Gut microbiota and their metabolites in stroke: From mechanistic study toward therapeutic perspectives

Stroke is a medical emergency with high incidence, mortality, disability rate, and multiple complications, which place a serious burden on families and society. Clinically, gastrointestinal dysfunction has been observed in a significant percentage of stroke patients, suggesting that gut microbiota may be a viable target for stroke prevention and therapy. In this review, we summarized the alterations in the intestinal environment following stroke across clinical and preclinical models, highlighting the changes in the major bacterial communities, including Bacteroidetes, Firmicutes, Proteobacteria and Actinomycetota, etc. Considering the connection between the brain-gut axis, we discussed the therapeutic potential for treating ischemic stroke by modulating the gut microbiota, including protection of the blood-brain barrier (BBB) and the intestinal barrier, as well as the application of fecal microbiota transplantation (FMT). Furthermore, we highlighted the main mechanisms of regulating gut microbiota to improve stroke outcomes, involving intestinal metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and phenylacetylglutamine (PAGln), endotoxin, hormones, and amino acids, as well as factors related to immunity, inflammation, and oxidative stress. Finally, we summarized potential targeted therapeutic approaches, such as natural small molecules, engineered probiotics, and bile acid-nanoparticles, etc. Collectively, these insights support the gut microbiota as a promising target for mitigating stroke risk, attenuating acute injury, and enhancing recovery.