Short-term β-lactam antibiotic exposure promotes peptidoglycan translocation to the brain and impairs functional connectivity and social recognition in mice

Broad-spectrum β-lactam antibiotics, such as ampicillin, disrupt the commensal gut microbiota and reduce its diversity. However, their potential short-term impact on the translocation of bacterial peptidoglycan (PGN) fragments to the brain and subsequent effects on brain function remain unexplored. In this study, we investigate the effects of a clinically relevant dose of ampicillin on PGN translocation into the brain, gene expression, brain functional connectivity, and social behavior in young adult mice. PGN translocation and gene expression were analyzed at 24-, 48-, and 72-h time points, while behavior, functional connectivity, and gut microbiota were analyzed at 72 h post-exposure. We find that ampicillin increases region-specific PGN translocation into the brain, which correlates with variations in the gene expression levels of PGN transporters and receptors in naïve animals. Antibiotic-treated mice exhibit impaired sociability and social recognition at 72 h post-exposure, which correlate with changes in the expression of synaptic (Syp, Ppp1r9b, Dlg4) and immune (Trem-2) genes in both the prefrontal cortex and striatum, along with disrupted brain functional connectivity. Furthermore, antibiotic-treated mice show an increase in the relative abundance of Gram-negative bacteria at 72 h post-exposure. Mice treated with iE-DAP, a unique PGN fragment from Gram-negative bacteria, exhibit key antibiotic-induced behavioral and molecular traits. Similar to antibiotic-treated mice, iE-DAP-exposed mice show impaired social recognition while maintaining normal motor activity, and reduced expression of synaptic-related genes in the prefrontal cortex and striatum. These findings provide novel insights into the neurobiological mechanisms underlying antibiotic-induced behavioral and functional disruptions and highlight the potential risks to brain health associated with repeated antibiotic use.