Abstract 17: Microglial Specific Aryl Hydrocarbon Receptor Activation Via Gut-derived Microbial Indole-metabolites Improves Outcomes After Neonatal-HIE

• DOI: 10.1161/str.53.suppl_1.17
• Publication Date: 2022-02-03T10:01:59Z
• Authors: Janelle Korf; Anna St Denis; Pedram Honarpisheh; Anik Banerjee; Eric Mohan; Frank Blixt; Romana Sharmeen; Juneyoung Lee; Maria P Blasco-Co...; Louise McCullough; Bhanu P Ganesh
• Keywords: Dysbiosis

Introduction: Neonatal Hypoxic Ischemic Encephalopathy (nHIE) is a major cause of mortality and morbidity in infants, occurring 1.5/1000 live births. Inflammation persists years after injury detrimentally affects neurocognitive outcomes children. Recent evidence shows that neuroinflammation gut alters microbial populations the (gut dysbiosis) reduces level bacteria capable producing beneficial, anti-inflammatory tryptophan (Trp) metabolites. Metabolites are detected by microglia (MG) with aryl hydrocarbon receptor (AHR). Ligand specific AHR activation can influence MG behavior CNS injury, potentially modifying recovery. We hypothesize nHIE leads to chronic dysbiosis reduced microbial-derived Trp metabolites, which exacerbates MG-induced damage. also Trp-derivatives bind reduce inflammation improve neurological males females. Methods: used modified Rice Vannucci Model on PND9 C57BL/6J mice investigate role as mediator microbiome-brain communication demonstrated direct metabolite modulation using vitro cell culture assays. Results: found an increase CD45 expression 24hrs (p=0.0169 p=0.0047 respectively, n=5). RT-qPCR SIM-A9 cells showed pretreatment indole-acetic-acid (IAA) followed LPS produced significantly more Il10 than pretreated agonist FICZ, suggesting activate response (p=0.013, n=8). IAA mildly Il1β , Il6 Tnfα administration. 16S rRNA sequencing, metabolomics analysis acute (24hrs) (7wks) cohorts detriments behavioral tasks dysbiotic changes nHIE. Conclusion: results increased MG, dysbiosis, alterations microbial-Trp metabolites In assays absence result greater inflammatory activity via pathway, supporting our hypothesis reduction worsens