Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice

ABSTRACT Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointes...

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Autores principales:	Marie Hagbom, Felipe Meira De Faria, Martin E. Winberg, Sonja Westerberg, Johan Nordgren, Sumit Sharma, Åsa V. Keita, Vesa Loitto, Karl-Eric Magnusson, Lennart Svensson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	diarrhea neurotrophic factors permeability rotavirus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8ed4ba094146458fb81565723b06ea5f
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spelling	oai:doaj.org-article:8ed4ba094146458fb81565723b06ea5f2021-11-15T15:56:57ZNeurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice10.1128/mBio.02834-192150-7511https://doaj.org/article/8ed4ba094146458fb81565723b06ea5f2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02834-19https://doaj.org/toc/2150-7511ABSTRACT Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system, which is composed of neurons and enteric glial cells (EGCs). We investigated whether the vagus nerve, serotonin (5-HT), EGCs, and neurotropic factors contribute to maintaining gut barrier homeostasis during rotavirus infection. Using subdiaphragmatic vagotomized and 5-HT3 receptor knockout mice, we found that the unaffected epithelial barrier during rotavirus infection is independent of the vagus nerve but dependent on 5-HT signaling through enteric intrinsic 5-HT3 receptors. Immunofluorescence analysis showed that rotavirus-infected enterocytes were in close contact with EGCs and enteric neurons and that the glial cell-derived neurotrophic factor (GDNF) was strongly upregulated in enterocytes of infected mice. Moreover, rotavirus and 5-HT activated EGCs (P < 0.001). Using Ussing chambers, we found that GDNF and S-nitrosoglutathione (GSNO) led to denser epithelial barriers in small intestinal resections from noninfected mice (P < 0.01) and humans (P < 0.001) and that permeability was unaffected in rotavirus-infected mice. GSNO made the epithelial barrier denser in Caco-2 cells by increasing the expression of the tight junction protein zona occludens 1 (P < 0.001), resulting in reduced passage of fluorescein isothiocyanate dextran (P < 0.05) in rotavirus-infected monolayers. This is the first report to show that neurotropic factors contribute to maintaining the gut epithelial barrier during viral insult. IMPORTANCE Human and mouse studies have shown that rotavirus infection is associated with low inflammation and unaffected intestinal barrier at the time of diarrhea, properties different from most bacterial and inflammatory diseases of the gut. We showed by in vitro, ex vivo, and in vivo experiments that neurotrophic factors and 5-HT have barrier protective properties during rotavirus insult. These observations advance our understanding of how the gut barrier is protected against rotavirus and suggest that rotavirus affects the gut barrier differently from bacteria. This is the first report to show that neurotrophic factors contribute to maintain the gut epithelial barrier during viral insult.Marie HagbomFelipe Meira De FariaMartin E. WinbergSonja WesterbergJohan NordgrenSumit SharmaÅsa V. KeitaVesa LoittoKarl-Eric MagnussonLennart SvenssonAmerican Society for Microbiologyarticlediarrheaneurotrophic factorspermeabilityrotavirusMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	diarrhea neurotrophic factors permeability rotavirus Microbiology QR1-502
spellingShingle	diarrhea neurotrophic factors permeability rotavirus Microbiology QR1-502 Marie Hagbom Felipe Meira De Faria Martin E. Winberg Sonja Westerberg Johan Nordgren Sumit Sharma Åsa V. Keita Vesa Loitto Karl-Eric Magnusson Lennart Svensson Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
description	ABSTRACT Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system, which is composed of neurons and enteric glial cells (EGCs). We investigated whether the vagus nerve, serotonin (5-HT), EGCs, and neurotropic factors contribute to maintaining gut barrier homeostasis during rotavirus infection. Using subdiaphragmatic vagotomized and 5-HT3 receptor knockout mice, we found that the unaffected epithelial barrier during rotavirus infection is independent of the vagus nerve but dependent on 5-HT signaling through enteric intrinsic 5-HT3 receptors. Immunofluorescence analysis showed that rotavirus-infected enterocytes were in close contact with EGCs and enteric neurons and that the glial cell-derived neurotrophic factor (GDNF) was strongly upregulated in enterocytes of infected mice. Moreover, rotavirus and 5-HT activated EGCs (P < 0.001). Using Ussing chambers, we found that GDNF and S-nitrosoglutathione (GSNO) led to denser epithelial barriers in small intestinal resections from noninfected mice (P < 0.01) and humans (P < 0.001) and that permeability was unaffected in rotavirus-infected mice. GSNO made the epithelial barrier denser in Caco-2 cells by increasing the expression of the tight junction protein zona occludens 1 (P < 0.001), resulting in reduced passage of fluorescein isothiocyanate dextran (P < 0.05) in rotavirus-infected monolayers. This is the first report to show that neurotropic factors contribute to maintaining the gut epithelial barrier during viral insult. IMPORTANCE Human and mouse studies have shown that rotavirus infection is associated with low inflammation and unaffected intestinal barrier at the time of diarrhea, properties different from most bacterial and inflammatory diseases of the gut. We showed by in vitro, ex vivo, and in vivo experiments that neurotrophic factors and 5-HT have barrier protective properties during rotavirus insult. These observations advance our understanding of how the gut barrier is protected against rotavirus and suggest that rotavirus affects the gut barrier differently from bacteria. This is the first report to show that neurotrophic factors contribute to maintain the gut epithelial barrier during viral insult.
format	article
author	Marie Hagbom Felipe Meira De Faria Martin E. Winberg Sonja Westerberg Johan Nordgren Sumit Sharma Åsa V. Keita Vesa Loitto Karl-Eric Magnusson Lennart Svensson
author_facet	Marie Hagbom Felipe Meira De Faria Martin E. Winberg Sonja Westerberg Johan Nordgren Sumit Sharma Åsa V. Keita Vesa Loitto Karl-Eric Magnusson Lennart Svensson
author_sort	Marie Hagbom
title	Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
title_short	Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
title_full	Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
title_fullStr	Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
title_full_unstemmed	Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice
title_sort	neurotrophic factors protect the intestinal barrier from rotavirus insult in mice
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/8ed4ba094146458fb81565723b06ea5f
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Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice

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