Abstract WP240: Beneficial Gut Microbiome-Derived Ligands Can Outcompete Detrimental Brain-Derived Ligands Of Aryl Hydrocarbon Receptor After Stroke

Abstract

Microbiome-derived ligands of the aryl hydrocarbon receptor (AHR) including tryptophan-derived indole acetic acid (IAA) have anti-inflammatory effects in some tissues. However, their effect on neuroinflammation after stroke is unknown. Brain-derived ligands of AHR (e.g. kynurenine) increase post-ischemia and are detrimental. Consistently, pharmacological inhibition of AHR after stroke reduces deleterious effects of kynurenine-mediated activation of AHR and improves outcome. However, whether IAA-mediated activation of AHR is detrimental or beneficial after stroke is unknown. We hypothesized that post-stroke treatment with IAA will reduce neuroinflammation and improve outcomes via beneficial activation of microglial (MG) AHR. We used a reversible middle cerebral artery occlusion (MCAO) model in aged (18mo) WT male mice to investigate temporal changes in biome-derived (IAA) versus host-derived (kynurenine) AHR ligands. Using metabolomics analysis, we determined that plasma levels of IAA can be restored in naïve aged mice by oral probiotics administration of AHR ligand producers. We found that brain kynurenine increases but plasma IAA decreases as early as 3 hours after MCAO in aged mice (n=4/gp, p=0.0029 ) while brain IAA levels remain unchanged. Our 16S rRNA-sequencing shows that aging leads to reduction in AHR ligand-producers (e.g. Bifidobacterium [B] and Lactobacillus [L] ). Oral gavage with AHR ligand-producing BBL-probiotic cocktail restored the age-related decline in plasma IAA both acutely (24 hours post-treatment) and chronically (weekly for 6 weeks, n=8/gp, p=0.0086 and p=0.0073 , respectively). Further, the increase in plasma levels of IAA after probiotic bacteriotherapy with AHR ligand producers was associated with modulation of AHR activity in the brain (decreased AHR expression in MG, n=8/gp, p=0.0119 ) and reduced MG activation ( p=0.0069 ). Our results show that IAA modulates MG-mediated neuroinflammation after stroke. We plan to utilize post-stroke treatment with IAA in aged WT mice and in inducible knock-out mice with microglial Ahr deletion to further validate our hypothesis. Future studies are needed to focus on the regulatory function of other biome-derived AHR ligands in post-stroke neuroinflammation.