Serum microbiome-related metabolites—including short-chain fatty acids and indole derivatives—predict outcome and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a two-timepoint LC–MS study

Background: Delayed cerebral ischemia (DCI) remains a major determinant of poor outcome after aneurysmal subarachnoid hemorrhage (aSAH). Growing evidence suggests that gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and tryptophan-related indole compounds, modulate neuroinflammation and cerebrovascular vulnerability. However, their temporal dynamics and clinical relevance after aSAH are insufficiently characterized. Methods: In this prospective observational study, 80 consecutive patients with aSAH were enrolled at a tertiary neurocritical care center. Serum concentrations of SCFAs (propionic, butyric, isobutyric, valeric, isovaleric, caproic acids) and tryptophan-derived metabolites (tryptophan, indole-3-propionic acid [IPA], indole-3-acetic acid, indole-3-lactic acid) were quantified using LC-MS on Day 1 and Day 9 after hemorrhage. Functional outcome at 3 months was assessed using the modified Rankin Scale (mRS), and DCI was diagnosed according to consensus criteria. Associations were analyzed using non-parametric statistics, ROC analyses, and multivariable logistic regression adjusted for established clinical confounders. Results: Patients with unfavorable 3-month outcomes (mRS 4-6) showed significantly lower Day 1 levels of propionic, isobutyric, and isovaleric acids, persistently reduced tryptophan at both time points, and markedly lower IPA concentrations on Day 9. DCI was associated with reduced tryptophan and propionic acid levels on both days and a pronounced decrease in IPA on Day 9. Tryptophan and propionic acid demonstrated excellent discriminative performance for outcome and DCI (AUCs up to 0.99). In multivariable models, low Day 1 propionic acid and low Day 9 IPA independently predicted unfavorable outcome, while Day 9 tryptophan, IPA, and propionic acid independently predicted DCI. Conclusion: Distinct temporal alterations in gut microbiota-derived metabolites after aSAH are strongly associated with functional outcome and DCI. SCFAs and tryptophan-related metabolites-particularly propionic acid, tryptophan, and IPA-emerge as promising biomarkers and potential mechanistic mediators in secondary brain injury after aSAH.