J Neurogastroenterol Motil.  2018 Oct;24(4):643-655. 10.5056/jnm18040.

Role of High-affinity Choline Transporter 1 in Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome

• Lin MJ
• Yu BP

• KMID: 2422854
• DOI: http://doi.org/10.5056/jnm18040

Abstract

BACKGROUND/AIMS
Irritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS.
METHODS
A rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility.
RESULTS
After 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production.
CONCLUSION
Upregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.

Keyword

Choline tranporter; Gastrointestinal motility; Interstitial cells of Cajal; Irritable bowel syndrome; Myenteric plexus

MeSH Terms

Acetylcholine
Ammonium Compounds
Animals
Blotting, Western
Choline*
Colon*
Enzyme-Linked Immunosorbent Assay
Gastrointestinal Motility
Interstitial Cells of Cajal
Irritable Bowel Syndrome*
Models, Animal*
Myenteric Plexus
Neurons
Rats*
RNA, Messenger
Transducers
Up-Regulation
Water
Acetylcholine
Choline
RNA, Messenger
Water