Co-exposure to microcystin-LR and polystyrene nanoplastics aggravates neuroinflammation by promoting AhR/NF-κB axis-mediated gut microbiota dysfunction

Microcystin-LR (MC-LR) and polystyrene nanoplastics (PS-NP) are common aquatic contaminants known to cause intestinal and neural toxicity in fish. However, their combined toxic effects and the role of gut-brain interactions are not well understood. Here, adult zebrafish were exposed to 1, 25 μg/L MC-LR and 1 mg/L PS-NP alone or in combination for 30 days to assess their toxicities. Mechanistically, co-exposure to MC-LR and PS-NP perturbed gut microbiota homeostasis, which mediated brain lesions and inflammation, manifesting as pronounced anxiety-like behavior via the gut-brain axis. Notably, MC-LR exposure induced intestinal damage and structural alterations, while PS-NP co-treatment exacerbated the disruption of intestinal barrier integrity and heightened gut inflammation. The impaired intestinal and blood–brain barrier allowed gut-derived lipopolysaccharide (LPS) to reach the brain, increasing inflammation and harming brain health. PS-NP worsen MC-LR toxicity by disrupting gut microbiota balance, reducing beneficial bacteria Lactobacillus , and increasing harmful bacteria Desulfovibrionaceae, which led to substantial disturbances in microbiota-derived tryptophan metabolism. This imbalance suppressed aryl hydrocarbon receptor (AhR) expression and activated the NF-κB signaling pathway with the brain, further intensifying neuroinflammation and abnormal neuronal development. In addition, supplementation with probiotics, Lactobacillus rhamnosus GG (LGG), can mitigate neuroinflammation induced by the combined exposure by remodeling gut microbiota. The study indicated that gut microbiota plays a key role in the intestine-brain communication, influencing neurotoxicity from combined MC-LR and PS-NP exposure. It elucidates how microcystins and nanoplastics jointly disrupt this axis and suggests a promising strategy for counteracting their combined toxic effects.