We have previously described a negative feedback loop that inhibits duodenal motility when nutrients are infused into the ileum and colon. In the present study, we examined the role of extrinsic innervation and plasma levels of peptide YY (PYY) in mediating this phenomenon. We perfused neurally intact (n = 5 dogs) or extrinsically denervated (n = 6 dogs) isolated loops of proximal colon with isomolar NaCl or a mixed-nutrient solution at 2 and 6 ml/min for 4 h during fasting or for 2 h beginning 15 min after a meal. Both rates of infusion with NaCl prolonged the cycle length of the duodenal migrating motor complex (MMC) in the group with neurally intact loops but not in the group with extrinsically denervated loops. Nutrient infusions increased the MMC cycle length in both groups. Integrated plasma concentrations of PYY were increased by nutrients but not by NaCl in both groups. These data suggest that increased volumes and unabsorbed nutrients in the proximal colon alter proximal small bowel motility. Volume-induced effects are mediated via extrinsic nerves, whereas nutrient-induced effects may be mediated by humoral factors, such as plasma PYY.