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.
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.
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DOI：
10.1016/j.lfs.2021.120153
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发表时间：
2022-01-01
期刊：
影响因子：
6.1
通讯作者：
Curras-Collazo MC
中科院分区：
文献类型：
--
作者：
Kozlova EV;Carabelli B;Bishay AE;Liu R;Denys ME;Macbeth JC;Piamthai V;Crawford MS;McCole DF;Zur Nieden NI;Hsiao A;Curras-Collazo MC
在海湾战争病（GWI）小鼠模型中，描述伴随过度运动疲劳和认知/情绪缺陷的神经炎症和肠道生态失调特征。成年雄性C57 Bl/6 N小鼠经口给予溴化吡啶斯的明28 d（5 d/wk）。6.5 mg/kg/d，b.i.d. (GW1)或8.7 mg/kg/d，q.d. (GW2)局部二氯苯醚菊酯（1.3 mg/kg）、局部N，N-二乙基间甲苯酰胺（33%）和束缚应激（5 min）。如随附文章[124]所述对动物进行表型评价，并在治疗后6.6个月（PT）处死，以测量脑神经炎症/神经性疼痛基因表达、海马神经胶质细胞酸性蛋白、脑白细胞介素-6、肠道生态失调和血清内毒素。与GW 1相比，GW 2显示出相对于假应激对照更强烈的神经炎性转录特征。两个GW组中，GW 2中的白细胞介素-6升高，海马CA 1中的星形胶质细胞增生。使用加权Unifrac的β多样性PCoA显示，在PT 188暴露于GW 2后，肠道微生物群落发生了变化。GW 1和GW 2均显示全身性内毒素血症，表明神经病理学特征的肠-脑机制。使用无菌小鼠，补充罗伊氏乳杆菌的益生菌比使用GW 2粪便的微生物群移植产生更少的肠道通透性。我们的研究结果表明，GW剂剂量依赖性地诱导与认知，运动疲劳和情绪GWI表型相关的差异神经病理学和肠道生态失调。建立一个全面的动物模型，概括了多个GWI症状域和神经炎症有显着的意义，揭示病理生理学，提高诊断和治疗GWI。
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). 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. 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. 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.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.3
作者：
Bonaz B;Bazin T;Pellissier S
通讯作者：
Pellissier S
影响因子：
4.7
作者：
Breit S;Kupferberg A;Rogler G;Hasler G
通讯作者：
Hasler G
影响因子：
3.3
作者：
Almolda, Beatriz;Costa, Manuela;Castellano, Bernardo
通讯作者：
Castellano, Bernardo
影响因子：
5.9
作者：
Bose D;Saha P;Mondal A;Fanelli B;Seth RK;Janulewicz P;Sullivan K;Lasley S;Horner R;Colwell RR;Shetty AK;Klimas N;Chatterjee S
通讯作者：
Chatterjee S