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 (e30 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.
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.
|Smith, Terence K; Gershon, Michael D (2015) CrossTalk proposal: 5-HT is necessary for peristalsis. J Physiol 593:3225-7|
|Okamoto, T; Barton, M J; Hennig, G W et al. (2014) Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil 26:556-70|
|Heredia, Dante J; Gershon, Michael D; Koh, Sang Don et al. (2013) Important role of mucosal serotonin in colonic propulsion and peristaltic reflexes: in vitro analyses in mice lacking tryptophan hydroxylase 1. J Physiol 591:5939-57|
|Feng, Cheng-Yuan; Hennig, Grant W; Corrigan, Robert D et al. (2012) Analysis of spontaneous and nerve-evoked calcium transients in intact extraocular muscles in vitro. Exp Eye Res 100:73-85|
|Heredia, Dante J; Grainger, Nathan; McCann, Conor J et al. (2012) Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestine. Am J Physiol Gastrointest Liver Physiol 303:G1004-16|
|Bayguinov, P O; Broadhead, M J; Okamoto, T et al. (2012) Activity in varicosities within the myenteric plexus between and during the colonic migrating motor complex in the isolated murine large intestine. Neurogastroenterol Motil 24:e185-201|
|Broadhead, Matthew J; Bayguinov, Peter O; Okamoto, Takanobu et al. (2012) Ca2+ transients in myenteric glial cells during the colonic migrating motor complex in the isolated murine large intestine. J Physiol 590:335-50|
|Okamoto, T; Bayguinov, P O; Broadhead, M J et al. (2012) Ca(2+) transients in submucous neurons during the colonic migrating motor complex in the isolated murine large intestine. Neurogastroenterol Motil 24:769-78, e354|
|Kim, Eun Ran; Kim, Kyoung Mee; Lee, Ji Yeon et al. (2012) The clue of Interstitial Cell of Cajalopathy (ICCpathy) in human diabetic gastropathy: the ultrastructural and electrical clues of ICCpathy in human diabetic gastropathy. Exp Toxicol Pathol 64:521-6|
|Bayguinov, Peter O; Hennig, Grant W; Smith, Terence K (2010) Calcium activity in different classes of myenteric neurons underlying the migrating motor complex in the murine colon. J Physiol 588:399-421|
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