The Mechanisms Of Cholestyramine Resin Improving Ischemic Cerebral Stroke Outcome In Obese Mice

BackgroundObesity is an important risk factor for cerebral ischemic stroke.It is demonstrated that gut dysbiosis plays an important role in the pathophysiology of cerebral ischemic stroke and obesity.It is proven that bile acid(BA)is a significant factor for high-fat diet(HFD)-induced gut dysbiosis.Cholestyramine resin(CR),a BA binding resin,confers protection against several cholestasis-related disorders.ObjectiveThis study aims to investigate whether CR improves stroke outcome in obese mice,as well as the underlying role of gut microbiota.MethodsMale C57BL/6J mice were randomly assigned into three groups.Normal diet(ND)group was raised with ND;45%HFD group fed a 45%HFD for eight weeks to induce an obese phenotype.In 45%HFD+CR group,CR was administered daily via oral gavage along with a 45%HFD for eight weeks.Body weight was recorded every week,the levels of blood lipids assessment and microbial profiling were performed after 8 weeks intervention.Then,middle cerebral artery occlusion(MCAO)model was established.At three days after stroke,infarct volume and the levels of serum inflammatory-related marks were determined,gut microbial composition was analyzed,the composition of BA and the levels of short chain fatty acids in cecal content were measured respectively.Furthermore,the roles of gut flora from different types of diet-fed mice in stroke outcome were elucidated by fecal microbiota transplantation(FMT).At three days after stroke,infarct volume,brain edema,neurological deficits and neuroinflammation were measured,intestinal barrier function and circulating inflammatory cytokines were determined,and the composition of the gut microbiota was analyzed.ResultsLong-term 45%HFD feeding induced an obesity phenotype and dyslipidemia.16S rRNA analysis revealed that obese mice displayed obvious gut dysbiosis.CR treatment alleviated 45%HFD-induced obesity,dyslipidemia and gut dysbiosis.Obese mice developed a larger infarct volume and higher serum levels of inflammatory cytokines after stroke,compared to their lean counterparts.Obese mice with stroke developed an obviously perturbed BA profile characterized by higher levels of glycodeoxycholic acid and taurodeoxycholic acid,and lower levels of butyrate in the cecal content.CR administration attenuated ischemic brain injury and systemic inflammation,modulated the stroke-perturbed BA profile and increased cecal butyrate level.Moreover,FMT experiments revealed that recolonization with dysbiotic microbiome from obese mice aggravated brain injury,intestinal barrier dysfunction and systemic inflammation in recipient mice after stroke,while these detrimental effects were weaken after recolonization with gut microbiome from CR-treated mice.ConclusionObesity induces gut dysbiosis,which worsens stroke outcomes,followed by the BA profile perturbation and butyrate level reduction.CR confers metabolic benefits and gut microbiota modulation in obese mice,alleviated ischemic brain injury and intestinal barrier disruption after stroke,which perhaps associated with gut microbial composition modulation,BA and butyrate metabolism alteration.