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Introduction: Infection is an important complication in the acute phase after stroke which effects up to 65% of stroke patients. These infections can in turn cause sepsis, which is a major contributor to hospital mortality. Emerging evidence indicates that these infections originate from the host commensal microbiota. We have found that stroke leads to increased gut permeability and bacterial translocation and that aged mice are more susceptible to post-stroke infections compared to young. We further investigated the possibility of how the response to infection differs between young and aged mice.Hypothesis: Impaired gut epithelial-specific response after stroke in aged mice leads to increased risk of infections and impaired recovery.Methods: Young (8-10 wks) and aged (18-20 mos) male mice (n=4-5/group) were subjected to either sham or 60-minute middle cerebral artery occlusion (MCAO) followed by reperfusion. Mice were sacrificed at day 8 after stroke. One cohort of mice (n=3/group) was evaluated for the histology and hypoxic barrier integrity. Finally, colonic epithelial cells (cECs) were isolated and changes of the gene expression in cECs were examined (n=4-5/group).Results: Epithelial dysfunction was observed in aged mice, including a decrease in goblet cells and mucus layer (P<0.05). Furthermore, stroke induced the loss of hypoxic barrier in the gut of aged mice. Intriguingly, multiple epithelial antimicrobial peptides of the regenerating islet-derived protein (Reg) family genes, which are produced by epithelial cells including deep secretory cells, were highly up-regulated following stroke only in young mice [~20 fold change in Reg3β and Reg3γ (P<0.05); ~2 fold change in Reg4 (P<0.05)]. In addition, aged mice showed decreased expression levels of goblet cell-secreting mucin (Muc) (~1.4 fold change in Muc2, P<0.05), whereas young mice retained expression after stroke.Conclusions: Our data indicates that 1) both aging and stroke impairs gut integrity and possibly leads to increase of infections and 2) epithelial cells could differentially respond to external stimuli after stroke, in an age-dependent manner. The current study provides the first insight into how intestinal epithelium is involved in the brain-gut axis in stroke.