A metabolic "double hit" in prefrontal gray and white matter shapes microbiota-related visual learning memory impairment in major depressive disorder.

BACKGROUNDVisual learning memory deficits are key issues in major depressive disorder (MDD), but the specific gut microbiota involved are not well understood. While gut dysbiosis and metabolic alterations in the frontolimbic region are linked to MDD, the influence of regional neurochemistry on the microbiota-cognition relationship remains unknown.

METHODSVisual learning memory was assessed in 38 MDD patients and 41 healthy controls (HC) using the Brief Visuospatial Memory Test-Revised. Gut microbiota were analyzed via 16S rRNA gene sequencing of fecal samples, and neurochemical ratios N-acetylaspartate/Creatine (NAA/Cr) and Choline/Creatine (Cho/Cr) in anterior cingulate cortex (ACC) and prefrontal white matter (PWM) were quantified using proton magnetic resonance spectroscopy.

RESULTSMDD exhibited visual learning memory deficits, elevated NAA/Cr in the right ACC, reduced NAA/Cr in the right PWM compared to HC. Ruminococcus abundance was increased in MDD and negatively correlated with visual learning memory. The relationship between Ruminococcus abundance and visual learning memory was moderated by NAA/Cr ratios in the ACC and PWM in a configuration-dependent manner. Specifically, the most pronounced negative association emerged when the ACC NAA/Cr ratio was high and the PWM NAA/Cr ratio was low.

CONCLUSIONSThe study indicates that simultaneous metabolic dysregulation in gray and white matter, shown by elevated ACC NAA/Cr and decreased PWM NAA/Cr, constitutes a "double hit" that exacerbated visual learning memory impairment associated with Ruminococcus in MDD. This dual impact underscores distinct yet interconnected vulnerabilities in gray and white matter, where microbiota-cognition associations are critically shaped by the broader neurochemical environment.