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Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment
AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048156/ https://www.ncbi.nlm.nih.gov/pubmed/34801513 http://dx.doi.org/10.1016/j.lfs.2021.120153 |
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author | Kozlova, Elena V. Carabelli, Bruno Bishay, Anthony E. Liu, Rui Denys, Maximillian E. Macbeth, John C. Piamthai, Varadh Crawford, Meli’sa S. McCole, Declan F. zur Nieden, Nicole I. Hsiao, Ansel Curras-Collazo, Margarita C. |
author_facet | Kozlova, Elena V. Carabelli, Bruno Bishay, Anthony E. Liu, Rui Denys, Maximillian E. Macbeth, John C. Piamthai, Varadh Crawford, Meli’sa S. McCole, Declan F. zur Nieden, Nicole I. Hsiao, Ansel Curras-Collazo, Margarita C. |
author_sort | Kozlova, Elena V. |
collection | PubMed |
description | AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI. |
format | Online Article Text |
id | pubmed-9048156 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-90481562022-04-28 Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment Kozlova, Elena V. Carabelli, Bruno Bishay, Anthony E. Liu, Rui Denys, Maximillian E. Macbeth, John C. Piamthai, Varadh Crawford, Meli’sa S. McCole, Declan F. zur Nieden, Nicole I. Hsiao, Ansel Curras-Collazo, Margarita C. Life Sci Article AIMS: To characterize neuroinflammatory and gut dysbiosis signatures that accompany exaggerated exercise fatigue and cognitive/mood deficits in a mouse model of Gulf War Illness (GWI). METHODS: Adult male C57Bl/6N mice were exposed for 28 d (5 d/wk) to pyridostigmine bromide (P.O.) at 6.5 mg/kg/d, b.i.d. (GW1) or 8.7 mg/kg/d, q.d. (GW2); topical permethrin (1.3 mg/kg), topical N,N-diethyl-meta-toluamide (33%) and restraint stress (5 min). Animals were phenotypically evaluated as described in an accompanying article [124] and sacrificed at 6.6 months post-treatment (PT) to allow measurement of brain neuroinflammation/neuropathic pain gene expression, hippocampal glial fibrillary acidic protein, brain Interleukin-6, gut dysbiosis and serum endotoxin. KEY FINDINGS: Compared to GW1, GW2 showed a more intense neuroinflammatory transcriptional signature relative to sham stress controls. Interleukin-6 was elevated in GW2 and astrogliosis in hippocampal CA1 was seen in both GW groups. Beta-diversity PCoA using weighted Unifrac revealed that gut microbial communities changed after exposure to GW2 at PT188. Both GW1 and GW2 displayed systemic endotoxemia, suggesting a gut-brain mechanism underlies the neuropathological signatures. Using germ-free mice, probiotic supplementation with Lactobacillus reuteri produced less gut permeability than microbiota transplantation using GW2 feces. SIGNIFICANCE: Our findings demonstrate that GW agents dose-dependently induce differential neuropathology and gut dysbiosis associated with cognitive, exercise fatigue and mood GWI phenotypes. Establishment of a comprehensive animal model that recapitulates multiple GWI symptom domains and neuroinflammation has significant implications for uncovering pathophysiology, improving diagnosis and treatment for GWI. 2022-01-01 2021-11-18 /pmc/articles/PMC9048156/ /pubmed/34801513 http://dx.doi.org/10.1016/j.lfs.2021.120153 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Kozlova, Elena V. Carabelli, Bruno Bishay, Anthony E. Liu, Rui Denys, Maximillian E. Macbeth, John C. Piamthai, Varadh Crawford, Meli’sa S. McCole, Declan F. zur Nieden, Nicole I. Hsiao, Ansel Curras-Collazo, Margarita C. Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title | Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title_full | Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title_fullStr | Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title_full_unstemmed | Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title_short | Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment |
title_sort | induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of gwi showing persistent exercise fatigue and cognitive impairment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048156/ https://www.ncbi.nlm.nih.gov/pubmed/34801513 http://dx.doi.org/10.1016/j.lfs.2021.120153 |
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