Faculty, Staff and Student Publications

Language

English

Publication Date

2-19-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-57014-2

PMID

39971928

PMCID

PMC11839985

PubMedCentral® Posted Date

2-19-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Animals, Receptors, Aryl Hydrocarbon, Male, Gastrointestinal Microbiome, Mice, Ligands, Humans, Microglia, Stroke, Kynurenine, Dysbiosis, Mice, Inbred C57BL, Indoles, Disease Models, Animal, Infarction, Middle Cerebral Artery, Aging, Germ-Free Life, Neuroinflammatory Diseases

Published Open-Access

yes

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