Abstract
Ceftriaxone (CTX), a beta-lactam antibiotic, is widely used in drug seeking and relapse studies due to its ability to enhance glutamate transporter (GLT-1) expression in the brain. Since increased synaptic glutamate is believed to drive drug seeking and relapse, CTX's effect on GLT-1 offers potential for treating substance abuse. However, the effect of CTX on the gut microbiome remains unexplored. Mice received CTX at 200 mg/kg per day for 4 d, and its effects on the gut microbiome were assessed. CTX led to increased striatal GLT-1 expression and induced rapid, long-lasting dysbiosis, with females showing a greater response than males. Diversity metrics were significantly altered during the acute phase of CTX treatment. Alpha diversity showed varying recovery levels depending on sex, while beta diversity indicated that CTX-treated mice remained significantly different from controls. CTX caused significant increases in Bacillota and reductions in Bacteroidota. Most taxa were rapidly reduced by CTX, but Enterococcus and Bacillales expanded significantly. Metabolomic analysis revealed significant changes in microbial pathways related to substance use disorders. These findings indicate that CTX causes immediate and persistent alterations in the gut microbiome, highlighting the importance of considering the gut microbiome as a target in substance abuse treatment.