Diabetes leads to intestinal barrier dysfunction. 5-Hydroxytryptamine 4 receptor (5-HT4R) is distributed in the colonic mucosa, but little is known about the role of its
activation in diabetes-evoked colonic barrier dysfunction. This study investigates
whether activation of 5-HT4Rs on goblet cells (GCs) protects the colon from commensal bacterial translocation
in diabetic mice. Expression of 5-HT4R detected inside the colonic epithelium by RNAscope in situ hybridization was further observed within the mucin 2 (MUC2)–immunoreactive GCs.
In diabetic mice, neither 5-HT4R transcription nor protein levels were altered compared with those in nondiabetic
mice. Bacterial translocation was characterized by 16S rRNA RNAscope in situ hybridization and manifested in both crypts and lamina propria of the colon in diabetic
mice. Mucin production and MUC2 expression were significantly decreased in diabetic
mice. Furthermore, the loss of mitochondrial cristae of GCs and the down-regulation
of mitofilin, the core protein maintaining mitochondrial homeostasis, were observed
in diabetic mice. Long-term treatment with 5-HT4R agonist in diabetic mice not only prevented bacterial penetration of the whole colonic
mucosa but also promoted mucin production and MUC2 expression. Markedly, 5-HT4R agonist also restored the mitochondrial cristae of GCs and up-regulated mitofilin.
However, co-administration of 5-HT4R antagonist abolished the effects of 5-HT4R agonist on diabetic mice. These findings indicate that 5-HT4R in colonic mucosa is an effective target for the treatment of diabetes-induced colonic
mucous barrier dysfunction.
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Article Info
Publication History
Published online: March 22, 2022
Accepted:
March 2,
2022
Footnotes
Supported by Cutting-edge Research Project of the Chongqing Science and Technology Commission grant CSTC2014JCYJA10014 (H.Y.).
Disclosures: None declared.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
