| Background:Type 2 diabetes(T2D)is one of the major comorbidities in patients with acute ischemic stroke(AIS)that exacerbates brain injury,but the mechanism remains unclear.Recent studies have revealed that the pathology of cerebral ischemia/reperfusion can be influenced by the composition of the gut microbiota.The gut microbiota of T2D is featured by a decreased abundance of butyrate-producing bacteria.However,the role of the gut microbiota and the potential benefits of manipulating the dysbiotic gut microbiota in T2D are unknown.Objective:We compared the gut microbiota and the level of fecal butyrate between AIS patients with and without T2D.We further investigated whether the gut microbiota of T2D mice exacerbates AIS injury and whether modulating the gut microbiota by sodium butyrate(SB)attenuates AIS injury and investigated the underlying mechanism.Methods:We collected fecal samples from AIS patients with or without T2D within 72 hours of admission and drawn the first fast blood samples after admission to compare the gut microbiota,fecal butyrate level and plasma lipopolysaccharide(LPS),D-lactic acids(DLA)levels between the two groups.We supplied wild-type or T2D mice with SB or sodium chloride and compared the diabetes-related parameters during intervention and the gut microbiota and butyrate level after intervention.Then the mice were subjected to middle cerebral artery occlusion(MCAO)and the infarct volume were compared.We used wild-type mice as the recipients of fecal microbiota transplantation(FMT).After two weeks of antibiotics treatment,the recipient mice were transplanted with the gut microbiota from donor mice and then were subjected to MCAO.We compared the infarct volume,gut barrier function,expression of the adhesion molecule of the brain and the blood-brain barrier related measurements.Results:Compared with the gut microbiota of AIS patients without T2D,the gut microbiota of AIS patients with T2D was dysbiotic,characterized by decreased abundance of butyrate-producing bacteria and decreased concentration of butyrate,whereas the levels of LPS and DLA in the blood were increased.We also discovered that the composition of the gut microbiota of T2D mice resembled that of AIS patients with T2D.SB intervention improved diabetes-related parameters such as fast blood glucose level,blood lipid,serum proinflammatory factors including IL-6,TNF-α and IL-1β,and modulated the gut microbiota,elevating abundance of butyrate-producing bacteria and butyrate level.Moreover,SB intervention reduced the infarct volume of T2D mice.Compared with mice that received gut microbiota of T2D mice,mice received gut microbiota from SB treated T2D mice represented with reduced infarct volume,improved microglial cells activation in the infarcted side and less neuron apoptosis in the hippocampal CA1 region.We further found that the gut barrier of mice that received gut microbiota from SB treated T2D mice experienced less damage than mice that received gut microbiota from T2D mice,with decreased serum LPS,Lipopolysaccharide binding protein(LBP)and proinflammatory factors,which were accompanied by decreased expression of intercellular cell adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1)and matrix metalloprotein-9(MMP-9)in the brain,which protected the cerebral endothelial glycocalyx from degradation and blood-brain barrier related protein such as ZO-1,Occludin and Claudin-4 from destruction,and finally attenuated cerebral ischemia/reperfusion injury.Conclusion:The decreased abundance of the gut butyrate-producing bacteria and butyrate level of T2D results in deteriorated gut barrier,the LPS from the gut enters the circulation,enhancing the systemic inflammatory reaction and increasing the expression of adhesion molecules in the brain,which destroy the cerebral endothelial glycocalyx and further damage the blood-brain barrier,and finally exacerbate brain injury;while the gut microbiota modulated by SB improves the above inflammatory reactions and attenuates brain injury. |
PDF Full Text Request