The enteric nervous system, the "second" brain, is an independent nervous system that structurally resembles the "first" brain. Appropriate rectal distension elicits rectal (R-R) reflex contractions and simultaneous internal anal sphincter (R-IAS) reflex relaxations that together comprise the defecation reflex. The enteric nervous system, pelvic nerves and lumbar colonic nerves control both reflexes. Using the plasticity of enteric nervous pathways, a new therapy for repairing enteric neural dysfunction could be developed. In vivo experiments were performed on guinea pigs anesthetized with ethyl carbamate. We performed either a lower anterior resection as used for rectal cancer, without damaging the extrinsic nerves or a resection of a 2-cm segment of distal colon, 30 mm orally from the anal verge, with subsequent end-to-end one layer anastomosis of the exposed ends. The recovery of the defecation reflex was found to be the same in both the rectal transection and distal colonic resection procedures. Eight weeks after sectioning the intrinsic reflex nerve pathways in the rectum, the defecation reflex recovered to control levels, accompanied by a regeneration of the reflex pathways. The 5-HT(4) receptor agonist, mosapride (0.5 and 1.0 mg/kg), significantly (P<0.01) enhanced the recovered defecation reflex at this stage. Two weeks after local treatment with brain-derived neurotrophic factor (BDNF: 10(-6) g/ml) at the rectal anastomotic site, the R-IAS reflex relaxations recovered and some bundles of fine nerve fibers were able to be seen interconnecting the oral and anal ends of the myenteric plexus. Also surprisingly, new neurons were found to have generated from neural stem cells at the anastomotic ends. These new neurons had constructed mature enteric neural networks including ganglionic-like structures eight weeks after surgery. These results revealed the plasticity of enteric neurons, allowing the proposal of a new therapy for repairing enteric neural dysfunction at least after surgery.