Cholestyramine resin administration alleviated cerebral ischemic injury in obese mice by improving gut dysbiosis and modulating the bile acid profile

Obesity is a risk factor for cerebrovascular diseases. Accumulating evidence has revealed that gut dysbiosis plays an important role in the pathophysiology of cerebrovascular diseases. However, little is known about the role of gut dysbiosis in stroke in obesity. In this study, we established a rodent middle cerebral artery occlusion (MCAO) model to investigate whether obesity-induced gut dysbiosis exacerbates cerebral ischemic injury and the role of the bile salt sequestrant cholestyramine resin (CR) in gut microbiota and stroke outcome in obese mice. Long-term 45% high-fat diet (HFD) diet (8 weeks) induced an obesity phenotype and caused gut dysbiosis, resulting in a larger infarct volume and higher serum levels of inflammatory cytokines after stroke, compared to those in the lean counterparts. LC-MS/MS and GC analysis revealed that obese mice with stroke developed an obviously perturbed bile acid (BA) profile characterized by higher levels of deoxycholic acid and its conjugated forms, and lower levels of butyrate in the cecal content. CR administration improved the obesity-induced dysbiotic microbiome, attenuated ischemic brain injury and modulated the stroke-perturbed BA profile. Furthermore, fecal microbiota transplantation (FMT) experiments revealed that the impact of obesity on stroke and the neuroprotective effects of CR were mediated by gut microbiota. In conclusion, Obesity induces gut dysbiosis, worsens stroke outcomes, and perturbs the BA profile. The dysbiotic microbiome is an important linkage between obesity and stroke. CR confers metabolic benefits and neuroprotective effects in obesity, perhaps by modulating gut microbial composition and BA metabolism.