Abstract WP239: Intestinal Alkaline Phosphatase: A Novel Regulator Of The Gut-brain Axis In Acute Ischemic Stroke

Abstract

While strokes are typically associated with the brain, it is widely known that stroke outcomes are influenced by communication between the brain and peripheral organs. The gastrointestinal (GI) tract comprises a critical organ system that is affected during and after stroke, and the interaction between the GI tract and the brain in stroke is attributed to the modulation of the gut-brain axis. Intestinal alkaline phosphatase (IAP; gene: Akp3 ) is a brush border enzyme localized in the intestinal epithelium that regulates intestinal homeostasis by modulating inflammation and intestinal integrity. We hypothesized that IAP regulates the early post-stroke changes within the gut-brain axis, and that loss of IAP disrupts the gut-brain axis to worsen post-stroke outcomes and disrupt immune responses. We utilized 4-6 month-old male and female mice with a genomic deletion of Akp3 and their wild type (WT) littermate controls. Following the induction of photothrombotic stroke (PTS), stroke-injured mice and their sham controls were for evaluated for bacterial load, intestinal permeability, intestinal motility, neurological deficits, cerebral blood flow, and immune responses over the next 24 hours. Statistical analysis of Clark’s neurological score, laser speckle flowmetry, and 2,3,5-Triphenyltetrazolium chloride (TTC) staining at day 1 post stroke showed a main effect of stroke but no differences between genotypes. While no differences in intestinal motility were observed due to stroke or genotype, gut permeability to 3kD-FITC dextran quantified at 3.5 hours post-stroke was higher in Akp3-/- mice compared to WT mice. Further analysis of bacterial burden showed that anaerobic bacteria in the ileum were diminished in Akp3-/- mice post-stroke compared to WT counterparts. Quantification of immune cell populations in cervical lymph nodes and spleen showed that Akp3-/- mice displayed baseline decreases in monocyte and dendritic cell populations that were either maintained or further decreased at 24-hours post-stroke, suggesting that Akp3-/- mice are unable to mount an appropriate innate immune response in acute stroke. Taken together, the current results support the hypothesis that IAP shapes early outcomes and modulates the gut-brain axis in ischemic stroke.