Abstract Body: Introduction: The gut-brain axis is pivotal in recovery after stroke, with the gut microbiome playing a significant role in neurological outcomes. Akkermansia muciniphila (AKK), a beneficial gut bacterium, has shown promise in metabolic conditions. We hypothesize that AKK and its exosomes (AKK-Exo) can enhance stroke recovery by modulating gut-brain interactions. Methods: Human study: fecal samples from 88 ischemic stroke (IS) patients and 23 healthy elderly were analyzed using 16S rDNA sequencing. Animal study: 6-8 months old male mice subjected to photothrombotic middle cerebral artery occlusion were treated intragastrically with either AKK or AKK-Exo. Neurological recovery was evaluated over 2 weeks, accompanied by 16S rDNA sequencing and metabolomics analysis of fecal and plasma samples. The RT-PCR, Western blotting, and immunofluorescence were employed to assess inflammation, microglial activation, and white matter (WM) remodeling in the brain. Results: Human study demonstrated that IS disrupts gut microbiota, with an increase in pathogenic bacteria like Parabacteroides and a decrease in beneficial microbes like Lachnospira. Patients with higher levels of AKK exhibited better neurological outcomes. In the mouse model, both AKK and AKK-Exo treatments resulted in improvements in neurological function, also led to a restructuring of gut microecology, characterized by a reduction in pro-inflammatory bacteria and an increase in beneficial species. Moreover, the treatments were associated with a decrease in pro-inflammatory cytokine levels in both the brain and intestines. Metabolomics analysis revealed a notable reduction in trimethylamine N-oxide and an increase in beneficial metabolites such as sphingolipids and flavonoids. These metabolic changes were correlated with improved neurological outcomes. Molecular analyses further demonstrated that AKK and AKK-Exo treatments promoted the integrity of the gut barrier, reduced systemic inflammation, and induced an anti-inflammatory M2 microglial phenotype and facilitated WM remodeling in the brain. Conclusion: This study underscores the therapeutic potential of AKK and its exosomes in promoting recovery after IS, highlighting their role in gut-brain axis modulation. Our findings suggest that AKK and AKK-Exo could serve as promising therapeutic agents for improving stroke outcomes through microbiome-based interventions.
Keywords: Gut-brain axis, microbiome, ischemic stroke, Akkermansia, neuroinflammation