Chronic Exposure to Subtherapeutic Antibiotics Aggravates Ischemic Stroke Outcome in Mice

Dong, Xiaohui; Peng, Cheng; Zhang, Yu-Yi; Tao, Yulong; Xia, Tao; Zhang, Chuan; Chen, Alex F.; Xie, He-Hui

doi:10.1016/j.ebiom.2017.09.002

Cited by 12 publications

(15 citation statements)

References 18 publications

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“…We also find that carbon metabolism, with 15 enriched proteins, is the main metabolic pathway. It contributes to complex biological processes that suppress neuroinflammation, induction of hypoxia, and apoptosis, which is consistent with previous studies (Dong et al, 2017;Fedorovich et al, 2017;Correa-Costa et al, 2018). Our analysis reveals that most of the proteins were downregulated in these pathways, implying their important role in binding, metabolism and brain development, response to drug, and the immune system.…”

Section: Discussionsupporting

confidence: 91%

Proteomics Analysis of Brain Tissue in a Rat Model of Ischemic Stroke in the Acute Phase

Zheng

Zhou

Zeng

et al. 2020

Front. Mol. Neurosci.

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Background: Stroke is a leading health issue, with high morbidity and mortality rates worldwide. Of all strokes, approximately 80% of cases are ischemic stroke (IS). However, the underlying mechanisms of the occurrence of acute IS remain poorly understood because of heterogeneous and multiple factors. More potential biomarkers are urgently needed to reveal the deeper pathogenesis of IS. Methods: We identified potential biomarkers in rat brain tissues of IS using an iTRAQ labeling approach coupled with LC-MS/MS. Furthermore, bioinformatrics analyses including GO, KEGG, DAVID, and Cytoscape were used to present proteomic profiles and to explore the disease mechanisms. Additionally, Western blotting for target proteins was conducted for further verification. Results: We identified 4,578 proteins using the iTRAQ-based proteomics method. Of these proteins, 282 differentiated proteins, comprising 73 upregulated and 209 downregulated proteins, were observed. Further bioinformatics analysis suggested that the candidate proteins were mainly involved in energy liberation, intracellular protein transport, and synaptic plasticity regulation during the acute period. KEGG pathway enrichment analysis indicated a series of representative pathological pathways, including energy metabolite, long-term potentiation (LTP), and neurodegenerative disease-related pathways. Moreover, Western blotting confirmed the associated candidate proteins, which refer to oxidative responses and synaptic plasticity. Conclusions: Our findings highlight the identification of candidate protein biomarkers and provide insight into the biological processes involved in acute IS.

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Section: Discussionsupporting

confidence: 91%

Proteomics Analysis of Brain Tissue in a Rat Model of Ischemic Stroke in the Acute Phase

Zheng

Zhou

Zeng

et al. 2020

Front. Mol. Neurosci.

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“…Furthermore, long‐term administration of vancomycin actually impairs endothelial cell function in mice (Dong et al . ). Thus, if anything, it is possible that the antibiotic cocktail used may have exerted adverse direct effects on arterial function that countered the beneficial effects of gut microbiome suppression.…”

Section: Discussionmentioning

confidence: 97%

Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice

Brunt

Gioscia‐Ryan

Richey

et al. 2019

The Journal of Physiology

140

118

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Key pointsr Age-related arterial dysfunction, characterized by oxidative stress-and inflammation-mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases.Vienna E. Brunt received her PhD in Human Physiology from the University of Oregon in 2016. She is currently a postdoctoral fellow in Dr D. R. Seals' Integrative Physiology of Aging Laboratory at the University of Colorado Boulder. The studies described in the present study represent work carried out as part of an NIH T32 fellowship through the Division of Cardiology at the University of Colorado Denver. Her long-term research goals are to investigate the efficacy of novel interventions for preserving vascular function with ageing, thereby preventing and/or delaying the progression of cardiovascular diseases. Rachel A. Gioscia-Ryan completed her PhD in the Integrative Physiology of Aging Laboratory at the University of Colorado Boulder in 2016 and is currently in medical school at the University of Michigan. She is pursuing a career as a clinician-scientist conducting integrative physiological studies with the aim of improving human health and patient care. * These authors contributed equally to this work.Abstract Oxidative stress-mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age-related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation ('gut dysbiosis') has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3-4 weeks of treatment with broad-spectrum, poorly-absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age-related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut-derived metabolite trimethylamine N-oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area-under-the-curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s −1 vs. OC: 4.43 ± 0.38 m s −1 ; vs. OA: 3.52 ± 0.35 m s −1 ; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 μmol L −1 vs. OC: 7.2 ± 2.0 μmol L −1 ; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L −1 ; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and ...

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“…Therefore, several studies examined the impact of antibiotic treatment on the outcomes in hosts with ischemic brain injury. For example, Benakis et al (2016) reported that orally administered amoxicillin/clavulanic acid reduces ischemic brain injury in mice by regulating gut microbiota composition, while Dong et al (2017) reported that orally prophylactic treatment with an antibiotic cocktail consisting of chlortetracycline, penicillin VK, and vancomycin could not reduce microbial infection, and Winek et al (2016) reported that the depletion of gut microbiota by oral prophylactic treatment with an antibiotic cocktail consisting of ampicillin, vancomycin, ciprofloxacin, imipenem, and metronidazole deteriorates the outcome after murine stroke. Singh et al (2016) reported that fecal microbiota transplantation of healthy mice into middle cerebral artery (MCA) occlusion-operated mice alleviated the stroke outcome.…”

Section: Introductionmentioning

confidence: 99%

Orally Administered Antibiotics Vancomycin and Ampicillin Cause Cognitive Impairment With Gut Dysbiosis in Mice With Transient Global Forebrain Ischemia

Lee

Kim

2020

Front. Microbiol.

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Gut microbiota is closely associated with the occurrence of neuropsychiatric disorders. Antibiotics are frequently used to prevent pathogen infection in patients with brain ischemia. To understand the impact of prophylactic antibiotic treatment for patients with brain ischemia, we examined the effects of orally administered vancomycin and ampicillin on cognitive function and gut microbiota composition in mice with transient global forebrain ischemia (tIsc). tIsc operation and orally gavaged vancomycin mildly and moderately caused cognitive impairment, respectively. However, the exposure of mice with tIsc to vancomycin or ampicillin severely impaired cognitive function in the Y-maze, novel object recognition, and Banes maze tasks. Furthermore, their treatments induced NF-κB activation as well as active microglia (NF-κB+/Iba1+ and LPS+/Iba1+ cells) and apoptotic (caspase 3+/NeuN+) cell population in the hippocampus, whereas the brain-derived neurotrophic factor (BDNF)+/NeuN+ cell populations decreased. These treatments also caused colitis and gut dysbiosis. They increased the population of Proteobacteria including Enterobacter xiangfangenesis. Orally delivered fecal transplantation of vancomycin-treated mice with or without tIsc and oral gavage of Enterobacter xiangfangenesis also significantly deteriorated the cognitive impairment and colitis in transplanted mice with tIsc. These findings suggest that oral administration of antibiotics can deteriorate cognitive impairment with gut dysbiosis in patients with brain ischemia.

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Chronic Exposure to Subtherapeutic Antibiotics Aggravates Ischemic Stroke Outcome in Mice

Cited by 12 publications

References 18 publications

Proteomics Analysis of Brain Tissue in a Rat Model of Ischemic Stroke in the Acute Phase

Proteomics Analysis of Brain Tissue in a Rat Model of Ischemic Stroke in the Acute Phase

Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice

Orally Administered Antibiotics Vancomycin and Ampicillin Cause Cognitive Impairment With Gut Dysbiosis in Mice With Transient Global Forebrain Ischemia

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