Xinyi He

The human gastrointestinal tract harbors a complex and diverse microbial community. Emerging evidence has revealed bidirectional communication between the gut microbiome and the central nervous system, termed the “microbiota–gut–brain axis”. This axis serves as a critical regulator of glial cell function, positioning it as an essential target for ameliorating the onset and progression of ischemic stroke. In this review, we discuss the developments in the relationship between ischemic stroke and neuroinflammation via MGBA. The gut microbiome plays a critical role in signaling to microglia, astrocytes, and other immune components within this axis. We also summarize the interactions between the gut microbiota and glial cells under both healthy and ischemic stroke conditions. Additionally, we also focus on the role of microbiota-derived metabolites and neurotransmitters in ischemic stroke. Furthermore, we investigate the potential of targeting the intestinal and blood–brain barriers to improve MGBA. Finally, we evaluate the preclinical and clinical evidence for dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation in ischemic stroke. A comprehensive understanding of the MGBA is essential for developing MGBA-based treatment for ischemic stroke.

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO’s aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe–TMAO pathway.