Epigenetic regulation of post-stroke cognitive impairment by gut microbiota and their metabolites

Post-stroke cognitive impairment (PSCI) is a common and disabling complication after stroke, yet its underlying mechanisms remain incompletely understood. Emerging evidence indicates that gut microbiota (GM) and their metabolites play a critical role in the pathogenesis of PSCI through the microbiota-gut-brain (MGB) axis. Increasing studies have demonstrated that GM dysbiosis after stroke leads to alterations in microbial metabolites, including short-chain fatty acids (SCFAs), B vitamins, tryptophan metabolites, bile acids, and other neuroactive compounds, which can influence neuroinflammation, blood-brain barrier integrity, synaptic plasticity, and neuronal survival. Notably, many of these metabolites participate in epigenetic regulation, such as DNA methylation, histone modification, non-coding RNA regulation, chromatin remodeling and RNA modifications, thereby affecting gene expression related to cognitive function and neural repair. This review summarizes recent advances in the relationship between gut microbiota, microbial metabolites, and epigenetic mechanisms in PSCI, and discusses how microbiota-derived metabolites mediate epigenetic reprogramming involved in neuroinflammation, oxidative stress, and neuronal apoptosis. Furthermore, this review highlights potential therapeutic strategies targeting the gut microbiota and their metabolites, including microbiota modulation, metabolite supplementation, and epigenetic intervention. Understanding the interaction between gut microbiota-derived metabolites and epigenetic regulation may provide new insights into the pathogenesis and treatment of PSCI and support the development of personalized therapeutic strategies.