Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome.
OBJECTIVE
Serotonin (5-HT) is a critical signaling molecule in the gut. 5-HT released from enterochromaffin cells initiates peristaltic, secretory, vasodilatory, vagal, and nociceptive reflexes. Despite being pathophysiologically divergent, ulcerative colitis (UC) and irritable bowel syndrome (IBS) are both associated with clinical symptoms that include alterations in the normal patterns of motility, secretion, and sensation. Our aim was to test whether enteric 5-HT signaling is defective in these disorders.


METHODS
Rectal biopsy specimens were obtained from healthy controls and patients with UC, IBS with diarrhea (IBS-D), and IBS with constipation (IBS-C). Key elements of 5-HT signaling, including measures of 5-HT content, release, and reuptake, were analyzed with these samples.


RESULTS
Mucosal 5-HT, tryptophan hydroxylase 1 messenger RNA, serotonin transporter messenger RNA, and serotonin transporter immunoreactivity were all significantly reduced in UC, IBS-C, and IBS-D. The enterochromaffin cell population was decreased in severe UC samples but was unchanged in IBS-C and IBS-D. When 5-HT release was investigated under basal and mechanical stimulation conditions, no changes were detected in any of the groups relative to controls.


CONCLUSIONS
These data show that UC and IBS are associated with similar molecular changes in serotonergic signaling mechanisms. While UC and IBS have distinct pathophysiologic properties, these data suggest that shared defects in 5-HT signaling may underlie the altered motility, secretion, and sensation. These findings represent the first demonstration of significant molecular alterations specific to the gut in patients with IBS and support the assertion that disordered gastrointestinal function in IBS involves changes intrinsic to the bowel.
Coates
Matthew D
MD
Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
Mahoney
Christine R
CR
Linden
David R
DR
Sampson
Joanna E
JE
Chen
Jason
J
Blaszyk
Hagen
H
Crowell
Michael D
MD
Sharkey
Keith A
KA
Gershon
Michael D
MD
Mawe
Gary M
GM
Moses
Peter L
PL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology; D003248:Constipation / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D043183:Irritable Bowel Syndrome / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction; D014365:Tryptophan Hydroxylase / Q000235:genetics
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D014365:Tryptophan Hydroxylase