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 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-Manchon, Michael E. Maniskas, Jaroslaw Aronowski, Rodney M. Ritzel, Juneyoung Lee, Jun Li, Robert M. Bryan, Anjali Chauhan, Venugopal Reddy Venna, Louise D. McCullough () and Bhanu Priya Ganesh ()
Additional contact information
Pedram Peesh: The University of Texas McGovern Medical School
Maria P. Blasco-Conesa: The University of Texas McGovern Medical School
Ahmad El Hamamy: The University of Texas McGovern Medical School
Romeesa Khan: The University of Texas McGovern Medical School
Gary U. Guzman: The University of Texas McGovern Medical School
Parisa Honarpisheh: The University of Texas McGovern Medical School
Eric C. Mohan: The University of Texas McGovern Medical School
Grant W. Goodman: The University of Texas McGovern Medical School
Justin N. Nguyen: The University of Texas McGovern Medical School
Anik Banerjee: The University of Texas McGovern Medical School
Bryce E. West: The University of Texas McGovern Medical School
Kyung Ae Ko: The University of Texas McGovern Medical School
Janelle M. Korf: The University of Texas McGovern Medical School
Chunfeng Tan: The University of Texas McGovern Medical School
Huihui Fan: The University of Texas McGovern Medical School
Gabriela D. Colpo: The University of Texas McGovern Medical School
Hilda Ahnstedt: The University of Texas McGovern Medical School
Lucy Couture: The University of Texas McGovern Medical School
Solji Roh: The University of Texas McGovern Medical School
Julia K. Kofler: University of Pittsburgh School of Medicine
Jose F. Moruno-Manchon: The University of Texas McGovern Medical School
Michael E. Maniskas: The University of Texas McGovern Medical School
Jaroslaw Aronowski: The University of Texas McGovern Medical School
Rodney M. Ritzel: The University of Texas McGovern Medical School
Juneyoung Lee: The University of Texas McGovern Medical School
Jun Li: The University of Texas McGovern Medical School
Robert M. Bryan: Department of Anesthesiology
Anjali Chauhan: The University of Texas McGovern Medical School
Venugopal Reddy Venna: The University of Texas McGovern Medical School
Louise D. McCullough: The University of Texas McGovern Medical School
Bhanu Priya Ganesh: The University of Texas McGovern Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57014-2

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