Neuroinflammation and the Gut-Brain Axis in Ischemic Stroke: From Pathophysiological Mechanisms to Emerging Therapeutic Strategies

Deshpande A, Khardenavis V and Shetty A

Published on: 2026-03-08

Abstract

Background: Ischemic stroke remains a leading cause of death and long-term disability worldwide. Conventional therapeutic approaches, primarily centered on thrombolysis and thrombectomy, are limited by narrow eligibility windows and incomplete neuroprotection. Accumulating evidence has identified bidirectional communication between the gastrointestinal microbiome and the central nervous system, collectively termed the gut-brain axis, as a pivotal modulator of post-stroke neuroinflammatory cascades. This axis, mediated through neural, immunological, endocrine, and metabolic pathways, profoundly influences stroke pathogenesis, the extent of ischemic injury, and subsequent neurological recovery.

Objective: This comprehensive review synthesizes the current understanding of the neuroinflammatory mechanisms operative in ischemic stroke, examines the role of the gut-brain axis in modulating these processes, and evaluates the therapeutic potential of microbiome-targeted interventions as adjunctive strategies in stroke management.

Methods: A structured narrative review was conducted by searching PubMed, Scopus, Web of Science, and the Cochrane Library databases for articles published between January 2010 and December 2025. Search terms included combinations of ischemic stroke, neuroinflammation, gut-brain axis, gut microbiota, dysbiosis, short-chain fatty acids, trimethylamine N-oxide, neuroplasticity, and related terms. Preclinical and clinical studies, systematic reviews, and meta-analyses published in English were included.

Results: Post-stroke dysbiosis is characterized by a reduction in commensal bacterial diversity and the expansion of opportunistic pathogenic taxa, which amplify systemic and cerebral inflammatory responses. Microbial metabolites, notably short-chain fatty acids and trimethylamine N-oxide, serve as critical signaling molecules that modulate microglial activation, blood-brain barrier integrity, and adaptive immune cell trafficking to the ischemic penumbra. Preclinical evidence supports the efficacy of probiotics, fecal microbiota transplantation, dietary prebiotic supplementation, and targeted metabolite modulation in attenuating infarct volumes and improving functional outcomes. Early-phase clinical trials corroborate these findings, although large-scale randomized controlled evidence remains limited.

Conclusions: The gut-brain axis represents a compelling and mechanistically plausible therapeutic target in ischemic stroke. Microbiome-directed therapies hold substantial promise as adjuncts to conventional reperfusion strategies, though translational challenges including inter-individual microbiome variability, standardization of interventions, and identification of optimal therapeutic windows necessitate further investigation.