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Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress
Excessive dietary salt intake induces neuroinflammation and oxidative stress in the brain, which lead to sympathetic excitation, contributing to hypertension. However, the underlying mechanisms remain elusive. Accumulating evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-derived...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961329/ https://www.ncbi.nlm.nih.gov/pubmed/35359866 http://dx.doi.org/10.3389/fphar.2022.856914 |
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author | Liu, Gang Cheng, Jiayin Zhang, Tianhao Shao, Yingxin Chen, Xiangxu Han, Lihong Zhou, Ru Wu, Bin |
author_facet | Liu, Gang Cheng, Jiayin Zhang, Tianhao Shao, Yingxin Chen, Xiangxu Han, Lihong Zhou, Ru Wu, Bin |
author_sort | Liu, Gang |
collection | PubMed |
description | Excessive dietary salt intake induces neuroinflammation and oxidative stress in the brain, which lead to sympathetic excitation, contributing to hypertension. However, the underlying mechanisms remain elusive. Accumulating evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, is implicated in the pathogenesis of multiple cardiovascular diseases. The present study sought to determine whether central TMAO is elevated and associated with neuroinflammation and oxidative stress in the brain after long-term high salt (HS) diet intake and, if so, whether inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension. Sprague–Dawley rats were fed either a HS diet or a normal salt (NS) diet and simultaneously treated with vehicle (VEH) or 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) for 8 weeks. HS + VEH rats, compared with NS + VEH rats, had elevated TMAO in plasma and cerebrospinal fluid (CSF), increased blood pressure (BP), and increased sympathetic drive as indicated by the BP response to ganglionic blockade and plasma norepinephrine levels. HS-induced these changes were attenuated by DMB, which significantly reduced TMAO in plasma and CSF. Neuroinflammation as assessed by proinflammatory cytokine expression and NF-κB activity and microglial activity, and oxidative stress as measured by NAD(P)H oxidase subunit expression and NAD(P)H activity and reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) were increased in HS + VEH rats but were decreased by DMB. DMB had no effects on above measured parameters in NS rats. The results suggest that long-term HS diet intake causes elevation in TMAO in the circulation and brain, which is associated with increased neuroinflammation and oxidative stress in the PVN, an important cardiovascular regulatory center. Inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension by reducing neuroinflammation and oxidative stress in the PVN. |
format | Online Article Text |
id | pubmed-8961329 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89613292022-03-30 Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress Liu, Gang Cheng, Jiayin Zhang, Tianhao Shao, Yingxin Chen, Xiangxu Han, Lihong Zhou, Ru Wu, Bin Front Pharmacol Pharmacology Excessive dietary salt intake induces neuroinflammation and oxidative stress in the brain, which lead to sympathetic excitation, contributing to hypertension. However, the underlying mechanisms remain elusive. Accumulating evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, is implicated in the pathogenesis of multiple cardiovascular diseases. The present study sought to determine whether central TMAO is elevated and associated with neuroinflammation and oxidative stress in the brain after long-term high salt (HS) diet intake and, if so, whether inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension. Sprague–Dawley rats were fed either a HS diet or a normal salt (NS) diet and simultaneously treated with vehicle (VEH) or 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) for 8 weeks. HS + VEH rats, compared with NS + VEH rats, had elevated TMAO in plasma and cerebrospinal fluid (CSF), increased blood pressure (BP), and increased sympathetic drive as indicated by the BP response to ganglionic blockade and plasma norepinephrine levels. HS-induced these changes were attenuated by DMB, which significantly reduced TMAO in plasma and CSF. Neuroinflammation as assessed by proinflammatory cytokine expression and NF-κB activity and microglial activity, and oxidative stress as measured by NAD(P)H oxidase subunit expression and NAD(P)H activity and reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) were increased in HS + VEH rats but were decreased by DMB. DMB had no effects on above measured parameters in NS rats. The results suggest that long-term HS diet intake causes elevation in TMAO in the circulation and brain, which is associated with increased neuroinflammation and oxidative stress in the PVN, an important cardiovascular regulatory center. Inhibition of TMAO generation ameliorates HS-induced sympathetic excitation and hypertension by reducing neuroinflammation and oxidative stress in the PVN. Frontiers Media S.A. 2022-03-10 /pmc/articles/PMC8961329/ /pubmed/35359866 http://dx.doi.org/10.3389/fphar.2022.856914 Text en Copyright © 2022 Liu, Cheng, Zhang, Shao, Chen, Han, Zhou and Wu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Liu, Gang Cheng, Jiayin Zhang, Tianhao Shao, Yingxin Chen, Xiangxu Han, Lihong Zhou, Ru Wu, Bin Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title | Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title_full | Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title_fullStr | Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title_full_unstemmed | Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title_short | Inhibition of Microbiota-dependent Trimethylamine N-Oxide Production Ameliorates High Salt Diet-Induced Sympathetic Excitation and Hypertension in Rats by Attenuating Central Neuroinflammation and Oxidative Stress |
title_sort | inhibition of microbiota-dependent trimethylamine n-oxide production ameliorates high salt diet-induced sympathetic excitation and hypertension in rats by attenuating central neuroinflammation and oxidative stress |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961329/ https://www.ncbi.nlm.nih.gov/pubmed/35359866 http://dx.doi.org/10.3389/fphar.2022.856914 |
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