Gut Bacterial Metabolite Indole Worsens Stroke Inflammation
Researchers found that indole produced by gut bacteria worsens the inflammatory immune response after ischemic stroke by activating the aryl hydrocarbon receptor in dendritic cells. In mice, deleting AHR in these cells or inhibiting it pharmacologically improved stroke outcomes, increased regulatory T cells, and reduced neuroinflammation. The work identifies microbial tryptophan metabolism as a possible therapeutic target for limiting stroke damage.
Researchers linked indole-generating Escherichia coli to poorer ischemic stroke outcomes in both mice and patients. In their model, bacterial indole activated the aryl hydrocarbon receptor (AHR) in dendritic cells, setting off immune changes that worsened damage. Removing AHR specifically from dendritic cells preserved a subset of intestinal conventional type 1 dendritic cells and improved recovery.
Blocking AHR with drugs shifted gut-derived dendritic cells toward the meninges, raised regulatory T cells, and lowered neuroinflammation; removing Tregs erased the benefit. Mice lacking dendritic-cell AHR also resisted harm from indole-producing E. coli, direct indole exposure, and microbiota transplants from stroke patients. The authors frame this as a microbiota-AHR axis and a possible target in microbial tryptophan metabolism.
If confirmed in humans, targeting this pathway could complement existing stroke care, potentially benefiting older adults and others at risk of ischemic stroke. Clinicians may eventually use microbiome or metabolite profiles to identify patients likely to respond, while drug developers could pursue AHR inhibitors. However, translation remains uncertain, and any treatment would need to avoid disrupting beneficial immune functions.