BackgroundAneurysmal subarachnoid hemorrhage (aSAH) is frequently followed by persistent cognitive impairment, characterized by a complex and multifactorial pathological mechanism. While the role of the “microbiota-gut-brain axis” in neurocognition has garnered increasing attention, the specific ways in which gut microbiota and their derived metabolites might be associated with the development and progression of post-aSAH cognitive impairment remain largely undefined. Consequently, there remains a lack of systematic multi-omics evidence to elucidate these potential underlying associations.MethodsIn this prospective observational study, we enrolled 48 patients with intracranial aneurysms. Among them, patients with aSAH (n = 33) were divided into a cognitive impairment group (aSAH-CI, n = 18) and a group without cognitive impairment (aSAH-WCI, n = 15) based on a 6-month longitudinal neurocognitive assessment. Patients with unruptured intracranial aneurysms (UIA, n = 15) served as the control group. We integrated a multi-omics approach encompassing fecal metagenomics, untargeted metabolomics, and serological profiles of inflammation, oxidative stress, and apoptosis to explore the potential correlations between the host and the microbiome, as well as to identify early diagnostic biomarkers.ResultsFecal metagenomics revealed distinct gut dysbiosis in aSAH-CI patients, characterized by reduced alpha diversity, depletion of beneficial commensals (e.g., Agathobacter), and expansion of opportunistic pathogens (e.g., Enterococcus). Functional and metabolomic analyses identified a significant alteration in aromatic amino acid biosynthesis. Specifically, tyrosine metabolism was altered, marked by reduced levels of neurotransmitter precursors and elevated neurotoxic trace amines (tyramine and phenylethylamine). Serologically, aSAH-CI patients exhibited heightened systemic inflammation, oxidative stress, and apoptosis. Integrated multi-omics network analysis underscored a strong correlation between elevated trace amines, depleted Agathobacter, and systemic pathological indices. Notably, Agathobacter rectalis and tyramine demonstrated robust potential as early diagnostic biomarkers for cognitive impairment following aSAH.ConclusionOur findings suggest a potential dual-hit correlative signature via the microbiota-gut-brain axis in cognitive impairment following aSAH. We hypothesize that the depletion of aromatic amino acid-producing microbiota correlates with reduced neurotransmitter precursors, theoretically impairing synaptic repair. Concurrently, observed associations among opportunistic pathogens, trace amines, and systemic inflammatory and oxidative stress markers suggest a synergistic effect potentially linked to further neuronal damage.