Back to Search
Start Over
Colitis-Induced Small Intestinal Hypomotility Is Dependent on Enteroendocrine Cell Loss in Mice.
- Source :
-
Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2024; Vol. 18 (1), pp. 53-70. Date of Electronic Publication: 2024 Mar 02. - Publication Year :
- 2024
-
Abstract
- Background & Aims: The abdominal discomfort experienced by patients with colitis may be attributable in part to the presence of small intestinal dysmotility, yet mechanisms linking colonic inflammation with small-bowel motility remain largely unexplored. We hypothesize that colitis results in small intestinal hypomotility owing to a loss of enteroendocrine cells (EECs) within the small intestine that can be rescued using serotonergic-modulating agents.<br />Methods: Male C57BL/6J mice, as well as mice that overexpress (EEC <superscript>OVER</superscript> ) or lack (EEC <superscript>DEL</superscript> ) NeuroD1+ enteroendocrine cells, were exposed to dextran sulfate sodium (DSS) colitis (2.5% or 5% for 7 days) and small intestinal motility was assessed by 70-kilodalton fluorescein isothiocyanate-dextran fluorescence transit. EEC number and differentiation were evaluated by immunohistochemistry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining, and quantitative reverse-transcriptase polymerase chain reaction. Mice were treated with the 5-hydroxytryptamine receptor 4 agonist prucalopride (5 mg/kg orally, daily) to restore serotonin signaling.<br />Results: DSS-induced colitis was associated with a significant small-bowel hypomotility that developed in the absence of significant inflammation in the small intestine and was associated with a significant reduction in EEC density. EEC loss occurred in conjunction with alterations in the expression of key serotonin synthesis and transporter genes, including Tph1, Ddc, and Slc6a4. Importantly, mice overexpressing EECs revealed improved small intestinal motility, whereas mice lacking EECs had worse intestinal motility when exposed to DSS. Finally, treatment of DSS-exposed mice with the 5-hydroxytryptamine receptor 4 agonist prucalopride restored small intestinal motility and attenuated colitis.<br />Conclusions: Experimental DSS colitis induces significant small-bowel dysmotility in mice owing to enteroendocrine loss that can be reversed by genetic modulation of EEC or administering serotonin analogs, suggesting novel therapeutic approaches for patients with symptomatic colitis.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Mice
Male
Mice, Inbred C57BL
Disease Models, Animal
Serotonin metabolism
Benzofurans
Enteroendocrine Cells metabolism
Colitis pathology
Colitis chemically induced
Colitis complications
Gastrointestinal Motility drug effects
Intestine, Small pathology
Intestine, Small drug effects
Dextran Sulfate toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 2352-345X
- Volume :
- 18
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cellular and molecular gastroenterology and hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 38438014
- Full Text :
- https://doi.org/10.1016/j.jcmgh.2024.02.017