The gut microbiome plays a critical role in brain development and function, yet the neural mechanisms underlying microbiome-brain interactions during social processing remain poorly understood. We hypothesized that microbiome depletion fundamentally alters how the brain processes social information across different contexts.

We developed a three-day social context paradigm using FDG-PET neuroimaging in antibiotic-treated (ABX, n=10) and control (CON, n=10) mice. Mice underwent scanning in three contexts: isolation (day 1), familiar social interaction (day 2), and novel social interaction (day 3). Statistical parametric mapping identified brain regions showing significant context-dependent changes in glucose metabolism (p<0.001). ABX mice were administered a broad-spectrum antibiotic cocktail through the drinking water (ampicillin (1 g/L), vancomycin (0.5 g/L), neomycin (1 g/L), and metronidazole (1 g/L) in sterile drinking water), while control mice (CON) received regular drinking water

Microbiome depletion induced distinct context-dependent neural signatures. During transitions from isolation to familiar social contexts, CON mice showed appropriate engagement of social memory circuits (lateral entorhinal cortex, anterior cortical amygdaloid nucleus) with concurrent decreases in primary somatosensory and prelimbic regions. In contrast, ABX mice showed no significant changes between these contexts. When transitioning from isolation to novel social contexts, ABX mice exclusively engaged sensory processing regions (superior colliculus, secondary visual cortex, somatosensory barrel field) without any decreases in regional activity. During familiar-to-novel social transitions, ABX mice further increased sensory processing (visual cortex, somatosensory barrel field), while CON mice showed appropriate motor engagement and decreased somatosensory activity. Notably, ABX mice showed no decreases in neural activity during any context transition.

Microbiome depletion fundamentally alters context-dependent neural processing during social interaction, causing a shift from social memory circuits to compensatory sensory processing. This suggests microbiome-depleted animals maintain social functioning through alternative neural strategies that rely heavily on sensory information rather than appropriate social memory engagement. The absence of neural inhibition during context transitions in microbiome-depleted mice reveals a previously unrecognized mechanism by which microbiome alterations may contribute to social processing deficits in neurodevelopmental and psychiatric conditions.