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Metabolic endotoxemia promotes neuroinflammation after focal cerebral ischemia.
- Source :
-
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2020 Dec; Vol. 40 (12), pp. 2505-2520. Date of Electronic Publication: 2020 Jan 07. - Publication Year :
- 2020
-
Abstract
- Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria and a potent inflammatory stimulus for the innate immune response via toll-like receptor (TLR) 4 activation. Type 2 diabetes is associated with changes in gut microbiota and impaired intestinal barrier functions, leading to translocation of microbiota-derived LPS into the circulatory system, a condition referred to as metabolic endotoxemia. We investigated the effects of metabolic endotoxemia after experimental stroke with transient middle cerebral artery occlusion (MCAO) in a murine model of type 2 diabetes ( db/db ) and phenotypically normal littermates ( db/+ ). Compared to db/+ mice, db/db mice exhibited an altered gut microbial composition, increased intestinal permeability, and higher plasma LPS levels. In addition, db/db mice presented increased infarct volumes and higher expression levels of LPS, TLR4, and inflammatory cytokines in the ischemic brain, as well as more severe neurological impairments and reduced survival rates after MCAO. Oral administration of a non-absorbable antibiotic modulated the gut microbiota and improved metabolic endotoxemia and stroke outcomes in db/db mice; these effects were associated with reduction of LPS levels and neuroinflammation in the ischemic brain. These data suggest that targeting metabolic endotoxemia may be a novel potential therapeutic strategy to improve stroke outcomes.
- Subjects :
- Administration, Oral
Animals
Anti-Bacterial Agents administration & dosage
Anti-Bacterial Agents therapeutic use
Brain Ischemia pathology
Case-Control Studies
Cytokines metabolism
Diabetes Mellitus, Type 2 complications
Endotoxemia drug therapy
Endotoxemia physiopathology
Gastrointestinal Microbiome drug effects
Gastrointestinal Microbiome physiology
Gram-Negative Bacteria metabolism
Immunity, Innate drug effects
Infarction, Middle Cerebral Artery complications
Infarction, Middle Cerebral Artery pathology
Infarction, Middle Cerebral Artery veterinary
Lipopolysaccharides blood
Lipopolysaccharides pharmacology
Male
Mice
Models, Animal
Neurogenic Inflammation drug therapy
Neurogenic Inflammation physiopathology
Polymyxin B administration & dosage
Polymyxin B therapeutic use
Stroke metabolism
Survival Rate
Toll-Like Receptor 4 drug effects
Toll-Like Receptor 4 metabolism
Brain Ischemia metabolism
Endotoxemia metabolism
Lipopolysaccharides metabolism
Neurogenic Inflammation metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1559-7016
- Volume :
- 40
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 31910709
- Full Text :
- https://doi.org/10.1177/0271678X19899577