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

ABSTRACT

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‐HT ₄ 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.