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Rectal insulin instillation inhibits inflammation and tumor development in chemically-induced colitis


Yassin, Mohammad; Sadowska, Zuzanna; Tritsaris, Katerina; Kissow, Hannelouise; Hansen, Camilla H F; Forman, Julie L; Rogler, Gerhard; Troelsen, Jesper T; Pedersen, Anders E; Olsen, Jørgen (2018). Rectal insulin instillation inhibits inflammation and tumor development in chemically-induced colitis. Journal of Crohn's & Colitis, 12(12):1459-1474.

Abstract

Background & Aims The epithelial expression of the insulin receptor in the colon is previously reported to correlate with the extent of colonic inflammation. However, the impact of insulin signaling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer. Methods The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing (vil-Cre-INSR+/-) x (INSRfl/fl) to obtain (vil-Cre-INSR-/-) and their floxed littermates (INSRfl/fl) serving as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anesthetized wild type mice with chemically-induced colitis. Results We report higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we show that topically administered insulin in inflamed colons of wildtype mice reduces inflammation-induced weight loss and improves remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores, reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumors compared with the control group receiving phosphate-buffered saline only. Conclusions Rectal insulin therapy can potentially be a novel treatment targeting the epithelial layer to enhance mucosal healing in the ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.

Abstract

Background & Aims The epithelial expression of the insulin receptor in the colon is previously reported to correlate with the extent of colonic inflammation. However, the impact of insulin signaling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer. Methods The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing (vil-Cre-INSR+/-) x (INSRfl/fl) to obtain (vil-Cre-INSR-/-) and their floxed littermates (INSRfl/fl) serving as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anesthetized wild type mice with chemically-induced colitis. Results We report higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we show that topically administered insulin in inflamed colons of wildtype mice reduces inflammation-induced weight loss and improves remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores, reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumors compared with the control group receiving phosphate-buffered saline only. Conclusions Rectal insulin therapy can potentially be a novel treatment targeting the epithelial layer to enhance mucosal healing in the ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Gastroenterology
Language:English
Date:18 August 2018
Deposited On:30 Nov 2018 12:54
Last Modified:29 Jul 2020 08:11
Publisher:Oxford University Press
ISSN:1873-9946
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/ecco-jcc/jjy112
PubMed ID:30137286

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