Gut microbiota primes stroke severity via the AHR in intestinal dendritic cells

The gut microbiota modulates systemic immunity and neurological diseases, yet the underlying mechanisms remain unclear. Here, we identify the enrichment of indole-producing Escherichia coli being associated with worse outcomes in mice and patients with ischemic stroke. Microbial indole triggers an aryl hydrocarbon receptor (AHR)-dependent response in dendritic cells (DCs). DC-specific AHR deletion improves stroke outcomes and preserves intestinal conventional type 1 DCs. AHR deletion also promotes immunoregulatory and migratory transcriptional signatures and enhances CCR7-dependent migration in vitro. Pharmacological AHR inhibition favors gut-derived DC accumulation in the meninges, accompanied by increased regulatory T cells (Tregs) and reduced neuroinflammation, while Treg depletion abolishes the neuroprotection conferred by AHR inhibition. Detrimental effects of indole-producing Escherichia coli, indole administration, and microbiota transplantation from patients with stroke are attenuated in DC-specific AHR-deficient mice. These findings define a microbiota-AHR axis that programs intestinal immune responses before brain injury and highlight microbial tryptophan metabolism as a tractable therapeutic target.