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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045713-18
Application #
8214649
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Carrington, Jill L
Project Start
1992-02-28
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
18
Fiscal Year
2012
Total Cost
$299,507
Indirect Cost
$86,335
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
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
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
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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Dickson, Eamonn J; Heredia, Dante J; Smith, Terence K (2010) Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex. Am J Physiol Gastrointest Liver Physiol 299:G144-57
Dinning, P G; Smith, T K; Scott, S M (2009) Pathophysiology of colonic causes of chronic constipation. Neurogastroenterol Motil 21 Suppl 2:20-30

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