» Articles » PMID: 27480173

Protective Actions of Epithelial 5-Hydroxytryptamine 4 Receptors in Normal and Inflamed Colon

Abstract

Background & Aims: The 5-hydroxytryptamine receptor 4 (5-HTR or HTR) is expressed in the colonic epithelium but little is known about its functions there. We examined whether activation of colonic epithelial 5-HTR protects colons of mice from inflammation.

Methods: The 5-HTR agonist tegaserod (1 mg/kg), the 5-HTR antagonist GR113808 (1 mg/kg), or vehicle (control) were delivered by enema to wild-type or 5-HTR knockout mice at the onset of, or during, active colitis, induced by administration of dextran sodium sulfate or trinitrobenzene sulfonic acid. Inflammation was measured using the colitis disease activity index and by histologic analysis of intestinal tissues. Epithelial proliferation, wound healing, and resistance to oxidative stress-induced apoptosis were assessed, as was colonic motility.

Results: Rectal administration of tegaserod reduced the severity of colitis compared with mice given vehicle, and accelerated recovery from active colitis. Rectal tegaserod did not improve colitis in 5-HTR knockout mice, and intraperitoneally administered tegaserod did not protect wild-type mice from colitis. Tegaserod increased proliferation of crypt epithelial cells. Stimulation of 5-HTR increased Caco-2 cell migration and reduced oxidative stress-induced apoptosis; these actions were blocked by co-administration of the 5-HTR antagonist GR113808. In noninflamed colons of wild-type mice not receiving tegaserod, inhibition of 5-HTRs resulted in signs of colitis within 3 days. In these mice, epithelial proliferation decreased and bacterial translocation to the liver and spleen was detected. Daily administration of tegaserod increased motility in inflamed colons of guinea pigs and mice, whereas administration of GR113808 disrupted motility in animals without colitis.

Conclusions: 5-HTR activation maintains motility in healthy colons of mice and guinea pigs, and reduces inflammation in colons of mice with colitis. Agonists might be developed as treatments for patients with inflammatory bowel diseases.

Citing Articles

Chronic Stress-induced Serotonin Impairs Intestinal Epithelial Cell Mitochondrial Biogenesis via the AMPK-PGC-1α Axis.

Yang D, Sun Y, Wen P, Chen Y, Cao J, Sun X Int J Biol Sci. 2024; 20(11):4476-4495.

PMID: 39247815 PMC: 11380450. DOI: 10.7150/ijbs.97275.


Gut microbiota dysbiosis deteriorates immunoregulatory effects of tryptophan via colonic indole and LBP/HTR2B-mediated macrophage function.

Jiang L, Hao Y, Han D, Dong W, Yang A, Sun Z ISME J. 2024; 18(1).

PMID: 39180723 PMC: 11421149. DOI: 10.1093/ismejo/wrae166.


Novel 5-HT receptor antagonists modulate intestinal immune responses and reduce severity of colitis.

Kwon Y, Blass B, Wang H, Grondin J, Banskota S, Korzekwa K Am J Physiol Gastrointest Liver Physiol. 2024; 327(1):G57-G69.

PMID: 38713616 PMC: 11550998. DOI: 10.1152/ajpgi.00299.2023.


Antidepressant fluoxetine alleviates colitis by reshaping intestinal microenvironment.

Teng S, Yang Y, Zhang W, Li X, Li W, Cui Z Cell Commun Signal. 2024; 22(1):176.

PMID: 38475799 PMC: 10935910. DOI: 10.1186/s12964-024-01538-5.


Differential roles of serotonin receptor subtypes in regulation of neurotrophin receptor expression and intestinal hypernociception.

She M, Hsieh Y, Lin L, Tu C, Wu M, Hsin L Histol Histopathol. 2023; 39(7):903-919.

PMID: 38108436 DOI: 10.14670/HH-18-687.


References
1.
Li N, Ghia J, Wang H, McClemens J, Cote F, Suehiro Y . Serotonin activates dendritic cell function in the context of gut inflammation. Am J Pathol. 2011; 178(2):662-71. PMC: 3069907. DOI: 10.1016/j.ajpath.2010.10.028. View

2.
van der Sluis M, de Koning B, de Bruijn A, Velcich A, Meijerink J, van Goudoever J . Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006; 131(1):117-29. DOI: 10.1053/j.gastro.2006.04.020. View

3.
Heath J . Epithelial cell migration in the intestine. Cell Biol Int. 1996; 20(2):139-46. DOI: 10.1006/cbir.1996.0018. View

4.
Ghia J, Li N, Wang H, Collins M, Deng Y, El-Sharkawy R . Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology. 2009; 137(5):1649-60. DOI: 10.1053/j.gastro.2009.08.041. View

5.
Takaki M, Goto K, Kawahara I . The 5-hydroxytryptamine 4 Receptor Agonist-induced Actions and Enteric Neurogenesis in the Gut. J Neurogastroenterol Motil. 2014; 20(1):17-30. PMC: 3895605. DOI: 10.5056/jnm.2014.20.1.17. View