Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels

Background and aims: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would b...

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Main Authors: Shinji Ota, Hirotake Sakuraba, Hiroto Hiraga, Shukuko Yoshida, Miwa Satake, Yui Akemoto, Nahoko Tanaka, Rina Watanabe, Maeda Takato, Yasuhisa Murai, Kayo Ueno, Takenori Niioka, Makoto Hayakari, Yoh Ishiguro, Shinsaku Fukuda
Format: Article
Language:English
Published: Elsevier 2020-12-01
Series:Biochemistry and Biophysics Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2405580820301217
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author Shinji Ota
Hirotake Sakuraba
Hiroto Hiraga
Shukuko Yoshida
Miwa Satake
Yui Akemoto
Nahoko Tanaka
Rina Watanabe
Maeda Takato
Yasuhisa Murai
Kayo Ueno
Takenori Niioka
Makoto Hayakari
Yoh Ishiguro
Shinsaku Fukuda
author_facet Shinji Ota
Hirotake Sakuraba
Hiroto Hiraga
Shukuko Yoshida
Miwa Satake
Yui Akemoto
Nahoko Tanaka
Rina Watanabe
Maeda Takato
Yasuhisa Murai
Kayo Ueno
Takenori Niioka
Makoto Hayakari
Yoh Ishiguro
Shinsaku Fukuda
author_sort Shinji Ota
collection DOAJ
description Background and aims: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. Methods: Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. Results: Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. Conclusion: Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.
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spelling doaj.art-a8f12f396a6642898e2b1cd7dc3d4d4b2022-12-21T17:26:18ZengElsevierBiochemistry and Biophysics Reports2405-58082020-12-0124100811Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levelsShinji Ota0Hirotake Sakuraba1Hiroto Hiraga2Shukuko Yoshida3Miwa Satake4Yui Akemoto5Nahoko Tanaka6Rina Watanabe7Maeda Takato8Yasuhisa Murai9Kayo Ueno10Takenori Niioka11Makoto Hayakari12Yoh Ishiguro13Shinsaku Fukuda14Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Corresponding author. Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Shibata Irika Co.Ltd.Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanDivision of Pharmaceutical Science, Hirosaki University Hospital, Hirosaki, JapanDivision of Pharmaceutical Science, Hirosaki University Hospital, Hirosaki, JapanDivision of Pharmaceutical Science, Hirosaki University Hospital, Hirosaki, JapanDivision of Clinical Research, Hirosaki National Hospital, National Hospital Organization, Hirosaki, JapanDepartment of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, JapanBackground and aims: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs. Methods: Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used. Results: Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of MCT1 mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative. Conclusion: Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.http://www.sciencedirect.com/science/article/pii/S2405580820301217ButyrateColitisCyclosporineIntestinal epithelial cellsMonocarboxylate transporter 1
spellingShingle Shinji Ota
Hirotake Sakuraba
Hiroto Hiraga
Shukuko Yoshida
Miwa Satake
Yui Akemoto
Nahoko Tanaka
Rina Watanabe
Maeda Takato
Yasuhisa Murai
Kayo Ueno
Takenori Niioka
Makoto Hayakari
Yoh Ishiguro
Shinsaku Fukuda
Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
Biochemistry and Biophysics Reports
Butyrate
Colitis
Cyclosporine
Intestinal epithelial cells
Monocarboxylate transporter 1
title Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
title_full Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
title_fullStr Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
title_full_unstemmed Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
title_short Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
title_sort cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels
topic Butyrate
Colitis
Cyclosporine
Intestinal epithelial cells
Monocarboxylate transporter 1
url http://www.sciencedirect.com/science/article/pii/S2405580820301217
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