Metabolomic Markers and Pathways of Blood-Brain Barrier Damage: A Systematic Review

This study aimed to identify metabolites and metabolic pathways associated with blood-brain barrier (BBB) dysfunction in human and animal metabolomic research.

PubMed, Scopus, Web of Science, and Embase were searched (last search: 24 November 2025) without date limits. Original studies applying metabolomic techniques (¹H-NMR, LC-MS, GC-MS) to CSF, serum, or plasma and reporting metabolites linked to BBB damage were included. Study selection, full-text assessment, and data extraction were performed independently by two reviewers, with disagreements resolved by a third. Risk of bias was evaluated using SYRCLE and ROBINS-I tools. Metabolites reported in ≥ 2 studies were mapped to metabolic pathways using MetaboAnalyst with hypergeometric testing and Holm-Bonferroni and FDR corrections.

Of 12,182 records identified, eight studies (four human, four animal) met the inclusion criteria. Across these, 157 metabolites were identified, 25 of which were reported in more than one study. Frequently observed metabolites included glutamate, glutamine, alanine, choline, creatine, and branched-chain amino acids (valine, leucine, isoleucine). Pathway analysis revealed significant enrichment of alanine, aspartate and glutamate metabolism, nitrogen metabolism, and BCAA biosynthesis (FDR = 0.01). Glutamate and glutamine most consistently correlated with BBB dysfunction and neuroinflammatory processes. Substantial heterogeneity was observed, partly due to differences in analytical platforms, sample types, and reporting standards.

Metabolites and pathways related to glutamate, nitrogen metabolism, and BCAA may play key roles in BBB impairment. Metabolomics shows promise for identifying BBB biomarkers, but larger, methodologically standardized studies are required.

OSF identifier: dapu9.