The microbiota-gut-brain axis as a driver of secondary brain injury after aneurysmal subarachnoid hemorrhage: from bidirectional vicious cycle to therapeutic opportunities

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating stroke subtype with high morbidity and mortality, significantly contributed to by secondary brain injuries such as early brain injury and delayed cerebral ischemia. Despite advances in acute management, effective neuroprotective strategies remain an unmet need. The microbiota-gut-brain axis (MGBA), a pivotal bidirectional communication network, has recently emerged as a critical modulator of pathophysiology in acute brain injuries. However, its precise role and therapeutic potential in aSAH are not systematically defined. This review synthesizes clinical and preclinical evidence to move beyond correlation and delineate the spatiotemporal dynamics and the mechanisms that may underlie of MGBA dysregulation post-aSAH. We conceptualize a self-amplifying "brain-gut-brain" vicious cycle: the initial brain injury may disrupt intestinal barrier integrity and microbiota ecology via neuroendocrine and inflammatory pathways; in turn, gut-derived signals (e.g., altered microbial metabolites, endotoxin translocation) may propagate systemic inflammation and exacerbate neuroinflammation, blood-brain barrier disruption, and cerebral ischemia. We dissect this cycle by detailing the key molecular bridges (tryptophan metabolites, short-chain fatty acids, bile acids), signaling pathways (e.g., TLR4/NF-κB, NLRP3 inflammasome), and central effectors involved. Furthermore, we provide a critical, stratified evaluation of MGBA-targeting therapeutic strategies - including probiotics, prebiotics, fecal microbiota transplantation, and metabolite supplementation - assessing their mechanistic rationale, level of evidence, and translational challenges. Finally, we outline future directions emphasizing the need for defining therapeutic windows, establishing causal proof, and integrating MGBA modulation into multimodal neurocritical care. Harnessing the MGBA presents a novel and promising paradigm for developing adjunctive neuroprotective therapies to improve outcomes after aSAH.