Relex Pathways Controlling Intestinal Motility

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DESCRIPTION (provided by applicant): Functions of the large bowel include the recovery of water and electrolytes from the intestinal lumen and the use of bacteria to digest nutrients. To perform these functions the transit of intraluminal contents through the human colon is slow (=30 hrs) compared to transit through the small intestine (2-4hrs). The mechanisms underlying colonic storage and slow transit have remained elusive. Slow transit constipation (STC) has been associated with colonic elongation and other changes, including an excess production of nitric oxide (NO) in myenteric neurons. In this proposal we show that when the guinea-pig distal colon and rectum are impacted with fecal pellets they are elongated by 160% of their length when empty. Intrinsic reflexes activated by colonic elongation appear to promote storage by slowing fecal pellet evacuation. We provide evidence that colonic elongation activates myenteric mechanosensitive descending (NOS +ve) and ascending (Chat +ve) interneurons that initiate polarized descending inhibitory and ascending excitatory reflexes respectively. The descending inhibitory elongation reflex is dominant; it promotes storage by releasing NO to inhibit other mechanosensory interneurons that drive peristalsis. Elongation sensitive descending and ascending interneurons activated by colonic elongation appear to also project to submucosal ganglia and to the submucosal ICC network that produces slow waves, where they inhibit and excite submucosa neurons and ICC respectively. These stretch sensitive interneurons are unusual, since they also appear to function as sensory neurons and motor neurons. In addition, we have found that the monkey sigmoid colon, which is our translation model, has motor patterns that are similar to those in the guinea-pig colon and responds similarly to elongation. PUBLIC HEALTH RELEVANCE: Slow transit constipation has been associated with colonic elongation and an excess production of nitric oxide. The factors underlying slow transit and accommodation of fecal material along the large bowel are unclear. In this proposal we show that when the isolated large bowel contains fecal material it is normally elongated and propulsion is slowed. Colonic elongation activates intrinsic sensory neurons that release nitric oxide to inhibit nerve circuits driving peristalsis. The elongation associated with an impacted colon is likely a contributing factor in slow transit constipation.