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Updated: May 1, 2026
Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
Published on: July 6, 2022
Uncovering novel endocannabinoidome-gut microbiome-brain axis-based therapeutic targets in a Fragile X Syndrome mouse
Antonella Campanale1, Hayatte-Dounia Mir2, Elizabeth Dumais3
1Department of Psychiatry, McGill University, Montreal, QC, Canada.
Background:
Autism Spectrum Disorder (ASD) is a neurodevelopmental condition associated with increased risk of psychiatric, gastrointestinal, and metabolic comorbidities. Recent studies highlight the bidirectional role of the gut microbiome (GM) and endocannabinoidome (eCBome)-axis in the gut-brain axis, suggesting its therapeutic potential for ASD and comorbidities.
Methods:
We investigated the eCBome-GM-brain axis in the Fragile X Messenger Ribonucleoprotein 1 (Fmr1-/y) mouse model, known as a genetic model of ASD, to identify therapeutic targets. Fecal GM composition was analysed by 16S rDNA sequencing, brain eCBome profile by HPLC-MS/MS and qRT-PCR, and fecal short chain fatty acids by GC-FID.
Results:
Significant eCBome-GM-brain axis dysregulation was observed in Fmr1-/y compared to wild-type mice. GM analyses revealed potential gut dysbiosis, increased permeability, and inflammation. Specifically, elevated Akkermansia and Eubacterium siraeum-linked to gut barrier dysfunction-and Ruminococcus and Clostridium, associated with ASD severity, were identified. Concurrently, decreased levels of the gut health biomarker Roseburia and the taxa Helicobacter and Anaeroplasma were observed. Brain region-specific eCBome alterations underscored neuroinflammation. In the HPC, reduced anti-inflammatory dihomogamma-linolenic acid (DGLA) was accompanied by elevated pro-inflammatory 12-hydroxy-heptadecatrienoic acid, a mediator of microglial activation. In the PFC, decreased DGLA, 1/2-linoleoylglycerol, and N-linoleoyl-ethanolamine suggested neuroinflammation; elevated prostaglandin D2, a marker of autophagy impairment, underscores further mechanisms of dysfunction. Upregulation of cannabinoid type 2 and PPAR-γ receptor genes in the PFC suggested a compensatory response to neuroinflammation. Correlations between eCBome and GM alterations highlighted potential links between gut dysbiosis, systemic inflammation, and neurodevelopmental atypicalities.
Conclusions:
The Fmr1-/y ASD mouse model harbors significant eCBome-GM-brain axis alterations. This study highlights specific GM taxa and eCBome components as potential therapeutic targets for clinical validation in Fragile X Syndrome and ASD.
