Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
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
_version_ 1784695876382359552
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
work_keys_str_mv AT kozlovaelenav inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT carabellibruno inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT bishayanthonye inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT liurui inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT denysmaximilliane inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT macbethjohnc inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT piamthaivaradh inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT crawfordmelisas inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT mccoledeclanf inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT zurniedennicolei inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT hsiaoansel inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment
AT currascollazomargaritac inductionofdistinctneuroinflammatorymarkersandgutdysbiosisbydifferentialpyridostigminebromidedosinginachronicmousemodelofgwishowingpersistentexercisefatigueandcognitiveimpairment