Antibiotic-mediated gut microbiota depletion partially attenuates methamphetamine-induced reward and linoleic acid metabolic disturbance

Methamphetamine (METH) is a highly addictive psychostimulant that possesses potent toxicity to multiple organs. Emerging evidence has suggested associations between gut microbiota dysbiosis and METH-induced rewarding effects. However, the role and underlying mechanisms of gut microbiota in METH addiction remain poorly understood. Using a mouse conditioned place preference (CPP) model combined with multi-omics profiling of gut microbiota and metabolites, we first investigated how METH exposure affects gut microbiota composition. Then, Antibiotic (ABX)-mediated gut microbiota depletion was conducted to explore the role of gut microbiota in the METH-induced associative memory of context-reward (METH reward) and metabolic dynamics. Furthermore, associations among gut microbiota, metabolites, and behavioral phenotypes were determined to reveal the potential key microbial taxa and metabolites in METH reward. Finally, the key metabolite was intervened to reveal the role of it in the METH reward. Our results demonstrated that repeated METH administration induced significant alterations in gut microbiota profiles. ABX-mediated microbiota depletion attenuated METH-induced rewarding effects and metabolic perturbations, especially in linoleic acid (LA) metabolism. METH exposure led to an increase in, while gut microbiota depletion rescued the activation of LA metabolism. Correlation analyses consistently demonstrated associations among specific Bacterial species, LA metabolites, and CPP scores. Supplementation of LA could facilitate, while inhibition of its oxidative metabolism could attenuate the METH-induced CPP. These findings highlight LA metabolism as a potential mechanistic link between gut microbiota dysbiosis and METH reward. Future gut microbiota-targeted therapeutic interventions, particularly those modulating LA metabolism, may improve the treatment of METH use disorder.