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MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice.
Neurogastroenterol Motil. 2018 09; 30(9):e13348.NM

Abstract

BACKGROUND

Alterations in intestinal permeability regulated by tight junctions (TJs) are associated with immune activation and visceral hypersensitivity in irritable bowel syndrome (IBS). Myosin light chain kinase (MLCK) is an important mediator of epithelial TJ. The aim of this study is to investigate the role of MLCK in the pathogenesis of IBS using a post infectious IBS (PI-IBS) mouse model.

METHODS

Trichinella spiralis-infected PI-IBS mouse model was used. Urine lactulose/mannitol ratio was measured to assess intestinal epithelial permeability. Western blotting was used to evaluate intestinal TJ protein (zonula occludens-1) and MLCK-associated protein expressions. Immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was determined by abdominal withdrawal reflex in response to colorectal distension.

RESULTS

Eight weeks after inoculation with T. spiralis, PI-IBS mice developed decreased pain and volume thresholds during colorectal distention, increased urine lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and decreased zonula occludens-1 expression compared to the control mice. MLCK expression was dramatically elevated in the colonic mucosa of PI-IBS mice compared to the control mice, alongside increased pMLC/MLC and decreased MLCP expression. Administration of MLCK inhibitor and TJ blocker both reversed the increased intestinal permeability, visceral hypersensitivity, and Th1-dominant immune profile in PI-IBS mice.

CONCLUSION

MLCK is a pivotal step in inducing increased intestinal permeability promoting low-grade intestinal immune activation and visceral hypersensitivity in PI-IBS mice. MLCK inhibitor may provide a potential therapeutic option in the treatment of IBS.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, CA, USA.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

MeSH

AnimalsHyperalgesiaIntestinal MucosaIntestinesIrritable Bowel SyndromeMaleMiceMyosin-Light-Chain KinasePermeabilityTight Junctions

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29644768

Citation

Long, Y, et al. "MLCK-mediated Intestinal Permeability Promotes Immune Activation and Visceral Hypersensitivity in PI-IBS Mice." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, vol. 30, no. 9, 2018, pp. e13348.

Long Y, Du L, Kim JJ, et al. MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice. Neurogastroenterol Motil. 2018;30(9):e13348.

Long, Y., Du, L., Kim, J. J., Chen, B., Zhu, Y., Zhang, Y., Yao, S., He, H., Zheng, X., Huang, Z., & Dai, N. (2018). MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 30(9), e13348. https://doi.org/10.1111/nmo.13348

Long Y, et al. MLCK-mediated Intestinal Permeability Promotes Immune Activation and Visceral Hypersensitivity in PI-IBS Mice. Neurogastroenterol Motil. 2018;30(9):e13348. PubMed PMID: 29644768.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - MLCK-mediated intestinal permeability promotes immune activation and visceral hypersensitivity in PI-IBS mice. AU - Long,Y, AU - Du,L, AU - Kim,J J, AU - Chen,B, AU - Zhu,Y, AU - Zhang,Y, AU - Yao,S, AU - He,H, AU - Zheng,X, AU - Huang,Z, AU - Dai,N, Y1 - 2018/04/11/ PY - 2017/09/19/received PY - 2018/03/08/accepted PY - 2018/4/13/pubmed PY - 2019/11/7/medline PY - 2018/4/13/entrez KW - immune activation KW - intestinal permeability KW - myosin light chain kinase KW - post infectious irritable bowel syndrome KW - visceral hypersensitivity SP - e13348 EP - e13348 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol Motil VL - 30 IS - 9 N2 - BACKGROUND: Alterations in intestinal permeability regulated by tight junctions (TJs) are associated with immune activation and visceral hypersensitivity in irritable bowel syndrome (IBS). Myosin light chain kinase (MLCK) is an important mediator of epithelial TJ. The aim of this study is to investigate the role of MLCK in the pathogenesis of IBS using a post infectious IBS (PI-IBS) mouse model. METHODS: Trichinella spiralis-infected PI-IBS mouse model was used. Urine lactulose/mannitol ratio was measured to assess intestinal epithelial permeability. Western blotting was used to evaluate intestinal TJ protein (zonula occludens-1) and MLCK-associated protein expressions. Immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was determined by abdominal withdrawal reflex in response to colorectal distension. RESULTS: Eight weeks after inoculation with T. spiralis, PI-IBS mice developed decreased pain and volume thresholds during colorectal distention, increased urine lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and decreased zonula occludens-1 expression compared to the control mice. MLCK expression was dramatically elevated in the colonic mucosa of PI-IBS mice compared to the control mice, alongside increased pMLC/MLC and decreased MLCP expression. Administration of MLCK inhibitor and TJ blocker both reversed the increased intestinal permeability, visceral hypersensitivity, and Th1-dominant immune profile in PI-IBS mice. CONCLUSION: MLCK is a pivotal step in inducing increased intestinal permeability promoting low-grade intestinal immune activation and visceral hypersensitivity in PI-IBS mice. MLCK inhibitor may provide a potential therapeutic option in the treatment of IBS. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/29644768/MLCK_mediated_intestinal_permeability_promotes_immune_activation_and_visceral_hypersensitivity_in_PI_IBS_mice_ DB - PRIME DP - Unbound Medicine ER -