# Gut metabolites identified in cerebrospinal fluid of genetic interferonopathy support gut–brain endothelial dysfunction

## TL;DR

This study finds gut microbe metabolites in the cerebrospinal fluid of children with Aicardi–Goutières syndrome, suggesting a leaky gut-blood-brain barrier due to endothelial dysfunction.

## Contribution

The study identifies gut-derived metabolites in cerebrospinal fluid of AGS patients, suggesting a novel gut-brain connection in interferonopathies.

## Key findings

- Elevated gut microbe metabolites (indole, p-cresol, γ-butyrobetaine, N-butyryl-L-homoserine lactone) were found in AGS patient cerebrospinal fluid.
- These metabolites were also elevated in AGS patient serum, confirming systemic presence.
- The findings suggest gut microbe metabolite leakage due to gut-blood-brain barrier dysfunction in AGS.

## Abstract

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.