Abstract W MP88: Worsening Of Stroke Outcome With Age Is Associated With Increased Intestinal Permeability And Peripheral Inflammation

Abstract

Introduction: Aging remains the biggest risk factor for ischemic stroke. Initial observations into the role of aging on stroke outcome revealed that while aged mice had significantly smaller infarcts compared to young mice, they had greater long-term deficits in behavioral recovery. This study aimed to elucidate the role of systemic factors, such as intestinal stress, underlying the poor outcomes of aging mice after stroke. Methods: Young (8-12 wks) and aged (18-20 mos) wildtype mice were subjected to 90min of right middle cerebral artery occlusion (MCAO) followed by reperfusion. Intestinal permeability was measured with 4kDa FITC-dextran gavage. Mesenteric lymph node (MLNs) homogenates were plated on blood agar to measure bacterial growth. Bacterial endotoxin was measured using a LAL assay. Flow cytometry was used to assess immune cells. Plasma IL-6 was measured by ELISA. Results: Baseline gut permeability increased with age as evidenced by increased FITC-dextran extravasation across the intestinal lumina. Bacterial burden in MLNs and serum bacterial endotoxin levels were also elevated with age (p<0.05). These deficits were severely exaggerated by MCAO. A 200-fold increase was observed in the number of colony forming units in the MLNs of aged stroked mice compared to young (p<0.001). MHC II expression was enhanced on dendritic cells in aged MLNs and CD69 expression increased on circulating T-cells (p<0.05). Activated T-cells comprised the majority of infiltrating leukocytes in the ischemic hemisphere at 7 days post-stroke. This delayed recruitment of T-cells was associated with a 50% greater mortality of aged mice compared to young by 7 days. Plasma IL-6, a marker for sepsis, increased similarly at 6hr after MCAO in young and aged mice, but remained elevated in aged mice at 72hrs (p<0.05). Aged mice had lower body temperatures at 72hrs post-stroke (p<0.01). Conclusion: Our data suggest that the high mortality in aged mice after stroke is secondary to exacerbation of intestinal permeability, increased bacterial translocation, and subsequent induction of sepsis. This data points to gut-targeted interventions as a means to reduce the severity of peripheral inflammation and improve prognosis in aged stroke victims.