Benefits of equilibrium between microbiota- and host-derived ligands of the aryl hydrocarbon receptor after stroke in aged male mice

• DOI: 10.1038/s41467-025-57014-2
• Publication Date: 2025-02-19T14:28:33Z
• Authors: Pedram Peesh; Maria P. Blasco-C...; Ahmad El Hamamy; Romeesa Khan; Gary U. Guzman; Parisa Honarpisheh; Eric C. Mohan; Grant W. Goodman; Justin N. Nguyen; Anik Banerjee; Bryce E. West; Kyung Ae Ko; Janelle M. Korf; Chunfeng Tan; Huihui Fan; Gabriela D. Colpo; Hilda Ahnstedt; Lucy Couture; Solji Roh; Julia K. Kofler; Jose F. Moruno-Ma...; Michael E. Maniskas; Jaroslaw Aronowski; Rodney M. Ritzel; Juneyoung Lee; Jun Li; Robert M. Bryan; Anjali Chauhan; Venugopal Reddy V...; Louise D. McCullough; Bhanu Priya Ganesh
• Keywords: Stroke

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.