Gut microbiome-immune-metabolic mechanisms in cerebrovascular disease: evidence-graded insights from cerebral small vessel disease, ischemic stroke, and intracerebral hemorrhage.

Cerebrovascular disease is increasingly being examined in relation to the gut microbiome, but the field has not advanced evenly across disease phenotypes. A central challenge is to distinguish broad dysbiosis-based associations from microbial functions, host-facing metabolites, epithelial barrier injury, and immune pathways that may plausibly influence neurovascular vulnerability or recovery. This distinction is particularly important because cerebral small vessel disease, acute ischemic stroke, and intracerebral hemorrhage differ in time scale, vascular pathology, clinical exposure, and available microbiome evidence. This review evaluates gut microbiome-immune-metabolic mechanisms across these cerebrovascular contexts with a focus on microbial ecology, intestinal barrier dysfunction, microbial translocation, short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acid derivatives, tryptophan-linked metabolites, lipopolysaccharide (LPS)-related inflammatory signaling, and emerging multi-kingdom signals, including the gut virome and mycobiome. Current evidence is most convincing in acute ischemic stroke, where human cohort studies and experimental perturbation models link microbiome disruption, microbial metabolites, immune programming, and functional outcome. Evidence for imaging-defined cerebral small vessel disease remains more limited and is largely cross-sectional, whereas intracerebral hemorrhage is an emerging but mechanistically distinct domain. Virome- and mycobiome-related mechanisms remain exploratory and require longitudinal, multi-omics, and perturbation-based validation. This review argues that cerebrovascular microbiome research should move beyond taxonomic association toward time-resolved microbial function, host-facing metabolites, disease-specific host-microbe interfaces, and experimentally testable mechanisms. Candidate microbiome-directed interventions-including dietary, prebiotic, probiotic, postbiotic, fecal microbiota transplantation, defined microbial consortia, metabolite-targeted, and phage-based approaches-remain investigational. Their translation will require disease- and time-window-specific evaluation of biological target engagement, safety, and clinically meaningful outcomes. Longitudinal multi-omics cohorts, disease-specific models, and careful control of diet, antibiotics, vascular medications, hospitalization, and frailty will be essential for determining which gut microbiome-related pathways are causal, context-specific, modifiable, and therapeutically actionable.