The Gut Microbiota-Associated Metabolite Network in Ischemic Stroke: From Pathophysiological Imbalance to Potential Precision Intervention Strategies.

Ischemic stroke (IS) remains a leading cause of death and long-term neurological disability worldwide, and current treatment options are constrained by narrow therapeutic windows and limited neuroprotective efficacy. Accumulating evidence implicates the microbiota-gut-brain axis (MGBA) in the development and progression of IS. Following cerebral ischemia, bidirectional communication between the brain and gut is disrupted, resulting in gut microbial dysbiosis, impaired intestinal barrier function, and altered production of microbiota-associated metabolites that influence neuroinflammation, immune regulation, blood-brain barrier (BBB) integrity, and post-stroke recovery. Among these molecules, short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), tryptophan-derived metabolites, and lipopolysaccharide (LPS) have attracted particular attention. Importantly, these molecules differ in origin: SCFAs and several tryptophan-derived indoles are direct microbial products; TMAO is a host-microbial co-metabolite; primary BAs are host-derived and subsequently modified by gut bacteria; and LPS is a bacterial structural component. Rather than acting in isolation, these metabolites form an interconnected network characterized by synergistic, antagonistic, compensatory, and feedback interactions; however, only a subset of these interactions has been directly demonstrated in patients with IS or in experimental stroke models, and many remain inferred from studies in other cardiovascular, metabolic, or inflammatory conditions. At present, the strongest human evidence concerns associations of individual metabolites with stroke risk and outcomes, whereas the proposed network-level interactions remain largely inferential. This review therefore proposes "gut microbiota-associated metabolite network imbalance" as a conceptual, integrative, and hypothesis-generating framework for understanding IS pathophysiology, and summarizes current evidence on protective and injurious metabolite pathways, their crosstalk, and emerging therapeutic strategies. Metabolite-guided precision intervention remains largely investigational and will require prospective validation before clinical translation.