A Gut-Brain Axis Underlying Succinate-Associated Compulsive-Like Behavior

Emerging evidence indicates that gut microbiota influences host physiology and behavior through the microbiota-gut-brain axis, potentially contributing to the pathogenesis of obsessive-compulsive disorder (OCD). Our preliminary research demonstrated that mice colonized with fecal microbiota from OCD patients developed compulsive-like behaviors, associated with a significant increase in the microbial metabolite succinate. However, the mechanisms linking succinate to compulsive-like behavior remain to be fully elucidated. Here, we demonstrate that succinate is associated with significant compulsive-like behaviors. Succinate is associated with disruptions of glutamatergic neurons within the dorsal medial prefrontal cortex (dmPFC), and we characterize dual pathways linked to the behavioral abnormality: both by dmPFC microglial engagement via the succinate cognate receptor SUCNR1, and by gut-to brain signaling conveyed through vagal afferents and the 5-HT₄ receptor. Pharmacological modulation of the succinate metabolism pathway through succinate dehydrogenase inhibition ameliorates compulsive-like behavior in Hoxb8^-/- OCD-model mice. Circulating succinate levels significantly distinguish OCD patients from healthy controls with an AUC of 0.73, and correlate with prefrontal cortex activity on functional imaging. Collectively, our study delineates a gut-brain axis implicating succinate in central nervous system dysregulation associated compulsive-like behavior, elucidates novel immunometabolism and neural circuit mechanisms underlying OCD pathogenesis, and identifies druggable targets for potential precise interventions.