Microbial disruption in the gut promotes cerebral endothelial dysfunction

Cerebrovascular disease is a group of conditions characterized by disorders of the cerebral vessels. Endothelial dysfunction renders the vasculature at risk of impaired blood flow and increases the potential of developing cerebrovascular disease. The gut microbiota has been recently identified as a possible risk factor of cerebrovascular disease. However, a direct link between gut microbiota and cerebral vascular function has not been established. Therefore, the aim of this study was to determine the effect of gut bacterial disruption on cerebral endothelial function. Male inbred Sprague-Dawley rats were randomly assigned to receive either drinking water with (n = 4) or without (n = 4) a cocktail of nonabsorbable broad-spectrum antibiotics (streptomycin, neomycin, bacitracin, and polymyxin B). Three weeks of antibiotic treatment resulted in a significant reduction in bacterial load and shifts within the bacterial sub-populations as assessed using flow cytometry. Using pressure myography, we found that spontaneous tone significantly increased and L-NAME-induced vasoconstriction was significantly blunted in middle cerebral arteries (MCAs) harvested from antibiotic-treated rats. ATP-mediated dilations were significantly blunted in MCAs from antibiotic-treated rats compared to their control counterparts. Immunoblotting revealed that the eNOS-P/total eNOS ratio was significantly reduced in cerebral artery lysates from antibiotic-treated rats compared to controls. Our findings suggest that disruption of the gut microbiota leads to cerebral endothelial dysfunction through reduction of eNOS activity. This study highlights the potential of the microbiota as a target to reverse endothelial dysfunction and a preventative approach to reducing risk of stroke and aneurysms.