Stachyose supplementation attenuates ischemic stroke injury via gut-brain axis mediated adenine metabolism and neuroactive ligand-receptor signaling.

Stroke is a neurological disease with high incidence and severe disability. Stroke recovery is closely associated with the homeostasis of the gut-brain axis and the regulation of neuroinflammation and neuronal function. As a prebiotic with potent gut microbiota-regulating and anti-inflammatory activities, stachyose (STA) has been increasingly recognized for its beneficial effects on host health. To explore the neuroprotective effects of STA on stroke and its underlying mechanisms, we established a photothrombotic stroke mouse model and performed integrated multi-omics analyses, including 16S rRNA sequencing and metabolomics of feces, as well as metabolomics and transcriptomics of brain tissue. The 16S rRNA analysis showed that STA treatment significantly reshaped the gut microbial community structure in mice. Metabolomics of brain and feces further identified brain-gut shared metabolites, which may act as signaling molecules in the gut-brain axis, and these key metabolites were significantly correlated with specific microbial taxa and critical genes. Transcriptomic analysis of brain tissue revealed that STA treatment markedly regulated the neuroactive ligand-receptor interaction pathway, which is crucial for the synthesis, release and binding of neurotransmitters, as well as for neuronal survival, differentiation and maintenance of neural function. Collectively, STA may exert neuroprotective effects in stroke by regulating gut microbiota-associated metabolites and subsequently modulating the neuroactive ligand-receptor interaction signaling pathway, thereby mediating crosstalk along the gut-brain axis.