As emerging environmental contaminants, micro- and nanoplastics (MNPs) raise neurotoxic concerns. However, the mechanisms underlying their induction of emotional disorders remain poorly understood. In particular, intervention-oriented and functionally validated strategies for prevention and control are still lacking. To address this, we conducted a 28-day repeated oral exposure study in mice using a gradient of polystyrene nanoplastics (PS-NPs; 2, 10, and 50 mg/kg/day) spanning environmentally relevant doses, systematically assessing impacts along the microbiota-gut-brain axis. Our results showed that PS-NP exposure induced dose-dependent anxiety- and depression-like behaviors, with fluorescence tracing revealing predominant gut accumulation and limited brain distribution. Mechanistically, exposure induced gut microbiota dysbiosis, intestinal barrier impairment, and lipopolysaccharide translocation, ultimately leading to systemic inflammation and neuroinflammation. Serum biochemical analysis showed that gut dysbiosis initiates host tryptophan metabolism toward the kynurenine pathway by triggering inflammation and subsequent indoleamine 2,3-dioxygenase 1(IDO1) activation. Consistently, hippocampal transcriptomic and biochemical analyses confirmed decreased 5-HT levels and suppression of the downstream 5-HTA-cAMP-PKA-CREB-BDNF neurotrophic cascade, demonstrating comprehensive serotonergic disruption from substrate depletion to receptor dysfunction. Notably, the prebiotic galacto-oligosaccharides (GOS) restored intestinal homeostasis and ameliorated these anxiety- and depression-like behavioral and metabolic deficits, exerting protective effects by counteracting above pathway. Our work delivers a from-mechanism-to-solution understanding: it deciphers how microplastics disrupt the gut-brain axis to cause neurotoxicity and identifies GOS maintenance of intestinal health as a key mitigative strategy against plastic pollution risks. Therefore, maintaining intestinal health, particularly through dietary GOS, represents a viable strategy to mitigate the neurotoxicity induced by plastic pollution. 1
Gut-Brain Axis