Akkermansia muciniphila mediates antibiotic-induced impairment of female preference in mice
Antibiotic-induced disruptions of the gut microbiota have been linked to behavioral alterations, but the mechanisms underlying these effects remain poorly understood. Here, we demonstrate that combined vancomycin and rifampicin (VR) treatment in male C57BL/6 mice impairs female odor preference and reduces interaction time with female conspecifics in favor of males, without affecting general locomotion or anxiety-like behavior. VR-induced effects on the intestinal microbiome persisted for weeks after antibiotic withdrawal. Metabolomic profiling revealed brain ATP depletion upon vancomycin treatment, while intranasal administration of the electron transport chain uncoupler dinitrophenol (DNP) partially recapitulated antibiotics-induced social deficits. Microbiome analysis and functional tests identified Akkermansia muciniphila and short chain fatty acids acetate and propionate as key mediators of the behavioral phenotype. Strikingly, this VR-induced behavioral phenotype was reproducible in BALB/c mice, suggesting broad applicability. Our findings establish VR treatment as a model for microbiota-dependent social deficits, implicating mitochondrial metabolism and specific bacterial taxa in sexually dimorphic behaviors. These results highlight the need to consider neuroactive antibiotic effects in clinical and translational research.