Perturbations in the microbiota-gut-brain axis shaped by social status loss.

Social status is closely linked to physiological and psychological states. Loss of social dominance can lead to brain disorders such as depression, but the underlying mechanisms remain unclear. The gut microbiota can sense stress and contribute to brain disorders via the microbiota-gut-brain axis (MGBA). Here, using a forced loss paradigm to demote dominant mice to subordinate ranks, we find that stress alters the composition and function of the gut microbiota, increasing Muribaculaceae abundance and enhancing butanoate metabolism, and gut microbial depletion resists forced loss-induced hierarchical demotion and behavioral alteration. Single-nucleus transcriptomic analysis of the prefrontal cortex (PFC) indicates that social status loss primarily affected interneurons, altering GABAergic synaptic transmission. Weighted gene co-expression network analysis (WGCNA) reveals modules linked to forced loss in the gut microbiota, colon, PFC, and PFC interneurons, suggesting changes in the PI3K-Akt signaling pathway and the glutamatergic synapse. Our findings provide evidence for MGBA perturbations induced by social status loss, offering potential intervention targets for related brain disorders.