Gut metabolites identified in cerebrospinal fluid of genetic interferonopathy support gut–brain endothelial dysfunction
Year: 2026
Type: article
Study design: Observational Study
Abstract: Objective Aicardi–Goutières syndrome (AGS) is a rare genetic interferonopathy because of aberrant DNA or RNA metabolism with secondary host anti‐viral (interferon) activation. This metabolomics study aimed to improve the biological understanding of AGS and explore potential biomarkers. Methods We performed untargeted cerebrospinal fluid (CSF) metabolomics using a UPLC‐Q‐Exactive‐HFx Mass Spectrometry of 10 genetically confirmed AGS patients (8 males, mean 4.8 years, range 0.2–16.5) and age‐sex matched controls. Metabolites were then quantified and validated using UHPLC‐QqQ‐MS/MS in CSF and serum. Results We identified expected elevated inflammatory metabolites (neopterin and kynurenine) and unexpected elevated gut microbe metabolites in CSF samples: Indole, p‐Cresol, γ‐Butyrobetaine and N‐Butyryl‐L‐homoserine lactone (all P FDR < 0.05). Using a targeted assay, we confirmed elevation of these metabolites in CSF, and also in the serum of patients with AGS (all P < 0.01). Conclusion Our findings suggest gut microbe metabolite leakage traversing the gut–blood–brain barrier in AGS, potentially because of endothelial dysfunction.
DOI: 10.1002/cti2.70074
Institutions: The University of Sydney, Children's Hospital at Westmead, Sydney Children's Hospital, University of Technology Sydney, National University of Singapore, Khoo Teck Puat Hospital, National University Health System, UNSW Sydney, The George Institute for Global Health, Sydney Children’s Hospitals Network
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,070
OpenAlex ID: W7130564273