Dataset Information

Gut microbiota induce neutrophil activation that aggravates stroke pathology

ABSTRACT: Neutrophils, key players in the innate immune system, become activated following ischemic stroke. However, the influence of gut microbiota on neutrophil activation and its impact on inflammatory brain injury is not yet fully understood. In this study, we demonstrate that microbiota colonization in germ-free mice activates neutrophils and worsens disease outcomes. To investigate the phenotypic and molecular alterations in neutrophils, as well as their activity in stroke mice with either depleted or intact microbiota, we conducted a comparative proteomic analysis using liquid chromatography-based mass spectrometry. Our findings revealed that microbiota depletion leads to a downregulation of inflammatory proteins in circulating neutrophils and a reduction in neutrophil extracellular traps (NETs). A similar pattern was observed in neutrophils infiltrating the brain, accompanied by a decrease in infarct size and alleviated behavioral deficits.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Neutrophil, Blood

DISEASE(S): Brain Ischemia

SUBMITTER: Susmita Ghosh

LAB HEAD: Albert Sickmann

PROVIDER: PXD060229 | Pride | 2025-06-02

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	Sample_Table.xlsx	Xlsx
	Stroke_blood_neutrophils.sne	Other
	Stroke_brain_neutrophils.sne	Other
	Stroke_mice_Blood.zip	Other
	Stroke_mice_brain.zip	Other

Items per page:

1 - 5 of 6

Publications

Gut microbiota deficiency reduces neutrophil activation and is protective after ischemic stroke.

Tuz Ali A AA Ghosh Susmita S Karsch Laura L Antler Medina M Lakovic Vivian V Lohmann Sabrina S Lehmann Amber Hope AH Beer Alexander A Nagel Dennis D Jung Marcel M Hörenbaum Nils N Kaygusuz Viola V Qefalia Altea A Alshaar Belal B Amookazemi Niloufar N Bolsega Silvia S Basic Marijana M Siveke Jens T JT Heiles Sven S Grüneboom Anika A Lueong Smiths S Herz Josephine J Sickmann Albert A Hagemann Nina N Hasenberg Anja A Hermann Dirk M DM Gunzer Matthias M Singh Vikramjeet V

Journal of neuroinflammation 20250523 1

Neutrophils are readily activated immune cells after ischemic stroke in mice and patients. Still, the impact of gut microbiota on neutrophil activation and its influence on inflammatory brain injury remain undefined. We report that natural microbiota colonization of germ-free (GF) mice induces substantial neutrophil activation and deteriorates stroke pathology. The colonized Ex-GF stroke mice had considerably larger infarct sizes and higher sensorimotor deficits than GF littermates. Furthermore, ...[more]

PMID: 40410847

Similar Datasets

Project description:Background: Sustained sleep insufficiency impairs immune system and increases the adverse outcomes of cardiovascular diseases. However, the role and mechanisms prolonged sleep fragmentation (SF) on the outcomes of myocardial infarction (MI) remains elusive. Methods: Among 497 MI patients with complete sleep data participating in the National Health and Nutrition Examination Survey, the association between different types of sleep disorders and post-MI survivability was evaluated. We then developed a mouse model with 10 weeks of SF followed by MI surgery. Emergency hematopoiesis and neutrophil expansion were analyzed. Potential mechanisms were explored using bone marrow (BM) transplantation, anti-SiglecF neutralizing antibodies and Interferon alpha and beta receptor subunit 1 knockout (Ifnar1-/-) in BM. Results: Frequent nocturnal awakening independently predicted reduced survival rate of MI patients, with a hazard ratio (HR) of 2.136 (95% CI=1.142-3.995). Increased infarct size, deteriorated cardiac function and lower survival rate were also observed in MI mice pretreated with 10-week SF. SF facilitated post-MI neutrophil expansion and infiltration into infarct area, differentiating into SiglecFhi subset. Inhibition of SiglecFhi neutrophils allowed for the alleviations of post-MI cardiac remodeling. Furthermore, BM progenitors were skewed toward neutrophil lineage concomitant with the clonal expansion of granulocyte-monocyte progenitors (GMPs) in MI mice pretreated with 10-week SF. Transcriptome analysis and functional experiments revealed that activation of type I interferon (IFN) signaling was involved in this process, while depletion of Ifnar1 in BM and administration of IFNAR1-neutralizing antibodies significantly alleviated post-MI cardiac remodeling and neutrophil expansion. Conclusions: SF aggravates post-MI cardiac remodeling and dysfunction through promoting GMP differentiation and neutrophil expansion. Blockage of type I IFN could alleviate this detrimental influence.

Project description:Background: Transient ischemic attack (TIA) induces ischemic tolerance that can reduce the subsequent ischemic damage and improve prognosis of stroke patients. However, the underlying mechanisms remain elusive. Recent advances in plasma metabolomics analysis have made it a powerful tool to investigate human pathophysiological phenotypes and mechanisms of diseases. In this study, we aimed to identify the bioactive metabolites from the plasma of TIA patients for determination of their prophylactic and therapeutic effects on protection against cerebral ischemic stroke, and the mechanism of TIA-induced ischemic tolerance against subsequent stroke. Methods: Metabolomic profiling using liquid chromatography-mass spectrometry was performed to identify the TIA-induced differential bioactive metabolites in the plasma samples of 20 patients at day 1 (time for basal metabolites) and day 7 (time for established chronic ischemic tolerance-associated metabolites) after onset of TIA. Mouse MCAO-induced stroke model was used to verify their prophylactic and therapeutic potentials. Transcriptomics changes in circulating neutrophils of TIA patients were determined by RNA-sequencing. Multivariate statistics and integrative analysis of metabolomics and transcriptomics were performed to elucidate the potential mechanism of TIA-induced ischemic tolerance. Findings: Plasma metabolomics analysis identified five differentially upregulated metabolites associated with TIA-induced ischemic tolerance, namely all-trans 13,14 dihydroretinol (atDR), 20-carboxyleukotriene B4, prostaglandin B2, cortisol and 9-KODE. They were associated with the metabolic pathways of retinol, arachidonic acid, and neuroactive ligand-receptor interaction. Prophylactic treatment of MCAO mice with these five metabolites significantly improved neurological functions. Additionally, post-stroke treatment with atDR or 9-KODE significantly reduced the cerebral infarct size and enhanced sensorimotor functions, demonstrating the therapeutic potential of these bioactive metabolites. Mechanistically, we found in TIA patients that these metabolites were positively correlated with circulating neutrophil counts. Integrative analysis of plasma metabolomics and neutrophil transcriptomics further revealed that TIA-induced metabolites are significantly correlated with specific gene expression in circulating neutrophils which showed prominent enrichment in FoxO signaling pathway and upregulation of the anti-inflammatory cytokine IL-10. Finally, we demonstrated that the protective effect of atDR-pretreatment on MCAO mice was abolished when circulating neutrophils were depleted. Interpretation: TIA-induced ischemic tolerance is associated with upregulation of plasma bioactive metabolites which can protect against cerebral ischemic damage and improve neurological functions through a positive role of circulating neutrophils.