Chronic exposure to Dextromethorphan disrupts intestinal integrity and brain metabolism in male mice.

Dextromethorphan (DXM), a centrally acting non-narcotic antitussive, is subject to abuse worldwide, yet the risks associated with its long-term intake remain unclear. In this study, we examined the behavioral effects of repeated once-daily intraperitoneal administration of DXM at doses of 30 mg/kg and 50 mg/kg for 14 consecutive days in male mice and evaluated the toxic effects and underlying mechanisms in the intestine and brain using exploratory magnetic resonance imaging and physiological and biochemical indicators. The results suggested that DXM administration may attenuate neuronal activity in the prefrontal cortex and hippocampus and was associated with intestinal and brain tissue damage as well as apoptosis. At the high dose, the pro-inflammatory cytokine IL-1β was increased by 30% in both intestinal and brain tissues, whereas the anti-inflammatory cytokine IL-10 was decreased by 15% in the intestine and by 35.7% in the brain. DXM exposure also altered the gut microbiota composition. In parallel, serum lipopolysaccharide (LPS) levels were increased by 1.3-fold, suggesting potential disruption of the intestinal barrier and possible systemic effects via circulation. DXM was associated with alterations in gut microbiota composition, and gut-derived metabolites were correlated with dysregulation of lysophosphatidylcholine (LPC) metabolism in the brain. The abnormal accumulation of LPC was associated with lipid metabolic disturbances, which were in turn correlated with alterations in the brain microenvironment and neuroinflammation. Collectively, these results suggest that long-term DXM exposure may be associated with intestinal injury and alterations in brain metabolism, providing insights into the potential health risks associated with chronic DXM abuse.