Ischemic stroke, arising from the abrupt interruption of cerebral blood flow, accounts for approximately 87% of all stroke events and remains the second leading cause of mortality and the foremost cause of acquired disability globally. Despite significant advances in acute reperfusion therapies, including intravenous thrombolysis with alteplase and tenecteplase, and endovascular mechanical thrombectomy, a substantial proportion of stroke survivors continue to experience persistent neurological deficits. The temporal constraints inherent to these interventions, coupled with the complex pathophysiology of ischemic brain injury extending well beyond the initial vascular occlusion, underscore the imperative need for complementary neuroprotective and neurorestorative strategies.

The pathobiology of cerebral ischemia is characterized by a multiphasic cascade encompassing excitotoxicity, oxidative stress, and a robust neuroinflammatory response that evolves over hours to weeks following the initial insult. Neuroinflammation, once regarded solely as a secondary injury mechanism, is now recognized as a dual-edged process: acute inflammatory activation exacerbates tissue damage through microglial hyperactivation, leukocyte infiltration, and pro-inflammatory cytokine release, whereas controlled inflammatory resolution and anti-inflammatory signalling are essential for debris clearance, angiogenesis, and neural repair.

In parallel with these advances in neuroinflammatory biology, the past decade has witnessed an exponential growth in our understanding of the gut-brain axis, a bidirectional communication network linking the enteric nervous system and the gastrointestinal microbiome with the central nervous system. The human gut harbors an estimated 3.8 trillion microorganisms encompassing over 1,000 bacterial species, collectively constituting a metabolically active organ that profoundly influences host immunity, neurotransmitter synthesis, and systemic inflammatory homeostasis. Perturbations of this microbial ecosystem, termed dysbiosis, have been implicated in a growing array of neurological conditions including Parkinson disease, Alzheimer disease, multiple sclerosis, epilepsy, and, increasingly, cerebrovascular disease.

The concept that gut microbiota may modulate stroke outcomes is supported by converging lines of evidence. Clinical studies have demonstrated significant alterations in the fecal microbiome composition of acute stroke patients compared with healthy controls, with a characteristic depletion of butyrate-producing commensals and an enrichment of pro-inflammatory taxa. Germ-free and antibiotic-treated animal models have further demonstrated that the absence or depletion of gut microbiota markedly influences infarct volumes, immune cell trafficking to the brain, and post-stroke behavioral outcomes. Microbial metabolites, including short-chain fatty acids, trimethylamine N-oxide, bile acids, and tryptophan derivatives, have been identified as key molecular mediators through which the gut microbiome exerts its cerebrovascular effects.

This review provides a comprehensive synthesis of the current evidence linking neuroinflammation, the gut-brain axis, and ischemic stroke pathophysiology. We systematically examine the mechanistic pathways through which gut microbial dysbiosis amplifies post-stroke inflammation, evaluate the preclinical and clinical evidence for microbiome-targeted therapeutic interventions, and identify critical knowledge gaps and future research directions that may inform the development of novel adjunctive strategies for stroke management and neurorehabilitation.

Acute Phase: Ischemic Cascade and Innate Immune Activation

The cessation of cerebral blood flow initiates a well-characterized ischemic cascade that unfolds in temporally distinct but overlapping phases. Within minutes of arterial occlusion, energy failure leads to the collapse of ionic gradients, uncontrolled release of glutamate, and massive calcium influx into neurons, triggering excitotoxic cell death in the ischemic core. In the surrounding penumbral tissue, where collateral perfusion partially sustains cellular viability, a more protracted injury process ensues, driven substantially by the inflammatory response.

Damage-associated molecular patterns (DAMPs) released from necrotic neurons, including high-mobility group box 1 (HMGB1), heat shock proteins, adenosine triphosphate, and nucleic acid fragments, activate innate immune receptors on resident brain cells. Toll-like receptors (TLRs), particularly TLR2 and TLR4 expressed on microglia, astrocytes, and cerebral endothelial cells, represent the principal pattern recognition receptors engaged in this process. TLR activation triggers nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling cascades, culminating in the transcriptional upregulation of pro-inflammatory cytokines, including interleukin-1 beta (IL-1b), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a).

Microglia, the resident immune sentinels of the central nervous system, undergo rapid morphological and functional transformation following ischemic insult. Within the first 24 hours, microglia adopt a predominantly pro-inflammatory phenotype characterized by the production of reactive oxygen species, matrix metalloproteinases (notably MMP-9), and chemokines that facilitate peripheral immune cell recruitment. Astrocytes, similarly activated, contribute to both inflammatory amplification through cytokine production and neuroprotection through glutamate buffering and neurotrophic factor secretion, depending on the temporal phase and local microenvironmental cues.

Blood-Brain Barrier Disruption and Peripheral Immune Infiltration

The blood-brain barrier (BBB), a highly selective interface composed of cerebral endothelial cells connected by tight junction proteins, pericytes, and astrocytic end-feet, serves as the primary gatekeeper regulating molecular and cellular trafficking between the systemic circulation and the brain parenchyma. Ischemia-induced neuroinflammation profoundly compromises BBB integrity through multiple mechanisms: MMP-mediated degradation of tight junction proteins (claudin-5, occludin, and zona occludens-1), oxidative damage to endothelial cells, and inflammatory cytokine-driven transcellular permeability changes.

BBB breakdown permits the infiltration of peripheral immune cells into the ischemic territory in a temporally orchestrated sequence. Neutrophils constitute the earliest infiltrating leukocyte population, arriving within 6 to 24 hours post-ictus, followed by monocyte-derived macrophages and lymphocytes over subsequent days. While neutrophils contribute to tissue injury through the release of reactive oxygen species, elastase, and neutrophil extracellular traps (NETs), monocyte-derived macrophages exhibit functional plasticity, adopting either tissue-damaging or reparative phenotypes depending on the local inflammatory milieu.

Among adaptive immune cells, T lymphocytes play particularly complex roles. Gamma-delta T cells and CD4+ T-helper 1 (Th1) and Th17 subsets exacerbate ischemic injury through interferon-gamma and IL-17 production, respectively, whereas regulatory T cells (Tregs) and Th2 cells contribute to inflammation resolution through IL-10 and transforming growth factor-beta (TGF-b) secretion. Notably, the gut has emerged as a major source of these stroke-modulating T cell populations, providing a critical mechanistic link between the enteric immune compartment and cerebral ischemic pathology.

Resolution Phase and Neuroplasticity

Beyond the acute injurious phase, the neuroinflammatory response undergoes a phenotypic shift that is essential for tissue repair, neural circuit remodeling, and functional recovery. This transition, typically commencing 3 to 7 days post-stroke, involves the conversion of microglia and macrophages toward anti-inflammatory and phagocytic phenotypes, the expansion of Tregs, and the local production of neurotrophic factors including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor-1 (IGF-1).

This reparative milieu supports the endogenous processes of neuroplasticity: axonal sprouting, dendritic remodeling, synaptogenesis, neurogenesis from subventricular and subgranular zone progenitor populations, and angiogenesis. The balance and timing of the inflammatory-to-reparative transition profoundly influence long-term neurological outcomes, and strategies that modulate this transition represent an attractive therapeutic paradigm. Critically, the gut-brain axis exerts significant influence over both the pro-inflammatory and resolution phases of post-stroke neuroinflammation, as detailed in the following sections.

Neural Pathways

The vagus nerve, the longest cranial nerve, constitutes the principal neural conduit of the gut-brain axis. Vagal afferent fibers, whose cell bodies reside in the nodose ganglion, terminate in the intestinal mucosa where they respond to mechanical stretch, luminal nutrient composition, and microbial metabolites. Signals transmitted via vagal afferents to the nucleus tractus solitarius in the brainstem modulate central autonomic, neuroendocrine, and behavioral circuits. Reciprocally, vagal efferent fibers mediate the cholinergic anti-inflammatory pathway, whereby acetylcholine released at the splenic nerve terminus suppresses macrophage TNF-a production through alpha-7 nicotinic acetylcholine receptor (a7nAChR) activation.

The enteric nervous system, comprising approximately 500 million neurons organized in the myenteric and submucosal plexuses, operates with considerable autonomy but maintains continuous communication with the central nervous system through both vagal and spinal afferent pathways. Gut microbiota influence enteric neuronal activity through the production of neurotransmitters and neuroactive compounds, including serotonin (approximately 95% of the body total is synthesized in enterochromaffin cells under microbial regulation), gamma-aminobutyric acid, dopamine, and norepinephrine.

Immunological Pathways

The gastrointestinal tract constitutes the largest immune organ in the human body, harboring approximately 70% of all immunocytes. Gut-associated lymphoid tissue (GALT), encompassing Peyer patches, isolated lymphoid follicles, and the mesenteric lymph nodes, serves as a primary site for immune cell education and differentiation. Commensal microbiota shape the development and functional programming of innate and adaptive immune cells through continuous antigenic stimulation and metabolite-mediated signaling. Segmented filamentous bacteria promote Th17 cell differentiation in the small intestinal lamina propria, while Clostridium clusters IV and XIVa induce colonic Treg expansion through butyrate production.

The relevance of gut immune programming to stroke pathophysiology was elegantly demonstrated in landmark studies showing that antibiotic-induced depletion of intestinal microbiota altered the balance of effector and regulatory T cells in the gut, reduced cerebral immune cell infiltration following experimental middle cerebral artery occlusion, and decreased infarct volumes by up to 60%. Importantly, these neuroprotective effects were abolished by adoptive transfer of pro-inflammatory intestinal T cells, confirming the gut as a critical reservoir of stroke-modulating immune populations.

Metabolic and Endocrine Pathways

Microbial metabolism of dietary substrates generates a vast repertoire of bioactive metabolites that serve as signaling molecules within the gut-brain axis. Short-chain fatty acids (SCFAs), principally acetate, propionate, and butyrate, are the most extensively studied class of microbial metabolites. Produced through anaerobic fermentation of dietary fiber by Firmicutes and Bacteroidetes species, SCFAs exert pleiotropic effects: they maintain intestinal epithelial barrier integrity, modulate immune cell function through G-protein-coupled receptor (GPR41, GPR43, GPR109a) activation and histone deacetylase (HDAC) inhibition, and directly influence central nervous system function.

Trimethylamine N-oxide (TMAO), derived from the hepatic oxidation of trimethylamine produced by gut bacterial metabolism of dietary choline, phosphatidylcholine, and L-carnitine, has emerged as a significant pro-atherogenic and pro-thrombotic metabolite. Elevated circulating TMAO concentrations have been independently associated with increased risk of incident cardiovascular events and have been demonstrated to promote platelet hyperreactivity and endothelial dysfunction, mechanisms directly relevant to stroke pathogenesis.

The hypothalamic-pituitary-adrenal (HPA) axis provides an additional endocrine conduit. Gut dysbiosis-associated systemic inflammation activates the HPA axis, elevating circulating cortisol concentrations that, in turn, modulate BBB permeability, cerebral immune responses, and neuronal vulnerability to ischemic injury. Furthermore, microbial tryptophan metabolism yields indole derivatives, kynurenine pathway metabolites, and serotonin, each exerting distinct effects on neuroinflammation, neurotransmission, and cerebrovascular tone.

Clinical Evidence of Stroke-Associated Dysbiosis

Multiple clinical studies have characterized the gut microbiome alterations associated with acute ischemic stroke. A seminal study by Yin and colleagues, analyzing fecal samples from 349 stroke patients and matched controls through 16S ribosomal RNA gene sequencing, identified significant reductions in the alpha-diversity indices of stroke patients, with particular depletion of Roseburia, Faecalibacterium, and Blautia genera, all major butyrate producers. Conversely, opportunistic and pro-inflammatory taxa, including Enterobacteriaceae, Desulfovibrio, and Atopobium, were significantly enriched in the stroke cohort.

Subsequent metagenomic studies have refined these observations. A large multi-center investigation involving over 1,200 participants demonstrated that specific gut microbial signatures could predict stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS) score at admission, and that dysbiosis severity correlated with 90-day functional outcomes assessed by the modified Rankin Scale. Longitudinal profiling has revealed that while some dysbiotic changes are detectable within 48 hours of stroke onset, suggesting a pre-existing vulnerability, others evolve progressively during hospitalization, potentially driven by stroke-associated autonomic dysfunction, dysphagia-related nutritional changes, antibiotic exposure, and immobility.

Mechanisms of Stroke-Induced Gut Dysfunction

The relationship between stroke and gut dysbiosis is bidirectional. Stroke induces gut dysfunction through several interconnected mechanisms. First, sympathetic hyperactivation following cerebral ischemia, mediated through the hypothalamic autonomic centers, reduces intestinal motility and alters mucosal blood flow, creating an environment conducive to dysbiosis. Second, systemic immunodepression, a well-recognized consequence of acute stroke involving the HPA axis and sympathetic-adrenomedullary pathway, compromises gut mucosal immune surveillance, permitting bacterial overgrowth and translocation.

Third, ischemic stroke directly impairs intestinal epithelial barrier function. Elevated serum concentrations of intestinal fatty acid-binding protein (I-FABP) and D-lactate, markers of enterocyte damage and increased intestinal permeability respectively, have been documented within 24 hours of stroke onset. This increased intestinal permeability, colloquially termed the leaky gut phenomenon, facilitates the translocation of bacterial products, most notably lipopolysaccharide (LPS), into the systemic circulation. Circulating LPS activates TLR4 on systemic immune cells and cerebral endothelial cells, amplifying both peripheral and central neuroinflammatory responses and establishing a deleterious positive feedback loop.

Table 1: Summary of Key Microbial Metabolites Implicated in Post-Stroke Neuroinflammation.

Abbreviations: BBB, blood-brain barrier; FMO3, flavin-containing monooxygenase 3; FXR, farnesoid X receptor; GPR, G-protein-coupled receptor; HDAC, histone deacetylase; LPS, lipopolysaccharide; NF-kB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; TGR5, Takeda G-protein receptor 5; TLR4, Toll-like receptor 4; TMA, trimethylamine; TMAO, trimethylamine N-oxide; Treg, regulatory T cell.

Short-Chain Fatty Acids and Microglial-Neuronal Crosstalk

SCFAs, particularly butyrate, exert potent anti-inflammatory effects within the central nervous system through multiple complementary mechanisms. As HDAC inhibitors, SCFAs epigenetically reprogram microglial gene expression, suppressing pro-inflammatory transcriptional programs while enhancing the expression of anti-inflammatory mediators. Butyrate administration in rodent stroke models has been shown to reduce microglial activation markers (Iba-1, CD68), decrease the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and promote the microglial expression of arginase-1, a marker of the reparative phenotype.

Beyond direct microglial modulation, SCFAs support BBB integrity by upregulating tight junction protein expression in cerebral endothelial cells, an effect mediated through GPR-dependent signaling and epigenetic modification of claudin-5 and occludin gene promoters. Germ-free mice, which exhibit markedly reduced circulating SCFA concentrations, display increased BBB permeability that is normalized upon recolonization with SCFA-producing bacteria or exogenous SCFA supplementation. These observations establish a mechanistic link between gut microbial depletion, SCFA deficiency, and the amplified BBB disruption observed in post-stroke dysbiosis.

TMAO and Cerebrovascular Risk Amplification

TMAO has emerged as a metabolite of particular relevance to cerebrovascular disease. Meta-analytic evidence from prospective cohort studies encompassing over 25,000 participants indicates that each 10 micromol/L increment in circulating TMAO is associated with a 12% increase in the relative risk of major adverse cardiovascular events, including ischemic stroke. Mechanistically, TMAO promotes atherosclerosis by enhancing macrophage foam cell formation, upregulating scavenger receptor expression, and impairing reverse cholesterol transport. Additionally, TMAO activates the NLRP3 inflammasome in endothelial cells and macrophages, driving IL-1b and IL-18 secretion and propagating vascular inflammation.

In the context of acute stroke, elevated admission TMAO concentrations have been independently associated with larger infarct volumes on diffusion-weighted magnetic resonance imaging and with poorer 90-day functional outcomes, suggesting that TMAO may directly contribute to the severity of ischemic brain injury. Inhibition of the microbial enzyme trimethylamine lyase, using compounds such as 3, 3-dimethyl-1-butanol (DMB) or iodomethylcholine, has demonstrated efficacy in reducing TMAO concentrations and attenuating atherosclerotic lesion development in preclinical models, representing a potential therapeutic strategy amenable to clinical translation.

Immune Cell Trafficking: The Gut-Brain Immune Highway

A paradigm-shifting finding in the field has been the demonstration that immune cells primed in the gut directly migrate to the brain following ischemic stroke. Using intravital imaging, photoconversion techniques, and parabiosis models, investigators have tracked the migration of gamma-delta T cells from intestinal Peyer patches to the leptomeninges and brain parenchyma within 24 hours of experimental stroke. These gut-educated gamma-delta T cells, a major source of IL-17, amplify local neuroinflammation and contribute to infarct expansion. Conversely, gut-derived Tregs that migrate to the ischemic brain promote inflammation resolution and enhance neurological recovery.

The gut-brain immune trafficking pathway involves the upregulation of specific integrin-chemokine receptor pairs on intestinally primed lymphocytes, including the interaction between alpha-4-beta-7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), as well as CCR6-CCL20 and CXCR3-CXCL10 axes, which facilitate their homing to cerebral endothelial surfaces and subsequent transendothelial migration. Therapeutic targeting of these homing mechanisms, for example through anti-integrin antibodies, has shown neuroprotective efficacy in preclinical stroke models, although potential immunosuppressive side effects warrant careful evaluation.

Table 2: Preclinical Evidence for Microbiome-Targeted Interventions in Ischemic Stroke.

Abbreviations: BBB, blood-brain barrier; DMB, 3,3-dimethyl-1-butanol; FMT, fecal microbiota transplantation; HDAC, histone deacetylase; MCAO, middle cerebral artery occlusion; SCFA, short-chain fatty acid; TMA, trimethylamine; TMAO, trimethylamine N-oxide; Treg, regulatory T cell.

Probiotics and Synbiotics

The therapeutic administration of defined microbial consortia represents the most extensively investigated microbiome-directed intervention in the context of cerebrovascular disease. Preclinical studies employing single-strain (Lactobacillus plantarum, Bifidobacterium longum, Clostridium butyricum) and multi-strain probiotic preparations have consistently demonstrated reductions in post-stroke infarct volumes, attenuation of cerebral inflammatory markers, and improvement in behavioral outcomes. The mechanisms underlying these benefits include enhanced SCFA production, reinforcement of intestinal epithelial barrier function through mucin and tight junction protein upregulation, competitive exclusion of pathogenic taxa, and direct immunomodulatory effects on dendritic cells and T lymphocyte subsets.

Early-phase clinical trials have begun to evaluate probiotics in stroke populations. A randomized controlled trial involving 200 acute ischemic stroke patients reported that a 14-day course of a multi-species probiotic reduced circulating high-sensitivity C-reactive protein, IL-6 concentrations, and the incidence of post-stroke infections compared with placebo. A separate study demonstrated improvements in gastrointestinal symptoms and nutritional status among dysphagic stroke patients receiving probiotic supplementation via nasogastric tube. However, these trials have been limited by small sample sizes, heterogeneous probiotic formulations, and short follow-up periods, precluding definitive conclusions regarding long-term neurological efficacy.

Fecal Microbiota Transplantation

Fecal microbiota transplantation (FMT), involving the transfer of a processed fecal suspension from a healthy donor to a recipient, offers a more comprehensive approach to microbiome restoration compared with single-strain probiotics. FMT achieves near-complete engraftment of the donor microbial community, restoring both taxonomic diversity and functional metabolic capacity.

In rodent models of ischemic stroke, FMT from healthy donors to dysbiotic stroke animals has consistently reduced infarct volumes, suppressed cerebral and systemic inflammatory markers, and improved sensorimotor function. Conversely, FMT from stroke patients to germ-free mice has been shown to exacerbate experimentally induced infarcts, providing bidirectional evidence for the causal role of the post-stroke dysbiotic microbiome in determining injury severity. While FMT has achieved regulatory approval for recurrent Clostridioides difficile infection, its application in acute neurological conditions remains investigational, with concerns regarding donor screening, infectious complications, and the optimal timing and route of administration requiring resolution through dedicated clinical trials.

Dietary Interventions and Prebiotics

Dietary composition represents a dominant determinant of gut microbiome structure and function. The Mediterranean dietary pattern, characterized by high intake of fiber, polyphenols, monounsaturated fatty acids, and omega-3 polyunsaturated fatty acids, has been consistently associated with reduced stroke risk in large epidemiological studies. Mechanistically, Mediterranean diet adherence promotes the abundance of SCFA-producing bacteria, reduces circulating TMAO concentrations, and attenuates systemic inflammatory biomarkers. Targeted prebiotic supplementation with specific oligosaccharides, resistant starches, and fermentable fibers has demonstrated the capacity to selectively enrich beneficial microbial populations and enhance SCFA production, offering a practical, scalable, and cost-effective approach to microbiome modulation in stroke prevention and recovery.

Targeted Metabolite Modulation and Postbiotics

An emerging therapeutic paradigm involves the direct administration of beneficial microbial metabolites (postbiotics) or pharmacological inhibition of harmful metabolite production, bypassing the complexities of live microbial therapies. Sodium butyrate supplementation, administered orally or parenterally, has demonstrated neuroprotective efficacy in multiple preclinical stroke models. Similarly, the administration of indole-3-propionic acid, a microbially derived tryptophan metabolite and potent antioxidant, has shown protective effects against ischemia-reperfusion injury through free radical scavenging and aryl hydrocarbon receptor activation.

On the harmful metabolite front, pharmacological inhibition of gut microbial TMA lyase enzymes (CutC/D) represents a precision approach to reducing TMAO-mediated cardiovascular risk. First-generation inhibitors including DMB and fluoromethylcholine have demonstrated efficacy in preclinical models without adverse effects on microbial viability, and second-generation compounds with improved potency and oral bioavailability are currently in preclinical development.

Despite the considerable promise of microbiome-targeted therapies in ischemic stroke, several critical challenges must be addressed to facilitate clinical translation. First, inter-individual variability in microbiome composition, influenced by genetics, diet, geography, medication use, and comorbidities, implies that uniform therapeutic approaches may yield heterogeneous responses. The development of precision microbiome medicine, incorporating baseline microbiome profiling and individualized intervention selection through machine learning algorithms and multi-omic integration, will be essential to optimize therapeutic efficacy.

Second, the identification of optimal therapeutic windows for microbiome-directed interventions in the stroke care continuum remains undefined. Whether pre-stroke prophylactic microbiome optimization (in populations identified as high-risk through metabolomic or metagenomic biomarkers) or post-stroke acute microbiome restoration offers greater benefit requires systematic evaluation through adequately powered, time-stratified clinical trials.

Third, methodological standardization in microbiome research, including uniform protocols for fecal sample collection, DNA extraction, sequencing platforms, bioinformatic pipelines, and metabolomic analyses, is urgently needed to ensure reproducibility and comparability across studies. The establishment of international stroke-microbiome registries and biobanks would facilitate large-scale collaborative investigations and meta-analyses.

Fourth, the integration of advanced technologies, including single-cell transcriptomics of gut and brain immune populations, spatial metabolomics, organoid-based co-culture systems modeling the gut-brain interface, and AI-driven multi-omic data analysis, promises to reveal previously inaccessible mechanistic details and identify novel therapeutic targets. Finally, the emerging field of engineered probiotics, genetically modified to produce specific neuroprotective metabolites or to express therapeutic payloads (such as anti-inflammatory cytokines) selectively at sites of intestinal inflammation, represents a futuristic but potentially transformative approach.

The gut-brain axis has emerged as a fundamental modulatory pathway in the pathophysiology of ischemic stroke, operating through intricately interconnected neural, immunological, metabolic, and endocrine mechanisms. Post-stroke dysbiosis, characterized by the depletion of beneficial commensals and the expansion of pro-inflammatory taxa, amplifies neuroinflammatory cascades, compromises blood-brain barrier integrity, and impedes the endogenous reparative processes essential for neurological recovery. Conversely, the restoration of microbial homeostasis through probiotics, fecal microbiota transplantation, dietary modification, or targeted metabolite modulation has demonstrated consistent neuroprotective efficacy in preclinical models, with encouraging preliminary results from early clinical studies.

As the field advances from mechanistic characterization toward clinical implementation, the convergence of microbiome science, neuroinflammatory biology, and precision medicine holds transformative potential. The gut-brain axis offers not merely a novel therapeutic target but a fundamentally new framework for understanding cerebrovascular disease, one that recognizes the human organism as an integrated ecosystem in which distant microbial communities exert profound influence over central nervous system health and disease. Realizing the full therapeutic potential of this paradigm will require sustained investment in translational research, rigorously designed multicenter clinical trials, and the development of regulatory frameworks capable of accommodating the unique complexities of microbiome-based therapeutics.

The authors declare no conflicts of interest relevant to this article.

Funding

This review article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgments

The authors acknowledge the contributions of all researchers whose work has been cited in this review and thank the editorial team of the International Journal of Neurobiology for the opportunity to contribute to this field of inquiry.

Author Contributions

AD conceptualized the review, performed the literature search, and drafted the manuscript. VK and AS contributed to critical appraisal of the literature, manuscript revision, and intellectual content. All authors reviewed and approved the final version of the manuscript.

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