Gut-brain axis: a revolutionary paradigm in the pathogenesis and treatment of ischemic stroke

Ischemic stroke is a devastating neurological disorder. Despite advances in acute reperfusion therapy, patients still face high risks of poor functional recovery and stroke recurrence, highlighting the urgent need to explore new pathological mechanisms and therapeutic targets. In recent years, the Gut-Brain Axis-a bidirectional communication network connecting the brain, gut, and gut microbiota-has provided a novel framework for understanding stroke pathophysiology. This review systematically summarizes how gut microbiota correlates with the progression of major stroke risk factors including hypertension and atherosclerosis, and explicitly distinguishes that most human observational data only support correlative associations, while causal evidence is largely limited to preclinical animal models. We further clarify the two-way communication pathway after stroke: cerebral ischemia impairs intestinal barrier function and causes microbial imbalance through autonomic and inflammatory responses; in turn, disturbed gut microbiota and metabolites correlate with aggravated brain damage and hindered repair via immune, metabolic, and neural signaling, mainly by regulating neuroinflammation and controlling key metabolites such as short-chain fatty acids and trimethylamine N-oxide. Based on these mechanisms, we comprehensively assess preclinical and clinical evidence of microbiota-targeted interventions, including dietary modification, probiotics, and fecal microbiota transplantation. We emphasize that existing clinical evidence is mostly derived from small-sample, single-center trials with inconsistent outcomes, and large-scale multicenter sham-controlled randomized controlled trials are mandatory before any routine clinical application can be recommended. We also discuss key challenges such as distinguishing causal relationships from correlative observations, bridging preclinical translational gaps, and addressing inter-individual heterogeneity across patient populations, and propose future translational research directions. Targeting the Gut-Brain Axis represents a promising preclinical systemic strategy for stroke prevention, acute care, and long-term rehabilitation, yet robust human validation is still lacking. This approach marks a fundamental paradigm shift in the field of stroke research, though overoptimistic clinical translation expectations should be avoided given the substantial unresolved translational limitations.