, duodenal, and ileal perfusion of marker and test solutions, aspiration, and intestinal manometry. We studied ileal effects on gastric acid output in the unstimulated, interdigestive state (during early phase II, N = 6), and during endogenous stimulation by intraduodenal essential amino acid perfusion, N = 6) and on release of candidate humoral mediators, peptide YY (PYY) and glucagonlike peptide-1 (GLP-1), both known inhibitors of human gastric acid secretion. Compared with ileal saline perfusion, ileal carbohydrate (total caloric load: 60 kcal) decreased interdigestive gastric acid output by 64% (P < 0.01), and endogenously stimulated output by 68%, respectively (P < 0.005). Under all experimental conditions, ileal carbohydrate increased plasma GLP-1 by 80-100% (all P < 0.005). Ileal lipid perfusion had similar inhibitory effects on gastric acid output and stimulatory effects on GLP-1 release as had ileal carbohydrate. By contrast, ileal perfusion with peptone had no or only weak effects on either acid output or plasma GLP-1. Plasma PYY concentrations and suppression of gastric secretion in response to ileal perfusions were not correlated. In humans, both interdigestive and endogenously stimulated gastric acid output are inhibited in response to intraileal carbohydrate or lipids, but not protein.(ABSTRACT TRUNCATED AT 250 WORDS)