Pancreatic exocrine secretion is regulated by the physicochemical properties and nutrient composition of gastric and intestinal chyme. The present study examined integrative feedback mechanisms involved in the physiological control of pancreatic secretion, with particular emphasis on interactions between pancreatic juice, bile, and gut-derived regulatory and metabolic signals. A chronic porcine model enabling selective withdrawal and controlled reintroduction of pancreatic juice and bile into defined intestinal segments was employed. Duodenal and ileal exposure to pancreatic juice suppressed pancreatic enzyme secretion, while intraduodenal administration of pancreatin elicited a biphasic inhibitory response. Interruption of bile flow to the duodenum resulted in increased pancreatic protein output and was associated with reduced circulating cholecystokinin concentrations. In contrast, intraduodenal infusion of bile acids attenuated pancreatic exocrine secretion. Prolonged bile deprivation led to sustained pancreatic hypersecretion accompanied by a marked reduction in biliary leptin output. Collectively, these findings indicate that pancreatic exocrine secretion in pigs is regulated by multiple interacting feedback pathways operating along the gastrointestinal tract. The observed responses support functional contributions of protease-dependent luminal feedback, distal intestinal sensing, hormone-dependent regulation, and bile-associated metabolic modulation.