Effects of 3,4-methylenedioxymethamphetamine on the gut microbiota and metabolites in the small intestine, cecum, and colon of male rats

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a widely abused recreational drug that has also gained interest for potential clinical applications in mental health. With the growing recognition of gut microbiota's role in mental health, this study examined whether repeated oral MDMA administration could affect gut microbiota in the small intestine, cecum, and colon of male rats. Repeated oral MDMA administration (10 mg/kg/day for 14 days) caused significant changes in the gut microbiota across these regions, with distinct effects observed in each. PICRUSt2 analysis revealed significant alterations in several metabolic pathways in these regions, indicating potential shifts in microbial functional capabilities associated with MDMA treatment. Untargeted metabolomics analysis revealed that MDMA significantly altered levels of two metabolites—ferulic acid and methylmalonic acid—in the colon, without changes in the blood, small intestine, or cecum. Notably, methylmalonic acid levels in the colon positively correlated with Lawsonibacter and Oscillibacter . These findings suggest that repeated oral MDMA treatment can alter gut microbiota composition across intestinal regions, potentially contributing to its pharmacological effects. • MDMA, a commonly abused drug, is also being explored for potential clinical applications in mental health. • Repeated oral administration of MDMA induced significantly altered gut microbiota in the small intestine, cecum, and colon. • The effects of MDMA on the gut microbiota varied distinctly across these regions. • MDMA modulated the levels of two metabolites, ferulic acid and methylmalonic acid, in the colon. • MDMA alters gut microbiota composition across intestinal regions, potentially contributing to its pharmacological effects.