Researchers at LMU have discovered how a metabolite produced by gut bacteria can influence brain damage after stroke.

How much damage a stroke causes in the brain depends strongly on how quickly blood flow can be restored. The patient’s own immune response that follows the stroke also plays an important role. A team at the Institute for Stroke and Dementia Research (ISD) at LMU Klinikum, led by Dr. Corinne Benakis, has now identified a specific bacterial signal that shapes this immune response and influences stroke outcome.

The researchers found that in mice with severe stroke, gut bacteria capable of producing indole, a metabolite that is only produced in the gut, become more abundant. These bacteria carry the gene tnaA, which allows them to convert the amino acid tryptophan, found in food, into indole. In mice, the team showed that indole-producing bacteria worsened brain injury after stroke.

Indole acts on a receptor called AHR (aryl hydrocarbon receptor), found in dendritic cells — immune cells that patrol the intestinal lining and help coordinate immune responses. When the researchers switched off AHR specifically in dendritic cells, mice were better protected against brain injury.

“Dendritic cells have long extensions, like arms, that allow them to sense changes in their environment, including metabolites produced by gut bacteria. When we switched off AHR, the behavior of these cells changed completely: dendritic cells were more potent to migrate from the intestine to the meninges, the membrane surrounding the brain. These dendritic cells also promoted protective T cells and helped reduce the damage in the brain,” says Dr. Rosa Delgado Jiménez, who shares first authorship with Alexandria Ruggles and Mujeeb Adedokun.

The researchers also found evidence that this pathway may be relevant in humans. In a cohort of human patients with ischemic stroke, the ISD team found that higher abundance of bacterial TnaA was associated with poorer functional outcome. Samples for this research were provided by the teams of Fernández-Cadenas in Barcelona and Lorenz Hirt in Lausanne. Bacteria carrying tnaA gene, capable of producing indole, were also more abundant in people with risk factors for stroke, which include obesity and type 2 diabetes.

The study also drew on the Transregional Collaborative Research Centre TRR 355, a DFG-funded research network on regulatory T cells. "This work required expertise that a small group like ours could not have covered alone," says Benakis. "The TRR 355 network supported us financially, and we also benefited from the expertise of group leaders within the consortium. In addition, we collaborated with Michael Zimmermann at EMBL and Michael Gigl at TUM, to detect tryptophan metabolites and microbial indole, which is technically challenging. It was a real team effort."

The findings raise an important question for future research: could changing the gut microbiome or the metabolites it produces in healthy individuals help prepare the immune system to respond differently if a stroke occurs? “We usually think of stroke as an injury restricted to the brain, but our findings show that the gut can help shape the immune response to that injury,” says Delgado Jiménez. “We still need to determine whether the mechanism we identified in mice also occurs in patients, but our findings open new avenues for investigating whether the gut microbiota could eventually be targeted to improve stroke outcome, including through preventive approaches in people at increased risk of stroke.” says Benakis.