Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice
Pedram Peesh, Maria P. Blasco-Conesa, Ahmad El Hamamy, Romeesa Khan, Gary Guzman, Parisa Honarpisheh, Eric C. Mohan, Grant W. Goodman, Justin Nguyen, Anik Banerjee, Bryce E. West, Kyung Ae Ko, Janelle Korf, Chunfeng Tan, Huihui Fan, Gabriela Delevati Colpo, Hilda Ahnstedt, Lucy Couture, Solji Roh, Julia Kofler, Jose F. Moruno-Manchon, Michael E Maniskas, Jaroslaw Aronowski, Rodney M. Ritzel, Juneyoung Lee, Jun Li, Robert M. Bryan, Anjali Chauhan, Venugopal Reddy Venna, Louise D. McCullough, Bhanu Priya Ganesh
Abstract
Recent studies have highlighted the crucial role of microglia (MG) and their interactions with the gut microbiome in post-stroke neuroinflammation. The activation of immunoregulatory pathways, including the aryl hydrocarbon receptor (AHR) pathway, is influenced by a dynamic balance of ligands derived from both the host and microbiota. This study aimed to investigate the association between stroke-induced dysbiosis and the resultant imbalance in AHR ligand sources (loss of microbiota-derived [indole-based] and increase of host-derived [kynurenine-based]) after stroke. Microbiota-derived AHR ligands decreased in human plasma and remained low for days following an ischemic stroke highlighting the translational significance. Transient-middle-cerebral-artery-occlusion was performed in aged wild-type and germ-free male mice. MG-AHR expression and activity increased in both in vivo and ex vivo stroke models. Germ-free mice showed altered neuroinflammation and antigen presentation while aged mice showed reduced infarct volume and neurological deficits following treatment with microbiota-derived AHR ligands after stroke. Restoring a balanced pool of host- and microbiota-derived AHR ligands may be beneficial after stroke and may represent a therapeutic target. Peesh et al. show that ischemic stroke reduces microbiota-derived and increases host-derived aryl (AHR) hydrocarbon ligands. Post-stroke treatment with indole-based AHR ligands improved microglia-mediated antigen processing and co-stimulatory immune functions.