Gut metabolites identified in cerebrospinal fluid of genetic interferonopathy support gut-brain endothelial...

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.

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.

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).

Our findings suggest gut microbe metabolite leakage traversing the gut-blood-brain barrier in AGS, potentially because of endothelial dysfunction.