The Gut Microbiome Worsens the Maladaptive Immune Response to Stroke
Added to the growing list of specific ways in which the gut microbiome can contribute to degenerative aging, researchers here note that indole produced by gut microbiobes provokes a chain of events that worsens the maladaptive inflammatory immune response to the damage of an ischemic stroke, increasing the overall harm done. Like many of these recent single metabolite discoveries, there is a single point of intervention that may be used to reduce the impact of indole on the immune system, and thereby improve stroke outcomes.
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.